Database for analyzing gene function and method of analyzing gene function by DSPA

TECHNICAL FIELD

The method of this application relates to analysis of unknown gene function, to a gene function database used for the analysis and to a method constructing the database. More particularly, the invention of this application relates to a novel method for analyzing function of function-unknown gene which is useful as a genetic material for the pharmacogenomics and for the manufacture of various useful proteins by means of genetic engineering and to a gene function database used for the analysis as well as a method for constructing the database.

BACKGROUND ART

As a result of the human genome project, all of human gene sequences will be soon elucidated. It is predicted that, in near future, causative genes for all genetic diseases will be made clear. Identification of causative genes for diseases is expected to greatly contribute in correct and simple diagnosis of diseases or in effective preventive treatment and therapy.

However, although many causative genes have been identified already, the greater part thereof has not yet been applied for the development of therapeutic drugs or others. That is because functions of the causative genes (functions of expression products) have not been elucidated yet. For example, even when the relevancy of the causative gene with pathology is made clear using knockout mice, etc., the action mechanism of a genetic product during that process is ambiguous and, therefore, it is not possible to search a compound (a lead compound) affecting a gene product (a target protein) and to develop the drug using such a compound.

Until now, analysis of gene function is greatly dependent upon discretion of researchers, and a lot of labor and expense have been paid for analysis of one gene function. It is predicted that, in future, identification of a gene product relating to an expression product of the causative gene for disease among huge numbers of genetic products will become more and more difficult, and there has been a strong demand for development of a new method for analysis of gene function.

The invention of this application has been achieved under the above-mentioned circumstances, and objects of the invention are to provide a novel method for a simple and correct analysis of function of function-unknown genes, a database for analyzing gene function used for the analysis method and a method of constructing the database.

DISCLOSURE OF INVENTION

As an invention for solving the above-mentioned objects, this application provides a method for construction of a gene function database, which comprises:

- (a) ensuring the viability against a plural number of drugs (D₁, D₂, D₃, . . . D_n) at various concentrations, of transformed eukaryotic cells overexpressing a plural number of function-known genes (g₁, g₂, g₃, . . . g_n) and their parental cell lines;
- (b) calculating the ratio of the concentration value of the drug to inhibit the viability of the transformed cell to an extent of 40% (IC₄₀value) to the IC₄₀value of the parental cell line;
- (c) calculating the logarithmic values of the ratios of the above (b) for the known genes (g₁, g₂, g₃, . . . g_n); and (d) calculating the correlation coefficients among the known genes (g₁, g₂, g₃, . . . g_n) for the logarithmic values of the above (c).

In the method for constructing the database, it is a preferred embodiment that “n” of the known genes (g_n) is 50 or more, and that “n” of the drugs (D_n) is 40 or more.

This application further provides a gene function database, which is constructed by the above constructing method.

This application furthermore provides a method of analyzing functions of a function-unknown gene (g_x) on the basis of DSPA (Drug Sensitivity Pattern Analysis) using the gene function database set forth above, which comprises:

- (i) measuring the IC₄₀value for each drug from the viability at various concentrations of a plural number of drugs (D₁, D₂, D₃, . . . D_n) for transformed eukaryotic cells overexpressing the unknown gene (g_x),
- (ii) calculating the correlation coefficients between the unknown gene (g_x) and known genes (g₁, g₂, g₃, . . . g_n) from the IC₄₀values of the above (i) by the same method as in the calculation of the correlation coefficient among the known genes (g₁, g₁, g₃, . . . g_n) of the gene function database, and
- (iii) determining that the function of the known gene showing a significant correlation coefficient to the unknown gene (g_x) is related to the function of the unknown gene (g_x).

This application still further provides a method for constructing the database according to claim 1, wherein the data of the unknown gene (g_x) whose function is determined by the method of analyzing functions is added to database as a data of the function-known gene, and still furthermore provides a gene function database constructed by the constructing method set forth above.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is examples of selection of high-expression cells by Western blotting method.

FIG. 2 is an example of calculating the ratio of IC₄₀values from a curve showing the dependency of concentration of drug on viability. The range of an arrow in the drawing shows log 0.23=−0.64.

FIG. 3 is another example for calculating the ratio of IC₄₀values from a curve showing the dependency of concentration of drug on viable rate.

FIG. 4 shows graphs where drug-sensitivity ratios of genes having high functional relationship (IkB-SR and IKK-DN) and genes having low functional relationship (IkB-SR and p16) are subjected to a logarithmic plotting.

BEST MODE FOR CARRYING OUT THE INVENTION

The gene function database of this application is constructed by the following steps (a) to (d).

Step (a):

There are measured the viabilities, against a plural number of drugs (D₁, D₂, D₃, . . . D_n) at various concentrations, of transformed eukaryotic cells overexpressing a plural number of function-known genes (g₁, g₂, g₃, . . . g_n) and their parental cell lines.

The function-known genes are those where functions of the expression products thereof have been known already and, with regard to their numbers, not less than 50 or, preferably, not less than 100 genes are used. Full-length cDNA of each of those genes is integrated into an expression vector for eukaryotic cells and the recombinant vector is transfected into eukaryotic cells. With regard to the expression vector, known vectors such as pRc-CMV, pcDNA3 and pMSG may be appropriately used. With regard to the eukaryotic cells, there may be exemplified cell lines such as mouse fibroblast cell NIH3T3 and Ha-ras-NIH3T3 although they are non-limitative. Transfectants may be selected using an appropriate selecting drug depending upon the type of the drug-resistant gene of the vector. All of cell lines into which each of the genes (g₁, g₂, g₃, . . . g_n) is introduced are checked for gene expression by Western blotting method or Northern blotting method, and the most highly expressed cell line is selected.

Then, with regard to those gene-introduced cells and the parental cell line thereof, their viabilities to a plural number of drugs at various concentrations are measured. The drugs are physiologically active substances (such as cytokines) or drugs which have been known to affect the viabilities of the parental cell line, and they are other than the object drugs for the drug-resistant gene owned by the vector used for the introduction of the gene. Forty kinds or more of drugs are used.

Cell viabilities can be measured by various known methods, and MTT method is preferred. The MTT method is a method where coloration of formazan which is a metabolite of MTT dye (tetrazolium salt 3-(4,5-dimethylthiasol-2-yl)-2,5-diphenyltetralin bromide) by mitochondrial succinic dehydrogenase of growing cells is measured (J. Immunol. Methods 65: 55-63, 1983; J. Immunol. Methods 116: 151-158, 1989) and, because of its quickness and precision, it has been used as a method for measuring the cell growth.

Step (b):

There are calculated the ratios of the concentration value of the drug to inhibit the viabilities of the transformed cell to an extent of 40% (IC₄₀value) to the IC₄₀value of the parental cell line. Thus, for example, ratio of the IC₄₀values can be calculated from the concentration-dependent curve on the viability as shown in FIG. 2 and FIG. 3 prepared in the Examples mentioned later.

Step (c):

With regard to all of the known genes (g₁, g₂, g₃, . . . g_n), there are calculated the logarithmic values of the ratios calculated in the above step (b). The logarithmic values are inputted, for example, into a list (Table 2) prepared in the Examples mentioned later.

Step (d):

There are calculated the correlation coefficients among the known genes (g₁, g₂, g₃, . . . g_n) for the logarithmic values of the above step (c). The correlation coefficients thereof (r) can be expressed as shown in the list (Tables 3 to 14) which are prepared in the Examples mentioned later, and can be subjected to a test of significance by t-test.

By the above-mentioned method, there is prepared a gene function database equipped with information how the function-known genes are functionally related to each other. The database is inputted into a computer and used for a method of analyzing gene functions which will be mentioned later.

Now the method of analyzing gene functions provided by this application will be illustrated.

The method of analyzing gene functions of this invention using DSPA is a method where function-unknown gene (g_x) is analyzed using the above gene function database and comprises the following steps (i) to (iii).

Step (i):

There is measured the IC₄₀value for each drug from the viabilities at various concentrations of a plural number of drugs (D₁, D₂, D₃, . . . D_n) for transformed eukaryotic cells overexpressing the unknown gene (g_x).

Types of the vector for recombination of cDNA of unknown gene (g_x), the eukaryotic cells and the drugs and measurement of the viabilities are the same as those in the above step (a) for the construction of the gene function database.

Step (ii):

There are calculated the correlation coefficients between the unknown gene (g_x) and the known genes (g₁, g₂, g₃, . . . g_n) from the IC₄₀value of the above step (i) by the same method (steps (b) to (d)) as in the calculation of the correlation coefficients among the known genes (g₁, g₂, g₃, . . . g_n) of the gene function database.

Step (iii):

There is determined that the function of the known gene showing a significant correlation coefficient to the unknown gene (g_x) is related to the function of the unknown gene (g_x).

Thus, in the t-test for the calculation of the correlation coefficient “r”, t={r²(n−2)/(1−r²)}^1/2(n: data numbers). Therefore, in case the data for 40 or more kinds of drugs are available, the correlation coefficient “r” is significant when it is not less than 0.4 or not more than −0.4. More preferably, when the case where correlation coefficient “r” is not less than 0.5 or not more than −0.5 is used as a standard, it is possible to clearly specify the relationship among the genes. In the case of each of genes shown in Tables 3 to 14, the gene Ha-ras for example shows a correlation of not less than 0.5 to Ki-ras (r=0.71), N-ras (0.56) and erbB2 (0.53), and shows a correlation of not more than −0.5 to Cip-1 (−0.55), RhoA (−0.55) and C/EBPb (−0.50) whereupon it is noted that Ha-ras is functionally related to those genes. When there is such a high correlation between unknown gene and known gene, it is can be judged that the function of the known gene is related to the function of the unknown gene as well.

Incidentally, the above steps (ii) and (iii) can be quickly processed by a computer. Further, when the data of the function-unknown gene being newly functionally analyzed by the method of analyzing the gene functions are appropriately added to the above-mentioned database, it is now possible to be developed to a database having higher accuracy.

As a result of the method of analyzing gene functions as mentioned above, function of the unknown gene can be quickly decided, and action mechanism of the genetic product can be estimated with a high accuracy. Thus, in most cases, overexpression of gene affects the molecule which is related to the product thereof. The molecule affected as such further affects the surrounding molecules and, as a result, a pathway such as a signal transduction is activated or inactivated. Such a cell shows a different sensitivity to the drugs which act the molecule relating to the pathway. Alternatively, it also shows a different sensitivity to a physiologically active substance acting on the same pathway such as cytokines. On the other hand, it has been confirmed that, in the case of genes where their functional relations have been known already (such as p53 and p21), similar sensitivity to the drugs is noted. It is presumed that there are several decades of main signal transduction pathways and that, even when minor routes accompanied therewith are included, there are about 100 kinds. Accordingly, by constructing a database where result of influence (or result of non-influence) to sensitivity to drugs by overexpression of function-known genes (preferably, 100 kinds or more) made into a pattern using the correlation value for each other followed by comparing the result of the overexpression of function-unknown genes with the database, it is possible to identify the pathway concerning the product of the function-unknown genes. Further, when the pathway is investigated, a direct action mechanism of the genetic product can be elucidated with a high accuracy.

The invention of this application will now be illustrated in more detail and specifically by way of the following Examples, although the invention of this application is not limited to the following Examples.

EXAMPLES
1. Materials

With regard to the function-known genes, the genes shown in the left column of Table 2 were used. With regard to the drugs, those shown in Table 1 were dissolved in DMSO to an extent of 100-fold of the maximum concentration for the search of the drugs and used. With regard to the cells, incubated NIH3T3 or ras-NIH3T3 cells were used.

TABLE 1

Tyrosine kinase inhibitors

HMA
herbimycin A
Src, Abl inhibitor

erbstatin

EGFR inhibitor

genistein

Tyr kinase, topo II inhibitor

Ser/Thr kinase inhibitors

Staurosporine

PKC, cdk, MLCK inhibitor

K252a

CaM-kinase inhibitor

H-7

PKA, PKC, PKG inhibitor

GF109203X

PKC inhibitor

Y-27632

ROCK inhibitor

olomoucine

cdk inhibitor

Phosphatase inhibitors

OA
okadaic acid
PP1, PP2A inhibitor

cantharidin

PP2A inhibitor

Na vanadate
sodium vanadate
tyrosine phosphatase inhibitor

NaAsO₂
sodium arsenite
tyrosine phosphatase inhibitor

Anti-cancer drugs

MMC
mitomycin C
DNA cross-linker

5-FU
5-fluorouracil
thymidine synthetase inhibitor

CDDP
cisplatin
DNA cross-linker

MTX
methotrexate
DHFR inhibitor

MIT
mitoxantrone
DNA strand break

ACR
aclarubicin
DNA intercalator

IFM
ifosfamide
DNA alkylation

ACD
actinomycin D
RNA polymerase inhibitor

HU
hydroxyurea
ribonucleotide reductase inhibitor

6-TG
6-thioguanine
purine metabolism inhibitor

CPT
camptothecin
topoisomerase I inhibitor

PPL
pepleomycin
DNA strand break

VCR
vincristine
microtubule depolymerization

Protease inhibitors

ALLN
Ac-Leu-Leu-leucinal
calpain/proteasome inhibitor

ONO-3403

trypsin inhibitor

ONO-5046

elastase inhibitor

ICEin-III
ICE inhibitor-III
caspase inhibitor

Others

wortmannin

PI3-K inhibitor

manumycin

farnesyltransferase inhibitor

cytochalasin D

actin polymerization inhibitor

ouabain

Na⁺, K⁺-ATPase inhibitor

A23187

Ca²⁺ionophore

BAPTA-AM

Ca²⁺chelator

thapsigargin

Ca²⁺-APTase inhibitor

U73122

phospholipase C inhibitor

SnPP

heme oxygenase inhibitor

curcumin

5-lipoxygenase & cyclooxygenase inhibitor

forskolin

adenylate cyclase activator

IBMX

phosphodiesterase inhibitor

CHX
cycloheximide
protein synthesis inhibitor

SNAP

NO donor

resveratrol

antioxidant; estrogen-R agonist, COX1 inhibitor

ribonucleotide reductase inhibitor

sulindac

COX inhibitor

IMT
indomethacin
COX1/2 inhibitor, phospholipase A2 inhibitor

NaN₃
sodium azide
cytochrome a/a3 binding

β-elemene

herb medicine

2. Methods
(1) Preparation of Cells Overexpressing Genes

Full-length cDNA of each function-known genes was incorporated into an expression vector (pRc-CMV, etc.) and transfected into NIH3T3 cells by a common method. Transformed cells were isolated using the resistance to G-418 as an index and the expression of the transfected gene in each cell was investigated by Western blotting method to select a highly expressing line. FIG. 1 shows examples of gene expression by Western blotting method.

(2) Measurement of Cell Viabilities by MTT Method

Cell viabilities were measured according to the following procedures.

- 1) From the 2nd to the 11th rows of a 96-well plate were filled with DMEM (50 μl). The 12th row was filled with 100 μl of DMEM.
- 2) The 1st row was filled with 98 μl of DMEM.
- 3) Drugs (2 μl each) were added into the 1st row.
- 4) Continuous double-dilution was conducted from the 1st to the 9th rows. Fifty μl were taken out from the 9th row and discarded. The plate was preserved in a CO₂incubator.
- 5) Cells (each high-expressing cells and the parental cell line) were detached from the medium using a trypsin solution, suspended in 10% CS-DMEM and transferred to a test tube and cell numbers (cell/ml) were counted.
- 6) The cells were diluted to a concentration of 1×10⁵cells/ml, and 50 μl of the cell suspension were added to the 1st to the 11th rows of the plate followed by gently stirring.
- 7) The plate was transferred to the CO₂incubator and incubated for 3 to 4 days.
- 8) MTT (5 mg/ml in PBS) (10 μl) was added to the 1st to the 12th rows of the plate and incubated in the CO₂incubator at 37° C. for 4 hours.
- 9) A reaction stop solution (0.04N HCl in isopropanol) (150 μl) was added followed by mixing well and being allowed to stand at room temperature for about 2 hours.
- 10) Coloration of formazan which was a metabolite of the MTT dye was measured using a microplate reader. The measurement wavelength was 574 nm and the reference wavelength was 655 nm. The 10th and the 11th rows of the plate were 100% controls and the 12th row was a 0% control.

(3) Calculation of Logarithmic Values of Ratios of IC₄₀Values

As an index for the sensitivity of highly gene-expressing cells and the parental cell line to various drugs, each of the IC₄₀values thereof was specified and ratios of the IC₄₀values were calculated. FIG. 2 and FIG. 3 are the examples where ratios of IC₄₀values were calculated from a curve showing the dependency on the concentration of the chemical versus the viability. After that, logarithmic values of ratios of IC₄₀values were calculated from each gene. Table 2 is a part of the list of the logarithmic values.

TABLE 2

Stauro-

GF109203X
sporine
K252a
H-7
HMA
Genistein
Erbstatin
Ouabain
6-TG
OA
SnPP
Vanadate
ALLN

Ha-ras
−0.39
0.30
0.65
0.23
−0.35
−0.35
0.08
0.32
−0.19
0.11
0.28
−0.33
0.15

Ki-ras
−0.40
0.38
0.15
0.28
−0.14
0.00
0.04
0.18
−0.30
0.04
0.18
−0.30
0.11

N-ras

0.24
−0.16
0.30
0.43
0.42
−0.22
0.56
−0.22
0.00
0.14
−0.09
0.17

v-src
−0.29
−0.05
−0.22
−0.07
−0.35
−0.60
−0.05
0.00
0.00
0.18
−0.17
0.00
0.10

erbB2
−0.40
0.04
0.15
0.00
−0.55
−0.60
−0.05
0.18
−0.12
−0.19
−0.25
−0.40
−0.05

p53 (wt)
0.62
0.07
0.05
0.00
−0.22
0.26
0.17
0.09
0.32
−0.05
−0.18
0.00
0.18

Cip-1
0.30
0.00

0.00
−0.30

0.16
0.47
−0.15
−0.66
0.00
0.18

p16/INK4A
0.48
−0.22
−0.22
0.08
0.41
0.40
0.51
0.63
0.46
0.06
−0.05
0.11
0.09

Bax
0.22
−0.22
−0.11
0.08
−0.05
0.20
0.27
0.40
0.36
0.00
0.17
0.00
−0.10

Bax
0.27
0.00
0.60
0.00
0.15
0.38
0.04
0.00
−0.05
0.00
0.10
0.32
0.11

TK
0.00
0.46
0.23
−0.55
0.00
0.08
0.05
0.00
−0.17
0.00
0.00
0.16
0.00

m-calpain
0.35
0.00
0.13
0.15
0.00
0.18
0.00
0.05
0.29
−0.08
−0.07
−0.10
0.00

cAMP-PK-CS
0.27
−0.12
−0.04
0.15
0.12
0.00
0.05
0.00
0.14
0.08
0.02
0.00
0.20

calpastatin

0.04
0.1
−0.14
−0.14
0.127
−0.2
−0.3
−0.25
−0.04
0.486
0.00
0.10

CP-antisense
0.00
−0.15
0.00
0.00
−0.10
0.00
0.06
0.28
0.14
0.13
0.10
0.04
0.00

DAN
0.65
0.48
−0.46
0.18
−0.05
0.20
0.20
0.74
0.64
0.04
−0.49
0.30
0.00

Regucalcin
−0.05
−0.09
−0.34
−0.02
−0.20
0.00
0.00
−0.12
0.20
−0.10
0.32
0.00
0.00

cystatin alpha
0.60
0.30
−0.10
0.60
−0.12
0.28
0.08
1.28
0.60
0.08
0.00
0.08
0.07

cystatin E
0.27
0.40
−0.19
−0.05
0.00
0.21
−0.06
0.49
0.00
−0.52
0.11
0.20
0.19

caspase-1
0.23
0.22
0.04
0.00
0.00
−0.12
−0.22
1.26
0.34
0.00
−0.15
−0.11
−0.04

caspase-3
0.82
0.00
0.15
−0.15
0.08
0.04
−0.10
0.65
1.16
0.00
−0.40
0.14
−0.09

caspase-2
0.92
0.18
0.37
0.28
0.10
0.30
−0.07
−0.05
0.18
0.06
−0.33
0.40
−0.04

RhoA
0.24
0.15
0.10
0.35
0.13
0.31
0.14
0.15
0.69
0.00
0.14
0.28
0.00

RhoA-DN

0.14
0.28
0.22
−0.10
0.00
−0.02
0.45
0.41
0.00
0.08
−0.12
0.00

PDGF-R
0.00
0.24
0.10
−0.07
0.19
0.32

0.34
0.22
0.16
−0.07
0.22
0.22

PDGF-R-Del
0.91
0.28
0.10
0.28
0.00
0.33
0.00
0.19
0.51
0.21
0.08
0.00
0.10

Glucocorticoid-R
0.27
−0.28
0.13
0.08
−0.11
0.02
0.06
0.04
0.09
0.06
0.00
0.03
0.12

STAT1
0.41
0.00
0.15
0.08
−0.05
0.10
0.04
0.04
0.20
0.14
0.08
0.00
0.17

CBP8
0.16
0.19
0.28
−0.06
0.09
0.10
0.14
0.58
0.38
0.12
0.56
0.03
0.11

PKCalpha-KN
0.22
0.00
0.16
0.14
0.09
0.16

0.00
0.26
0.09
−0.14
0.23
0.11

PKCalpha-KN
0.62
−0.10
0.02
0.20
−0.10
0.24
0.00
0.06
0.38
0.00
0.00
0.08
−0.01

PKCepsilon-KN
−0.17
−0.07
0.00
−0.21
−0.11
0.00
−0.12
−0.15
0.00
0.00
0.27
0.09
0.07

PKCepsilon-KN
0.32
−0.10
−0.09
0.16
0.09
0.19
0.00
−0.12
0.00
0.00
0.24
0.18
0.19

TPA
0.09
−0.12
−0.13
0.00
−0.07
−0.09
0.00
−0.08
0.00
0.12
−0.20
−0.03
−0.09

(PKC downreg

ERK-DN
0.48
0.06
0.05
0.14
0.00
0.00
0.13
0.48
0.32
0.00
0.00
0.00
0.00

JNK-DN
0.58
0.14
−0.28
0.09
−0.14
−0.10
0.11
−0.08
0.00
−0.07
−0.11
−0.17
−0.24

p38-DN
0.58
−0.05
−0.15
0.10
−0.05
0.00
0.06
0.41
0.33
0.12
0.10
−0.04
0.04

HSP40
−0.07
0.30
0.07
0.15
0.00
0.00
0.00
0.00
0.50
−0.02
0.28
−0.03
0.18

HSP90

0.22
0.56
−0.03
0.40
0.41
0.26
0.92
0.57
0.07

0.02
0.16

CaMKIIa
0.04
0.12
0.04
0.00
0.00
−0.15
0.14
0.23
0.00
0.00
0.24
−0.13
0.00

CaMKIIa-Active

−0.04
0.10
0.13
0.51
0.23
0.21
0.60
0.62
0.14
0.30
0.01
0.20

HNF1
0.345
0
−0.207
0.149
0.161
0.234
0.391
0.103
0.46
0
0.138
0.046
0.16

HNF3b
0.21
0.00
−0.21
−0.11
−0.18
−0.21
−0.03
−0.23
0.03
0.08
0.24
0.22
0.28

HNF4
0.40
0.04
−0.22
0.09
−0.08
−0.15
2.00
−0.08
0.00
0.08
0.46
−0.03
−0.15

coup
0.46
0.08
0.00
0.28
0.42
0.44
0.33
0.49
0.45
0.00
0.51
−0.10
0.06

C/EBPa
0.00
0.00
−0.48
−0.35
0.00
−0.43
0.11
0.00
0.00
0.12
−0.00
−0.02
0.00

C/EBPb

−0.23
0.25
0.00
0.45
0.19
0.48
0.00
0.30
0.21
−0.50

0.31

p33/ING1
−0.28
0.62
0.28
0.00
0.38
0.78
0.11
0.10
0.46
0.11
−0.23
−0.30
0.08

T.Tn
−0.10
0.00
0.00
0.00
0.00
−0.25
0.48
0.28
0.00
−0.16
0.00
0.46
0.48

Thapsi-

Wort-
Manu-

3403
5046
ICEin-3
Forskolin
U73122
gargin
BAPTA-AM
mannin
mycin
A23187
NaAsO2
CHX
b-elemene

Ha-ras
−0.22
0.00
0.32
0.26
−0.19
0.00
−0.20
0.34
−0.30
−0.28
0.04
−0.19
−0.26

Ki-ras
−0.30
0.51
0.30
0.36
−0.60
−0.05
−0.15
0.34
−0.24
0.06
0.08
−0.43
−0.10

N-ras
−0.17
0.23
0.38
0.54
−0.54
0.08
0.00
0.14
−0.09
0.20
−0.19
−0.42
0.07

v-src
−0.05
0.51
−0.14
−0.46
−0.59
0.32
−0.22
0.08
0.00
−0.19
0.11
−0.32
−0.35

erbB2
−0.15
0.80
0.18
0.28
−0.96
0.11
−0.40
0.16
−0.05
−0.07
−0.15
−0.64
−0.46

p53 (wt)
0.04

0.23
0.98
0.11
−0.05
0.00
0.40
0.12
0.30
0.20
0.85
0.00

Cip-1
0.04
−0.14
0.08

0.08
0.04
0.00

0.12
0.04
0.30
1.77
0.00

p16/INK4A
0.29
0.22
0.15
0.70
0.28
−0.64
0.20
0.30
0.08
0.00
0.16
0.04
0.12

Bax
0.12
−0.07
−0.12
0.00
0.00
−0.21
0.15
0.14
−0.07
0.00
−0.10
−0.08
0.14

Bax
0.00
0.00
0.00
−0.26
0.00
0.20
0.00
0.10
0.06
−0.09
0.34
0.00
0.00

TK
0.09
−0.24
−0.15
0.56
0.00
0.06
0.00
0.00
0.00
0.00
0.18
−0.13
−0.14

m-calpain
0.00
−0.04
−0.06
0.25
−0.14
0.05
0.00
0.18
0.05
0.26
−0.16
0.22
0.00

cAMP-PK-CS
0.00
0.00
0.00
0.51
−0.18
0.05
−0.10
−0.07
0.08
−0.08
0.07
0.23
−0.10

calpastatin
0.00
−0.1
−0.088
−0.09
−0.313
0.046
0
−0.14
0.02
−0.12
0
0.31
0.18

CP-antisense
0.00
−0.06
−0.19
−0.05
−0.10
−0.30
0.06
−0.12
0.00
−0.36
0.02
0.00
0.00

DAN
0.08
0.26
0.00
0.88
0.36
0.18
0.70
0.52
0.00
0.40
−0.15
0.72
0.04

Regucalcin
0.12
−0.38
0.00
−0.10
−0.66
0.20
−0.39
−0.28
0.04
0.03
0.03
0.08
−0.09

cystatin alpha
−0.10

0.32
0.72
0.04
0.04
0.34
0.45
−0.19
0.26
−0.05
0.34
0.08

cystatin E
−0.15
0.36
0.07
0.29
−0.07
0.00
−0.02
0.00
0.00
0.22
0.15
0.00
0.07

caspase-1
−0.06
0.40
0.11
0.34
0.53
−0.30
0.60
0.20
−0.06
−0.22
−0.21
−0.05
0.11

caspase-3
0.00
0.40
0.13
1.12
0.53
−0.17
0.60
0.45
0.04
0.28
0.11
0.10
0.28

caspase-2
0.15
0.51
0.04
−0.34
−0.02
−0.07
0.23
0.52
0.08
0.48
0.18
0.74
0.26

RhoA
0.00
0.11
0.19
0.47
0.12
0.26
0.00
0.24
−0.04
0.26
0.07
0.14
0.00

RhoA-DN
0.22
0.00
0.00
−0.36
−0.35
0.06
0.09
0.00
−0.13
0.03
0.00
0.22

PDGF-R
0.00
0.36
0.20
0.16
−0.11
0.29
0.29
0.00
0.17
0.31
0.14
0.51
0.00

PDGF-R-Del
0.22
−0.07
0.00
0.51
0.00
0.24
0.31
0.07
0.09
0.15
0.00
0.39
0.16

Glucocorticoid-R
0.10
0.00
0.00
0.33
0.05
0.20
0.10
0.09
0.09
0.28
0.16
0.09
0.00

STAT1
0.16
0.05
0.09
0.51
0.18
0.30
0.10
0.00
0.00
0.31
0.16
0.00
0.05

CBP8
0.08
0.12
0.18
0.40
0.18
0.12
0.00
0.14
0.09
0.22
0.21
0.00
0.06

PKCalpha-KN
0.04
0.10
0.12
−0.47
−0.33
0.10
0.43
0.41
0.00
0.22
0.16
0.30
0.07

PKCalpha-KN
0.11
−0.05
0.33
0.00
−0.97
0.12
−0.42
−0.06
0.16
−0.05
0.22
0.29
−0.07

PKCepsilon-KN
0.04
−0.21
−0.21
0.00
−0.21
0.09
0.00
−0.15
−0.11
−0.28
−0.07
0.06
0.00

PKCepsilon-KN
0.00
0.00
0.33
0.00
−0.38
0.20
0.00
−0.28
0.16
0.15
0.35
0.20
−0.23

TPA (PKC downr
0.10
−0.10
−0.09
−0.17
−0.12
−0.23
−0.03
0.00
0.03
−0.22
−0.20
0.00
0.00

ERK-DN
0.10
0.00
0.00
0.08
0.00
−0.15
0.12
−0.11
−0.05
0.00
0.16
0.08
0.33

JNK-DN
0.22
−0.09
0.00
−0.22
−0.07
0.24
0.06
−0.09
−0.05
−0.08
−0.07
0.00
−0.04

p38-DN
0.14
−0.04
−0.11
−0.46
0.00
0.02
0.00
−0.18
0.00
−0.12
0.00
0.04
0.05

HSP40
0.17
−0.15
0.11
−0.39
−0.20
0.18
0.05
−0.07
−0.06
−0.16
−0.02
0.00
0.02

HSP90
0.36
0.52
0.22
0.94
0.18
0.09
0.60
0.18
−0.13
0.28
0.10
0.07
0.05

CaMKIIa
0.00
0.00
0.00
0.00
−0.05
0.09
−0.12
−0.15
0.00
0.00
0.00
0.04
0.16

CaMKIIa-Active
0.22
0.35
0.22
0.43
0.00
0.03
0.18
0.18
0.03
0.18
0.02
−0.09

HNF1
0.14
0.05
0.20
1.15
0.07
0.16
0.20
0.16
0.06
0.35
−0.14
0.38
0.02

HNF3b
0.22
−0.25
−0.09
0.00
−0.31
0.24
−0.07
0.24
−0.06
−0.16
0.00
0.07
−0.07

HNF4
−0.09
0.00
0.00
0.00
0.00
0.00
−0.10
0.14
0.00
0.19
0.00
0.22
0.33

coup
0.11
−0.04
−0.11
0.78
0.00
−0.30
0.09
0.10
0.09
−0.12
−0.19
0.12
0.52

C/EBPa
−0.41
0.00
−0.46
0.00
0.00
−0.09
−0.62
0.00
0.00
0.00
−0.40
0.00
0.00

C/EBPb
0.36
0.17
0.35
0.93
0.10
0.29
0.81
0.34
0.47
0.25
0.41
0.37
0.50

p33/ING1
0.00
−0.25
−0.15
0.63
0.28
0.49
0.00
0.00
0.18
0.26
−0.07
−0.30
−0.14

T.Tn
0.00
0.00
0.30
0.53
−0.26
0.32
0.11
0.36
0.28
−0.22
−0.05
0.00
−0.14

indicates data missing or illegible when filed

(4) Calculation of Correlation Coefficients by Logarithmic Values

In the list of the logarithmic values shown in Table 2, calculation of correlation coefficients by t-test was carried out in each line. FIG. 4 shows graphs where sensitivity ratios of IkB-SR and IKK-DN- and p16-introduced cells to chemicals were logarithmically plotted, and, between IkB and IKK which were functionally correlated, there was a high correlation (r=0.75) while, between IkB and p16 which were not related, the correlation coefficient was 0.09 with no significance. In Tables 3 to 14, the list of all correlation coefficients is shown by dividing into 12.

TABLE 3

Ha-ras
Ki-ras
N-ras
v-src
erbB2
abl
Ras-N-17
Rb
p53(wt)
Cip-1
p16/INK4A

Ha-ras
1.00

Ki-ras
0.71
1.00

N-ras
0.56
0.56
1.00

v-src
0.36
0.61
0.08
1.00

erbB2
0.53
0.76
0.35
0.64
1.00

abl
−0.16
−0.09
−0.05
−0.17
−0.07
1.00

Ras-N-17
0.11
−0.06
0.12
−0.24
−0.27
0.51
1.00

Rb
0.02
0.06
−0.15
−0.15
−0.02
−0.16
−0.01
1.00

p53 (wt)
−0.29
−0.30
−0.34
−0.44
−0.17
0.25
0.30
0.18
1.00

Cip-1
−0.55
−0.37
−0.37
−0.30
−0.31
0.19
0.18
−0.12
0.57
1.00

p16/INK4A
−0.36
−0.21
−0.18
−0.26
−0.17
0.18
0.06
−0.04
0.41
0.22
1.00

HSP40
−0.14
−0.13
−0.33
0.01
−0.01
0.03
−0.16
0.45
0.00
0.17
−0.20

HSP90
−0.23
−0.10
−0.32
−0.17
0.00
0.32
−0.01
0.43
0.42
0.15
0.46

Hsdj
−0.33
−0.05
−0.18
−0.11
−0.01
0.39
0.19
0.19
0.16
0.34
−0.04

DnaJ-61
−0.15
−0.05
0.05
−0.24
0.03
0.19
0.10
0.21
0.30
−0.05
0.17

Bax (N)
−0.36
−0.35
−0.01
−0.34
−0.27
0.09
−0.22
−0.10
0.08
0.25
0.10

Bax (F)
−0.20
0.00
−0.11
0.02
−0.06
−0.07
−0.10
0.11
0.08
0.18
0.56

IkB-SR
−0.24
−0.28
−0.12
−0.39
−0.28
−0.05
0.16
0.18
0.52
0.44
0.09

IKK-DN
−0.58
−0.49
−0.35
−0.48
−0.34
0.18
0.03
0.12
0.45
0.62
0.16

PDGF-R
−0.14
0.16
0.18
0.30
0.13
0.35
0.13
−0.20
0.11
0.26
−0.06

PDGF-R-Del
−0.38
−0.16
−0.37
−0.19
−0.17
0.19
0.14
0.34
0.45
0.43
0.38

Glucocorticoid-R
0.07
−0.08
0.06
−0.19
−0.04
−0.02
−0.05
−0.06
0.17
0.04
0.10

RhoA
−0.10
−0.04
0.11
−0.17
−0.07
0.17
0.07
0.16
0.33
0.10
0.18

RhoA-DN
−0.55
−0.35
−0.47
−0.22
−0.16
0.10
−0.05
0.26
0.29
0.53
0.23

CaMKIIa
0.34
0.05
0.15
−0.10
0.06
−0.32
−0.03
0.29
−0.16
−0.23
−0.16

CaMKIIa-Active
−0.08
0.12
0.14
−0.06
0.15
−0.10
−0.18
0.23
0.03
0.01
0.41

PKCalpha-KN
−0.12
−0.13
−0.11
0.13
−0.09
0.11
0.04
−0.10
−0.02
0.12
0.01

PKCalpha-KN
−0.07
0.10
0.05
0.16
0.32
0.08
0.03
0.19
0.35
0.31
0.03

PKCepsilon-KN
−0.33
−0.41
−0.36
−0.16
−0.28
0.10
−0.17
0.23
0.21
−0.05
0.18

PKCepsilon-KN
−0.09
0.12
0.19
0.22
0.16
−0.06
−0.16
−0.06
0.06
0.11
−0.15

TPA (PKC-)
−0.05
−0.20
−0.23
−0.06
−0.09
0.20
0.06
−0.01
0.18
0.08
0.12

Akt-DN
0.05
0.02
0.11
0.10
0.09
0.19
0.40
−0.15
0.36
0.17
−0.03

ERK-DN
−0.40
−0.34
−0.51
−0.23
−0.22
0.14
0.15
0.25
0.45
0.39
0.50

JNK-DN
−0.21
−0.20
−0.28
−0.03
−0.16
0.05
0.23
0.02
0.21
0.37
0.02

p38-DN
−0.30
−0.30
−0.35
−0.09
−0.19
−0.06
0.08
0.13
0.28
0.46
0.18

cAMP-PK-CS
0.08
0.19
−0.02
0.17
0.23
0.14
−0.29
0.18
0.17
−0.06
0.20

HSP40
HSP90
Hsdj
DnaJ-61
Bax (N)
Bax (F)
IkB-TDN
IKK-DN

Ha-ras

Ki-ras

N-ras

v-src

erbB2

abl

Ras-N-17

Rb

p53 (wt)

Cip-1

p16/INK4A

HSP40
1.00

HSP90
0.21
1.00

Hsdj
0.34
0.33
1.00

DnaJ-61
−0.05
0.26
0.40
1.00

Bax (N)
0.21
0.09
0.15
−0.06
1.00

Bax (F)
0.17
0.22
0.01
−0.17
0.19
1.00

IkB-SR
0.04
0.23
0.29
0.13
0.12
0.09
1.00

IKK-DN
0.25
0.28
0.41
0.16
0.39
0.16
0.75
1.00

PDGF-R
−0.02
0.32
0.10
0.05
0.02
−0.06
0.11
0.16

PDGF-R-Del
0.11
0.62
0.26
0.30
0.02
0.24
0.24
0.44

Glucocorticoid-R
−0.25
0.32
0.00
0.26
0.14
−0.03
0.14
0.06

RhoA
0.25
0.43
0.09
0.16
0.38
0.26
0.25
0.17

RhoA-DN
0.51
0.54
0.50
0.16
0.32
0.24
0.32
0.63

CaMKIIa
0.08
−0.01
−0.10
0.13
−0.20
−0.04
0.23
0.10

CaMKIIa-Active
0.04
0.67
0.16
0.14
−0.17
0.24
0.10
0.07

PKCalpha-KN
0.29
0.08
0.06
−0.27
0.44
0.27
−0.04
0.08

PKCalpha-KN
0.36
0.00
0.13
0.12
0.18
0.13
0.05
0.25

PKCepsilon-KN
0.30
0.27
−0.08
0.05
0.48
0.15
0.17
0.32

PKCepsilon-KN
0.13
−0.25
0.00
0.21
0.18
−0.13
−0.19
−0.10

TPA (PKC-)
0.16
0.15
0.10
−0.13
−0.02
0.04
−0.04
0.13

Akt-DN
−0.04
−0.05
0.19
0.18
−0.23
−0.05
0.37
0.02

ERK-DN
0.27
0.66
0.24
0.22
0.08
0.38
0.22
0.40

JNK-DN
0.21
0.09
0.14
−0.06
0.02
0.16
0.19
0.31

p38-DN
0.48
0.22
0.07
−0.10
0.10
0.42
0.23
0.40

cAMP-PK-CS
0.12
0.29
0.04
0.13
0.06
0.20
−0.10
−0.07

TABLE 4

Ha-ras
Ki-ras
N-ras
v-src
erbB2
abi
Ras-N-17
Rb
p53(wt)
Cip-1
p16/INK4A

14-3-3zWT
−0.16
−0.23
−0.30
−0.06
−0.02
−0.12
−0.03
0.34
0.21
−0.11
−0.02

TK
0.28
0.13
0.25
−0.10
0.08
0.11
0.26
0.16
0.03
−0.14
−0.19

caspase-1
0.16
0.03
0.20
−0.13
0.05
0.05
0.18
−0.13
0.05
−0.04
0.28

caspase-3
−0.23
−0.30
−0.23
−0.34
−0.14
0.24
0.19
0.07
0.52
0.18
0.52

caspase-2
−0.45
−0.36
−0.43
−0.18
−0.26
0.12
0.25
−0.03
0.36
0.47
0.38

cystatin alpha
0.12
0.17
0.45
−0.07
0.27
0.13
0.24
0.04
0.39
0.15
0.42

cystatin E
−0.13
−0.02
0.06
−0.16
0.02
0.14
0.33
0.20
0.51
0.25
0.28

u-calpain
−0.31
−0.27
−0.13
−0.39
−0.23
0.00
0.27
0.13
0.49
0.67
0.07

m-calpain
−0.30
−0.18
−0.05
−0.35
−0.10
0.22
−0.05
0.16
0.41
0.27
0.14

calpain 30K (N)
0.10
0.30
0.07
0.68
0.27
0.17
0.03
−0.15
−0.31
0.09
−0.54

calpain 30K (F)
−0.15
−0.14
−0.08
−0.19
−0.03
0.02
0.17
0.26
0.29
0.30
0.00

calpastatin
0.35
0.30
0.38
0.14
0.09
−0.31
0.00
0.22
−0.36
−0.28
−0.44

CP-antisense
−0.20
−0.17
−0.45
−0.04
−0.08
0.12
0.11
0.31
0.35
0.17
0.44

BH
−0.17
−0.27
−0.06
−0.37
−0.33
−0.29
0.03
0.11
0.19
0.29
0.01

DAN
−0.45
−0.45
−0.37
−0.33
−0.24
0.27
0.24
0.13
0.44
0.35
0.46

Regucalcin
−0.22
−0.12
−0.02
−0.15
−0.05
−0.10
−0.05
0.26
0.32
0.39
0.02

CathL-mut
−0.03
−0.14
−0.16
−0.09
−0.24
−0.36
−0.17
0.51
0.00
−0.20
−0.09

STAT1
0.13
0.01
0.09
−0.18
0.00
0.06
0.02
0.12
0.29
0.01
0.05

CBP
−0.25
−0.21
−0.32
−0.30
−0.07
−0.14
−0.18
0.40
0.28
0.04
0.43

P/CAF
−0.25
−0.18
−0.08
−0.40
−0.08
0.60
0.41
0.16
0.24
0.35
−0.02

HNF1
−0.05
−0.12
−0.01
−0.34
−0.05
0.15
0.20
0.26
0.60
0.07
0.34

HNF3b
−0.13
−0.27
−0.19
0.02
−0.11
−0.09
0.09
0.24
0.24
0.09
−0.03

HNF4
0.06
−0.04
−0.18
0.00
−0.01
−0.18
−0.03
−0.03
0.08
−0.06
0.14

coup
−0.25
−0.12
−0.17
−0.40
−0.18
0.06
0.13
0.57
0.52
0.19
0.54

C/EBPa
−0.13
−0.04
−0.09
−0.07
0.16
0.26
0.21
0.19
0.26
0.30
0.23

C/EBPb
−0.50
−0.25
−0.50
−0.04
−0.08
0.27
0.00
0.08
0.45
0.37
0.25

per-1
−0.07
−0.18
−0.19
0.24
0.03
−0.03
0.24
−0.17
0.16
0.37
−0.10

p33/ING1
−0.23
−0.03
−0.15
−0.21
0.04
0.29
−0.11
0.41
0.14
0.17
0.07

T.Tn
0.47
0.42
0.35
0.27
0.37
−0.13
0.06
−0.08
−0.21
−0.20
−0.22

CD44/H-CAM
−0.15
0.04
−0.26
0.15
0.09
−0.01
−0.31
0.34
−0.02
0.01
−0.18

CD44/3E
−0.22
−0.13
−0.39
0.03
−0.10
0.09
−0.05
−0.03
−0.05
0.15
−0.06

CD44/3s
−0.13
−0.11
−0.52
−0.03
−0.11
0.18
0.00
0.25
0.06
0.12
−0.13

Jagged-1
0.16
0.04
0.05
0.01
−0.14
−0.48
−0.17
0.34
−0.17
−0.12
−0.05

p94-WT
−0.37
−0.26
−0.26
−0.32
−0.25
−0.10
0.00
0.34
0.27
0.11
0.04

p94-mut
−0.23
−0.07
0.02
0.03
−0.14
−0.01
0.05
−0.02
0.04
−0.01
−0.10

E2F-High
−0.33
−0.34
−0.10
−0.32
−0.27
−0.01
0.06
0.05
0.42
0.34
0.00

HSP40
HSP90
Hsdj
DnaJ-61
Bax (N)
Bax (F)
IkB-TDN
IKK-DN

14-3-3zWT
0.28
0.14
0.19
0.13
−0.01
0.02
0.23
0.26

TK
−0.21
−0.06
−0.04
−0.12
−0.12
−0.20
0.16
−0.03

caspase-1
−0.14
0.37
−0.17
0.10
−0.16
0.05
−0.11
−0.10

caspase-3
0.03
0.63
0.06
0.27
0.15
0.31
0.09
0.20

caspase-2
0.08
0.19
0.20
−0.07
0.35
0.38
0.09
0.36

cystatin alpha
−0.02
0.51
0.04
0.32
−0.03
0.49
0.12
0.10

cystatin E
0.08
0.55
0.15
0.19
0.04
0.06
0.37
0.24

u-calpain
0.21
0.18
0.40
0.28
0.07
0.14
0.53
0.56

m-calpain
0.25
0.30
0.26
0.25
0.38
0.19
0.23
0.41

calpain 30K (N)
0.17
−0.58
0.36
−0.24
0.17
−0.56
−0.21
−0.16

calpain 30K (F)
0.17
0.28
0.44
0.14
−0.06
−0.05
0.49
0.39

calpastatin
0.00
−0.57
−0.15
−0.01
−0.01
−0.10
−0.06
−0.20

CP-antisense
0.38
0.51
0.11
0.20
0.11
0.38
0.11
0.21

BH
0.02
0.02
0.11
−0.04
0.14
0.06
0.72
0.57

DAN
0.21
0.43
0.28
0.20
0.24
0.48
0.15
0.38

Regucalcin
0.36
−0.08
0.20
0.20
0.13
0.08
0.39
0.37

CathL-mut
0.19
−0.09
−0.23
−0.22
0.20
0.06
0.16
0.11

STAT1
−0.12
0.41
0.03
0.21
−0.01
−0.04
0.19
0.01

CBP
0.10
0.70
0.07
0.32
0.08
0.10
0.26
0.34

P/CAF
0.13
0.14
0.51
0.18
0.12
−0.21
0.15
0.43

HNF1
−0.14
0.30
−0.01
0.43
−0.34
0.07
0.36
0.14

HNF3b
0.32
−0.10
−0.05
−0.09
0.19
0.05
0.27
0.16

HNF4
−0.09
−0.12
0.01
0.17
−0.22
0.17
0.20
0.16

coup
0.17
0.62
0.21
0.30
−0.06
0.43
0.42
0.38

C/EBPa
0.16
0.36
0.36
0.21
0.02
0.22
0.02
0.20

C/EBPb
0.03
0.53
0.33
0.16
−0.05
0.06
0.16
0.28

per-1
0.27
−0.14
0.06
−0.25
0.05
0.04
0.06
0.07

p33/ING1
0.18
0.34
0.26
0.21
−0.02
−0.02
−0.05
0.21

T.Tn
−0.14
−0.19
−0.12
−0.08
−0.37
−0.05
−0.01
−0.24

CD44/H-CAM
0.37
0.25
0.40
0.23
0.11
0.07
−0.06
0.03

CD44/3E
−0.03
0.13
0.20
0.08
−0.16
−0.22
0.04
0.14

CD44/3s
0.16
0.08
0.22
0.00
−0.14
−0.02
0.25
0.26

Jagged-1
0.06
0.23
−0.25
−0.16
−0.04
0.11
0.00
−0.09

p94-WT
0.12
0.13
0.24
0.11
−0.02
0.00
0.28
0.37

p94-mut
−0.18
−0.22
0.19
0.08
0.01
−0.05
0.17
0.12

E2F-High
0.03
−0.12
0.13
0.14
−0.02
−0.09
0.60
0.47

TABLE 5

Ha-ras
Ki-ras
N-ras
v-src
erbB2
abl
Ras-N-17
Rb
p53(wt)
Cip-1
p16/INK4A

E2F-Low
0.07
−0.11
0.06
−0.24
−0.08
−0.17
0.01
0.21
0.29
−0.17
0.04

FBRCA1-13
−0.02
−0.15
−0.15
0.03
−0.11
−0.08
−0.09
0.01
−0.25
−0.13
−0.13

FMDM2hwt-6
0.10
0.07
0.13
0.23
−0.03
−0.48
−0.18
−0.01
−0.50
−0.10
−0.35

p27-3
−0.17
−0.36
−0.31
−0.47
−0.41
−0.29
−0.01
0.50
0.21
−0.16
0.17

CAPN10-10
−0.02
0.05
0.01
−0.17
0.12
0.21
0.21
0.18
0.56
0.12
0.23

c-myc-1
−0.17
−0.26
−0.22
−0.30
−0.26
−0.16
0.10
0.15
0.51
0.16
0.21

MSSP-10
−0.02
−0.14
0.17
−0.21
−0.18
−0.47
−0.25
0.23
−0.33
−0.26
−0.19

MM1
−0.41
−0.23
−0.30
−0.28
−0.14
0.30
0.08
0.14
0.48
0.30
0.26

AMY1
0.06
0.03
0.03
−0.28
0.05
0.37
0.15
0.33
0.44
−0.07
0.24

Max
−0.04
−0.16
−0.08
−0.29
−0.15
0.27
0.00
0.32
0.21
−0.06
0.19

MDM2-hmut
−0.33
−0.32
−0.37
−0.31
−0.21
0.24
0.21
0.27
0.62
0.39
0.45

MDM2-mWT
0.04
0.02
−0.05
−0.02
0.02
0.19
0.26
0.15
0.48
0.04
0.33

TERT-WT
0.22
0.20
−0.01
0.15
−0.02
0.18
−0.02
−0.08
0.04
−0.08
−0.06

TERT-DN
−0.32
−0.13
−0.14
−0.17
0.01
0.54
0.23
−0.02
0.44
0.36
0.34

PTEN-WT
−0.07
−0.11
0.01
−0.31
−0.07
0.32
0.12
−0.16
0.22
0.03
0.21

PTEN-A3
−0.12
−0.24
0.07
−0.16
0.03
0.27
−0.05
−0.25
−0.07
−0.20
0.15

PTEN-G129R
0.15
0.00
0.13
−0.27
0.08
0.29
0.37
0.09
0.41
−0.12
0.18

Bcl-2
−0.26
−0.30
−0.33
−0.24
−0.30
0.27
0.06
0.26
0.12
0.15
0.21

per2
−0.11
−0.06
0.06
−0.31
−0.05
0.34
0.20
0.14
0.35
0.23
0.10

per3
0.17
0.12
0.22
−0.17
0.09
0.11
0.08
0.14
0.16
0.03
−0.11

Cyclin D1-11
0.15
0.10
0.21
0.04
0.04
−0.05
−0.24
0.01
−0.37
−0.19
−0.28

STAT2-4
0.07
0.05
0.06
−0.07
−0.13
−0.41
−0.42
0.19
−0.15
−0.18
−0.01

TSC1-4
−0.27
−0.41
−0.36
−0.37
−0.27
0.09
−0.04
0.27
0.30
0.20
0.05

Bad-22
−0.11
0.02
−0.05
−0.10
0.05
−0.10
0.01
0.33
0.35
0.36
−0.15

FAPP-4
0.14
0.17
0.20
−0.05
−0.08
−0.11
0.04
0.19
−0.10
−0.15
−0.26

FHO-6
−0.06
−0.07
0.01
−0.14
−0.12
−0.08
0.03
0.32
0.01
0.01
−0.03

F25 + lactacystin
−0.15
−0.10
−0.21
−0.22
−0.05
0.00
0.09
0.40
0.29
0.11
0.20

F25 + ONO5046
−0.15
−0.18
−0.27
−0.08
−0.21
−0.49
−0.23
0.41
−0.08
0.08
−0.04

F25 + CA-074
−0.01
0.03
−0.13
−0.07
−0.09
−0.46
−0.34
0.47
−0.08
−0.10
−0.15

F25 + PQQ
0.08
0.05
−0.01
−0.03
−0.15
−0.59
−0.37
0.37
−0.30
−0.27
−0.16

F25 + PD98059
0.02
0.17
0.12
0.10
0.10
−0.03
0.10
0.01
0.27
−0.02
0.19

F25 + ALLN
−0.24
−0.08
−0.13
0.05
0.01
0.17
0.15
−0.14
0.26
0.23
0.26

F25 + ONO3403
−0.47
−0.52
−0.55
−0.36
−0.25
0.08
−0.09
0.21
0.35
0.22
0.28

F25 + Y27632
−0.11
−0.26
−0.23
−0.30
0.01
−0.04
0.10
0.30
0.56
0.18
0.27

HSP40
HSP90
Hsdj
DnaJ-61
Bax (N)
Bax (F)
IkB-TDN
IKK-DN

E2F-Low
−0.12
−0.09
−0.14
0.39
−0.20
−0.23
0.33
0.03

FBRCA1-13
0.27
−0.14
0.02
0.21
−0.12
−0.14
−0.20
−0.09

FMDM2hwt-6
0.21
−0.43
−0.10
−0.10
−0.03
−0.09
−0.18
−0.19

p27-3
0.18
0.41
−0.01
0.23
0.00
0.15
0.24
0.15

CAPN10-10
−0.26
0.45
0.13
0.28
−0.20
0.04
0.21
0.06

c-myc-1
−0.03
0.37
−0.06
0.04
−0.07
0.13
0.24
0.10

MSSP-10
0.19
−0.19
−0.10
0.14
0.04
−0.06
0.11
0.01

MM1
0.27
0.55
0.39
0.25
0.04
0.15
0.21
0.28

AMY1
−0.08
0.32
0.18
0.48
0.08
−0.03
0.05
0.13

Max
0.10
0.29
0.08
0.22
0.02
0.01
−0.11
−0.03

MDM2-hmut
0.20
0.54
0.38
0.27
0.01
0.28
0.33
0.33

MDM2-mWT
0.01
0.24
0.04
0.20
−0.29
0.03
0.19
−0.04

TERT-WT
−0.02
−0.19
−0.18
−0.11
−0.10
0.02
−0.13
−0.15

TERT-DN
−0.15
0.53
0.34
0.25
−0.06
0.07
0.12
0.24

PTEN-WT
−0.16
0.24
0.06
0.39
−0.01
0.10
0.03
0.11

PTEN-A3
−0.01
−0.04
−0.07
0.12
0.25
−0.12
−0.31
−0.04

PTEN-G129R
−0.25
0.16
0.04
0.51
−0.30
−0.15
0.10
−0.11

Bcl-2
0.23
0.22
0.08
−0.09
0.13
0.12
−0.07
0.16

per2
−0.09
0.29
0.34
0.18
0.28
−0.04
0.14
0.29

per3
0.00
0.14
0.24
0.10
0.17
−0.02
0.16
0.18

Cyclin D1-11
0.05
−0.23
0.03
0.20
−0.16
−0.25
−0.07
−0.08

STAT2-4
−0.09
0.03
−0.31
−0.04
0.08
0.06
−0.08
−0.04

TSC1-4
0.52
0.24
0.16
−0.09
0.48
0.21
0.24
0.43

Bad-22
0.30
0.10
0.23
0.06
0.16
0.16
0.46
0.39

FAPP-4
−0.17
−0.18
0.04
0.07
0.02
−0.23
0.22
0.05

FHO-6
0.31
0.22
0.27
0.19
0.06
0.04
0.15
0.19

F25 + lactacystin
0.26
0.36
0.33
0.15
0.04
0.27
0.23
0.36

F25 + ONO5046
0.29
−0.01
−0.17
−0.30
−0.03
0.37
0.05
0.10

F25 + CA-074
0.32
0.04
−0.04
−0.03
−0.07
0.17
0.11
0.08

F25 + PQQ
0.27
−0.05
−0.14
−0.13
−0.07
0.15
−0.01
−0.16

F25 + PD98059
−0.40
0.05
−0.20
−0.01
−0.21
0.08
0.04
−0.13

F25 + ALLN
0.06
0.10
0.08
−0.03
0.14
0.22
−0.10
0.15

F25 + ONO3403
0.43
0.38
0.30
0.20
0.19
0.23
0.31
0.55

F25 + Y27632
0.12
0.34
0.19
0.45
−0.11
−0.03
0.35
0.29

TABLE 6

PDGF-R
PDGF-R
Glucoc
RhoA
RhoA-D
CaMKII:
CaMKII
PKCalph

PDGF-R
1.00

PDGF-R-Del
0.08
1.00

Glucocorticoid-R
0.03
0.37
1.00

RhoA
0.16
0.31
0.32
1.00

RhoA-DN
0.20
0.61
−0.02
0.29
1.00

CaMKIIa
−0.15
−0.07
0.01
−0.12
0.04
1.00

CaMKIIa-Active
0.15
0.39
0.20
0.19
0.29
0.16
1.00

PKCalpha-KN
0.40
−0.05
0.05
0.45
0.19
−0.28
−0.19
1.00

PKCalpha-KN
0.11
0.40
0.09
0.24
0.45
0.03
0.02
0.21

PKCepsilon-KN
0.00
0.25
0.12
0.41
0.25
−0.06
−0.14
0.49

PKCepsilon-KN
0.20
0.10
0.12
0.03
0.02
−0.08
−0.21
0.07

TPA (PKC-)
−0.18
0.20
0.11
−0.15
−0.03
−0.11
0.11
0.15

Akt-DN
0.49
−0.10
−0.08
0.00
−0.22
−0.02
−0.16
−0.01

ERK-DN
−0.06
0.62
0.09
0.32
0.72
0.16
0.39
0.16

JNK-DN
−0.12
0.53
0.14
0.10
0.28
0.12
−0.10
0.12

p38-DN
−0.11
0.37
−0.13
0.05
0.56
0.15
0.17
0.12

cAMP-PK-CS
0.18
0.36
0.40
0.30
−0.15
−0.06
0.21
0.03

PKCalpt
PKCeps
PKCeps
TPA (PK
Akt-DN
ERK-DN
JNK-DI
p38-DN
cAMP

PDGF-R

PDGF-R-Del

Glucocorticoid-R

RhoA

RhoA-DN

CaMKIIa

CaMKIIa-Active

PKCalpha-KN

PKCalpha-KN
1.00

PKCepsilon-KN
0.13
1.00

PKCepsilon-KN
0.69
0.01
1.00

TPA (PKC-)
0.09
0.24
−0.20
1.00

Akt-DN
0.29
−0.17
0.44
0.00
1.00

ERK-DN
0.30
0.35
−0.14
0.11
−0.04
1.00

JNK-DN
0.31
0.10
0.19
0.30
0.16
0.37
1.00

p38-DN
0.45
0.09
0.17
0.16
0.15
0.63
0.54
1.00

cAMP-PK-CS
0.40
0.30
0.34
0.47
−0.01
0.06
0.13
−0.07
1.00

TABLE 7

PDGF-R
PDGF-R-D
Glucocor
RhoA
RhoA-DN
CaMKIIa
CaMKIIa-Ac
PKCalpha
PKCalpha
PKCepsilL

14-3-3zWT
−0.12
0.08
−0.02
−0.17
0.08
0.13
0.00
0.11
0.19
0.44

TK
0.02
−0.17
−0.06
−0.07
−0.28
0.11
−0.13
−0.27
−0.07
−0.21

caspase-1
0.07
0.18
0.07
0.05
0.16
0.17
0.41
−0.18
−0.30
−0.15

caspase-3
0.01
0.48
0.38
0.57
0.30
−0.14
0.32
0.20
0.06
0.34

caspase-2
0.13
0.37
0.06
0.09
0.44
−0.31
−0.12
0.44
0.21
0.24

cystatin alpha
0.24
0.42
0.19
0.54
0.35
0.05
0.43
0.05
0.23
−0.15

cystatin E
0.38
0.16
−0.01
0.25
0.18
−0.01
0.24
0.03
0.16
0.02

u-calpain
0.05
0.48
0.21
0.11
0.49
0.04
0.12
−0.03
0.11
−0.13

m-calpain
0.13
0.54
0.44
0.57
0.36
−0.15
0.15
0.13
0.38
0.31

calpain
0.12
−0.29
−0.02
−0.26
−0.01
−0.35
−0.37
0.38
0.11
−0.06

30K (N)

calpain
0.14
0.19
−0.08
−0.12
0.28
0.07
0.19
−0.12
−0.26
−0.04

30K (F)

calpastatin
0.02
−0.28
−0.10
−0.27
−0.27
0.19
−0.38
−0.02
0.25
−0.09

CP-antisense
−0.10
0.30
−0.12
0.17
0.53
−0.01
0.15
0.17
0.35
0.31

BH
−0.16
−0.04
−0.04
−0.12
0.18
0.35
0.05
−0.13
−0.03
−0.02

DAN
0.20
0.37
0.15
0.34
0.40
−0.18
0.05
0.28
0.03
0.30

Regucalcin
0.00
0.19
−0.01
0.04
0.25
0.18
0.05
−0.15
0.72
0.06

CathL-mut
−0.33
−0.08
−0.21
−0.17
−0.01
0.32
−0.25
0.10
−0.01
0.46

STAT1
−0.01
0.44
0.78
0.34
−0.18
0.05
0.28
−0.15
0.01
0.12

CBP
−0.10
0.47
0.21
0.18
0.61
0.30
0.50
−0.26
0.03
0.22

P/CAF
0.16
0.21
−0.05
0.11
0.36
−0.03
−0.03
0.02
0.13
0.03

HNF1
0.05
0.33
0.33
0.36
−0.13
0.07
0.29
−0.22
0.12
0.08

HNF3b
−0.16
−0.03
−0.04
0.33
0.10
−0.07
−0.39
0.43
0.38
0.51

HNF4
−0.45
−0.06
−0.06
−0.15
−0.09
0.38
−0.06
−0.16
0.04
−0.09

coup
−0.18
0.52
−0.01
0.29
0.36
0.18
0.56
−0.18
0.20
0.19

C/EBPa
0.03
0.19
0.06
0.31
0.24
−0.20
0.12
0.09
0.26
−0.06

C/EBPb
0.24
0.39
0.15
0.11
0.30
−0.42
0.20
0.17
0.09
0.22

per-1
0.21
0.02
0.02
0.04
0.15
0.01
−0.23
0.39
0.45
0.04

p33/ING1
0.00
0.30
−0.08
0.13
0.26
−0.01
0.35
−0.30
−0.03
−0.03

T.Tn
0.11
−0.23
0.06
−0.11
−0.26
0.15
0.06
−0.25
−0.02
−0.48

CD44/H-CAM
0.15
0.15
−0.10
−0.13
0.20
0.07
0.03
−0.15
0.03
−0.06

CD44/3E
0.38
0.16
−0.01
−0.38
0.34
−0.19
0.01
−0.27
−0.30
−0.19

CD44/3s
0.05
0.04
−0.05
−0.15
0.35
−0.08
−0.26
−0.07
−0.31
0.07

Jagged-1
−0.06
−0.01
0.04
0.13
0.09
0.14
0.31
−0.05
−0.17
−0.08

p94-WT
−0.41
0.47
0.02
0.10
0.25
−0.20
0.18
−0.13
−0.02
0.18

p94-mut
−0.28
0.26
0.07
−0.02
−0.24
−0.23
−0.15
−0.05
−0.05
0.07

E2F-High
0.03
0.12
0.04
−0.07
0.03
−0.10
−0.12
−0.17
−0.14
0.19

14-3-3zWT
−0.12
0.08
−0.02
−0.17
0.08
0.13
0.00
0.11
0.19
0.44

PKCepsil
TPA (PKC-)
Akt-DN
ERK-DN
JNK-DN
p38-DN
cAMP-PK-
14-3-3W
TK
caspase-1

14-3-3zWT
0.07
0.33
0.13
0.21
0.09
0.17
0.13
1.00

TK
−0.06
−0.26
0.08
−0.26
−0.23
−0.22
−0.27
−0.02
1.00

caspase-1
−0.46
0.10
−0.17
0.33
0.01
0.12
−0.09
−0.30
−0.02
1.00

caspase-3
−0.31
0.21
−0.12
0.60
0.15
0.21
0.19
0.01
−0.02
0.49

caspase-2
−0.03
0.19
−0.03
0.41
0.27
0.30
−0.01
0.20
−0.25
−0.09

cystatin alpha
−0.05
0.05
0.23
0.46
0.15
0.26
0.29
−0.14
−0.12
0.69

cystatin E
0.16
0.01
0.57
0.41
0.13
0.27
0.02
0.23
0.19
0.20

u-calpain
−0.10
−0.03
0.23
0.35
0.48
0.41
−0.16
0.04
−0.16
0.18

m-calpain
0.00
0.16
−0.15
0.23
0.24
0.15
0.43
0.10
−0.25
0.06

calpain 30K (N)
0.24
−0.02
0.13
−0.50
−0.19
−0.23
−0.10
0.05
−0.08
−0.48

calpain 30K (F)
−0.44
−0.01
0.24
0.20
0.10
0.03
−0.11
0.21
0.14
0.15

calpastatin
0.44
−0.29
0.00
−0.49
−0.25
−0.19
−0.11
0.08
0.32
−0.34

CP-antisense
0.06
0.08
0.11
0.68
0.06
0.60
0.03
0.17
−0.16
0.16

BH
0.05
0.05
0.26
−0.01
0.15
0.25
−0.26
0.23
0.17
−0.23

DAN
−0.21
0.19
−0.01
0.47
0.22
0.23
0.16
0.16
−0.06
0.22

Regucalcin
0.65
0.11
0.35
0.02
0.24
0.34
0.14
0.25
−0.06
−0.36

CathL-mut
−0.10
0.11
−0.21
0.00
0.07
0.11
−0.02
0.43
0.08
−0.26

STAT1
0.04
0.23
0.12
0.11
0.29
−0.05
0.52
0.09
0.07
0.07

CBP
−0.14
−0.14
−0.25
0.56
−0.03
0.17
−0.01
0.12
−0.05
0.34

P/CAF
−0.21
0.02
−0.14
0.16
0.00
−0.14
−0.13
0.06
0.25
−0.01

HNF1
−0.03
0.06
0.25
0.17
0.07
−0.06
0.32
0.15
0.17
0.09

HNF3b
0.26
0.02
0.21
0.07
0.16
0.25
−0.08
0.38
0.19
−0.31

HNF4
−0.01
0.09
0.15
0.11
0.26
0.13
−0.05
0.24
0.02
−0.21

coup
−0.17
0.10
0.05
0.64
0.12
0.42
0.24
0.22
−0.04
0.19

C/EBPa
−0.07
0.02
−0.08
0.27
−0.02
0.09
0.02
−0.05
0.37
0.22

C/EBPb
−0.09
0.05
−0.01
0.47
0.04
0.05
0.13
0.12
0.01
−0.04

per-1
0.30
0.24
0.39
0.14
0.47
0.45
−0.04
0.27
−0.18
−0.13

p33/ING1
−0.20
−0.08
−0.30
0.13
−0.10
−0.08
0.11
−0.12
0.16
0.03

T.Tn
0.02
−0.31
0.05
−0.29
−0.20
−0.22
−0.06
−0.18
0.40
0.07

CD44/H-CAM
0.21
−0.09
0.15
0.07
0.07
0.07
0.27
0.07
−0.12
−0.22

CD44/3E
0.00
−0.19
−0.09
−0.07
−0.19
−0.21
−0.19
−0.07
0.01
−0.08

CD44/3s
−0.31
−0.18
−0.12
−0.01
−0.24
−0.18
−0.21
0.05
0.11
−0.15

Jagged-1
−0.18
−0.05
−0.29
0.00
−0.11
0.07
−0.07
−0.09
−0.06
0.26

p94-WT
−0.29
0.23
−0.25
0.19
0.27
0.17
−0.07
0.32
−0.07
−0.06

p94-mut
−0.09
0.23
0.13
−0.11
0.44
0.02
0.12
0.15
−0.17
−0.29

E2F-High
−0.13
0.09
0.32
−0.03
0.11
0.03
−0.01
0.41
−0.08
−0.16

14-3-3zWT
0.07
0.33
0.13
0.21
0.09
0.17
0.13
1.00

indicates data missing or illegible when filed

TABLE 8

PDGF-R
PDGF-R-D
Glucocor
RhoA
RhoA-DN
CaMKIIa
CaMKIIa-Ac
PKCalpha
PKCalpha
PKCepsil

E2F-Low
−0.07
−0.19
0.05
−0.10
−0.25
0.10
−0.16
−0.33
−0.22
0.17

FBRCA1-13
0.00
−0.29
−0.16
0.09
0.03
0.07
−0.08
0.24
−0.11
0.02

FMDM2hwt-6
−0.04
−0.31
−0.12
−0.09
−0.01
0.15
−0.08
0.10
−0.08
−0.19

p27-3
−0.49
0.23
0.08
0.27
0.19
0.24
0.18
−0.08
−0.21
0.30

CAPN10-10
−0.06
0.47
0.25
0.13
−0.13
−0.09
0.19
−0.32
0.07
−0.05

c-myc-1
−0.21
0.37
0.18
−0.03
−0.08
−0.04
0.17
−0.17
0.04
−0.01

MSSP-10
−0.23
−0.41
−0.17
−0.18
0.02
0.28
0.14
−0.15
−0.26
0.01

MM1
0.28
0.18
−0.15
0.26
0.29
−0.26
0.27
0.15
−0.05
0.14

AMY1
−0.18
0.28
0.25
0.15
−0.05
0.00
0.11
−0.14
0.09
0.25

Max
0.00
0.21
0.12
0.24
0.04
−0.03
0.10
0.01
−0.07
0.21

MDM2-hmut
−0.16
0.48
0.23
0.34
0.33
−0.17
0.31
0.00
0.11
0.23

MDM2-mWT
0.08
0.02
0.05
−0.01
−0.19
−0.19
0.12
−0.10
0.06
0.07

TERT-WT
0.02
−0.09
−0.06
−0.05
−0.32
−0.22
−0.34
0.19
−0.11
0.15

TERT-DN
0.45
0.30
0.11
0.21
0.14
−0.30
0.18
0.08
−0.06
0.00

PTEN-WT
0.05
0.28
0.39
0.14
0.05
−0.04
0.15
−0.07
−0.14
0.16

PTEN-A3
−0.32
0.08
0.01
0.14
−0.01
0.10
0.03
−0.11
0.08
0.17

PTEN-G129R
−0.01
0.10
0.37
0.24
−0.27
0.00
0.07
−0.16
−0.05
−0.01

Bcl-2
−0.10
0.19
−0.03
0.03
0.19
0.02
0.00
0.05
0.01
0.20

per2
0.18
0.47
0.27
0.13
0.15
0.08
0.19
−0.14
0.27
−0.02

per3
0.15
0.31
0.42
0.31
0.04
0.23
0.21
−0.06
0.37
−0.09

Cyclin D1-11
0.27
−0.18
0.05
0.11
−0.09
0.21
0.04
−0.23
−0.24
−0.18

STAT2-4
−0.10
0.14
0.29
−0.06
−0.19
0.31
0.13
−0.14
0.09
0.10

TSC1-4
−0.36
0.17
0.03
0.27
0.33
0.15
−0.04
0.32
0.25
0.54

Bad-22
0.13
0.24
0.04
0.37
0.35
0.11
0.00
0.09
0.25
0.14

FAPP-4
−0.06
−0.26
−0.15
−0.34
−0.24
0.22
−0.25
−0.20
−0.28
0.06

FHO-6
−0.20
0.48
0.26
0.25
0.34
0.34
0.41
−0.01
0.23
0.24

F25 + lactacystin
−0.09
0.44
0.09
0.31
0.40
0.04
0.33
0.13
0.23
0.17

F25 + ONO5046
−0.46
0.10
−0.09
0.05
0.16
0.17
0.09
0.02
−0.07
0.09

F25 + CA-074
−0.30
0.06
−0.17
0.04
0.14
0.30
0.12
−0.18
−0.01
0.09

F25 + PQQ
−0.39
−0.09
−0.18
−0.01
0.05
0.34
0.22
−0.15
−0.16
−0.02

F25 + PD98059
−0.06
0.29
0.09
0.08
−0.32
−0.23
0.05
−0.29
0.05
−0.09

F25 + ALLN
−0.03
0.33
−0.11
0.16
0.15
−0.25
−0.02
0.25
0.41
0.11

F25 + ONO3403
−0.45
0.50
0.12
0.25
0.52
0.10
0.19
0.02
0.33
0.41

F25 + Y27632
−0.08
0.43
0.20
0.16
0.23
0.24
0.24
−0.17
0.41
0.07

PKCepsil
TPA (PKC-)
Akt-DN
ERK-DN
JNK-DN
p38-DN
cAMP-PK-
14-3-3zw
TK
caspase-1

E2F-Low
−0.01
−0.05
0.30
−0.18
−0.38
−0.32
−0.02
0.34
0.18
−0.04

FBRCA1-13
0.02
−0.17
−0.09
−0.04
−0.17
−0.01
−0.23
−0.05
−0.25
−0.15

FMDM2hwt-6
0.16
−0.16
−0.12
−0.31
0.03
0.08
−0.35
−0.01
−0.19
−0.08

p27-3
−0.20
−0.06
−0.15
0.34
0.09
0.13
−0.05
0.20
−0.05
0.04

CAPN10-10
−0.08
0.10
0.23
0.30
0.25
0.01
0.31
0.03
0.31
0.23

c-myc-1
0.04
0.26
0.22
0.28
0.41
0.32
0.23
0.22
−0.08
0.15

MSSP-10
−0.07
−0.16
−0.10
−0.17
−0.31
0.02
−0.34
0.18
−0.13
−0.01

MM1
−0.08
0.33
0.20
0.32
0.13
0.10
0.20
0.16
−0.31
0.11

AMY1
0.00
0.19
−0.06
0.18
−0.20
−0.09
0.36
0.21
0.21
0.03

Max
−0.11
0.03
−0.19
0.26
−0.21
−0.13
0.25
0.02
0.24
0.18

MDM2-hmut
−0.27
0.36
0.17
0.53
0.08
0.24
0.30
0.20
−0.01
0.18

MDM2-mWT
0.03
0.26
0.52
0.07
−0.16
0.07
0.28
0.31
−0.06
0.02

TERT-WT
0.02
0.11
0.00
−0.15
−0.13
−0.03
0.23
0.00
−0.10
−0.15

TERT-DN
−0.19
0.02
0.11
0.29
0.03
−0.15
0.24
−0.09
0.12
0.21

PTEN-WT
−0.15
0.08
−0.09
0.17
0.01
−0.16
0.25
−0.06
−0.11
0.32

PTEN-A3
−0.06
0.12
−0.24
0.17
0.16
0.02
0.13
−0.11
−0.06
0.26

PTEN-G129R
−0.08
−0.02
0.26
0.00
−0.08
−0.34
0.18
0.01
0.21
0.15

Bcl-2
−0.20
0.20
−0.16
0.27
0.02
0.15
0.18
0.01
−0.02
0.02

per2
0.13
0.24
0.03
0.19
0.25
−0.02
0.40
−0.01
0.16
0.05

per3
0.22
0.25
−0.02
−0.03
0.21
−0.08
0.38
0.04
0.17
−0.05

Cyclin D1-11
0.01
−0.23
−0.15
−0.36
−0.30
−0.39
−0.07
−0.11
0.16
−0.10

STAT2-4
0.28
0.12
−0.37
−0.08
0.15
0.01
0.41
0.11
−0.12
−0.12

TSC1-4
−0.01
0.36
−0.10
0.36
0.32
0.37
0.29
0.32
−0.25
−0.15

Bad-22
−0.03
−0.26
−0.02
0.13
0.17
0.14
−0.04
0.07
0.19
0.00

FAPP-4
0.03
−0.03
0.04
−0.28
−0.09
−0.24
0.01
0.25
0.10
−0.21

FHO-6
0.05
0.28
−0.23
0.31
0.43
0.23
0.26
0.26
−0.20
0.05

F25 + lactacystin
−0.15
0.31
−0.22
0.29
0.21
0.20
0.21
0.37
−0.21
0.05

F25 + ONO5046
−0.16
0.15
−0.28
0.15
0.11
0.29
0.03
0.17
−0.07
−0.13

F25 + CA-074
−0.07
0.12
−0.28
0.03
−0.05
0.11
0.12
0.19
−0.08
−0.04

F25 + PQQ
−0.06
0.00
−0.30
−0.07
−0.08
0.08
−0.02
0.03
−0.12
0.00

F25 + PD98059
−0.01
−0.03
0.12
0.04
0.14
−0.05
0.22
0.03
0.22
0.05

F25 + ALLN
0.16
0.26
0.00
0.37
0.52
0.41
0.17
0.07
−0.17
0.09

F25 + ONO3403
−0.13
0.30
−0.16
0.53
0.30
0.51
0.22
0.38
−0.24
0.03

F25 + Y27632
0.11
0.14
0.28
0.37
0.21
0.23
0.18
0.29
0.10
0.06

indicates data missing or illegible when filed

TABLE 9

caspase-3
caspase-2
cystatin al
cystatin E
u-calpain
m-calpain
calpain 30K
calpain 30K

caspase-3
1.00

caspase-2
0.41
1.00

cystatin alpha
0.56
0.09
1.00

cystatin E
0.32
0.33
0.54
1.00

u-calpain
0.25
0.31
0.37
0.27
1.00

m-calpain
0.45
0.23
0.52
0.08
0.41
1.00

calpain 30K (N)
−0.43
0.03
−0.40
−0.37
−0.16
−0.25
1.00

calpain 30K (F)
0.12
0.18
0.21
0.43
0.55
0.14
0.13
1.00

calpastatin
−0.53
−0.17
−0.35
−0.21
−0.18
−0.23
0.14
−0.20

CP-antisense
0.38
0.25
0.28
0.31
0.09
−0.02
−0.28
0.01

BH
−0.18
0.08
−0.24
0.30
0.31
−0.12
−0.26
0.23

DAN
0.68
0.69
0.54
0.45
0.33
0.35
−0.37
0.32

Regucalcin
−0.16
0.02
−0.04
0.21
0.37
0.24
0.17
0.14

CathL-mut
−0.20
−0.04
−0.39
0.01
−0.13
0.01
−0.09
0.00

STAT1
0.40
−0.01
0.22
0.23
0.20
0.37
−0.10
0.11

CBP
0.41
0.10
0.32
0.32
0.16
0.17
−0.42
0.24

P/CAF
0.21
0.27
0.02
0.04
0.28
0.32
0.32
0.34

HNF1
0.44
−0.10
0.34
0.20
0.24
0.40
−0.42
0.13

HNF3b
0.06
0.13
−0.11
0.17
−0.01
0.02
0.27
−0.01

HNF4
−0.15
−0.05
−0.09
−0.08
0.04
−0.15
−0.37
0.01

coup
0.42
0.06
0.35
0.35
0.31
0.34
−0.66
0.20

C/EBPa
0.50
0.27
0.51
0.40
0.21
0.04
−0.26
0.19

C/EBPb
0.40
0.22
−0.07
0.02
0.17
0.20
0.02
0.14

per-1
−0.06
0.35
0.13
0.25
0.27
0.06
0.24
0.14

p33/ING1
0.12
−0.15
−0.03
−0.21
0.17
0.23
0.10
0.22

T.Tn
−0.24
−0.39
0.09
−0.07
−0.10
−0.16
−0.07
0.00

CD44/H-CAM
−0.21
−0.06
−0.20
−0.12
0.14
0.01
0.34
0.24

CD44/3E
−0.16
0.21
−0.29
0.04
0.09
−0.17
0.31
0.32

CD44/3s
−0.03
0.10
−0.25
−0.06
0.17
−0.02
0.43
0.45

Jagged-1
−0.03
−0.15
0.25
0.10
−0.01
−0.11
−0.37
0.04

p94-WT
0.29
0.24
−0.17
−0.09
0.36
0.41
−0.11
0.30

p94-mut
−0.06
0.08
−0.21
−0.06
0.22
0.25
0.02
0.13

E2F-High
−0.02
0.09
0.03
0.26
0.46
0.30
0.15
0.50

calpastatin
CP-antisens
BH
DAN
Regucalc
CathL-mut
STAT1
CBP
P/CAF
HNF1

caspase-3

caspase-2

cystatin alpha

cystatin E

u-calpain

m-calpain

calpain 30K (N)

calpain 30K (F)

calpastatin
1.00

CP-antisense
−0.19
1.00

BH
0.13
0.04
1.00

DAN
−0.36
0.35
−0.03
1.00

Regucalcin
0.16
0.13
0.47
−0.05
1.00

CathL-mut
0.31
0.11
0.27
−0.13
0.20
1.00

STAT1
−0.20
−0.17
0.05
0.13
0.08
−0.14
1.00

CBP
−0.35
0.42
0.19
0.26
0.14
0.13
0.17
1.00

P/CAF
−0.10
−0.11
−0.07
0.33
0.05
−0.15
−0.04
0.05
1.00

HNF1
−0.21
0.02
0.03
0.28
0.20
−0.14
0.44
0.16
0.15
1.00

HNF3b
0.22
0.29
0.17
0.17
0.30
0.40
−0.08
−0.11
−0.02
0.16

HNF4
−0.05
0.09
0.33
−0.01
0.10
0.17
−0.11
0.04
−0.16
0.22

coup
−0.24
0.54
0.21
0.26
0.22
0.16
0.15
0.45
0.11
0.53

C/EBPa
−0.14
0.31
−0.10
0.67
−0.08
−0.30
0.02
0.08
0.39
0.20

C/EBPb
−0.40
0.30
−0.28
0.36
−0.15
−0.17
0.08
0.11
0.26
0.34

per-1
−0.07
0.09
0.05
0.17
0.33
0.01
−0.03
−0.24
−0.02
−0.06

p33/ING1
−0.31
−0.01
−0.20
0.10
0.09
−0.08
0.08
0.32
0.50
0.25

T.Tn
0.27
−0.19
−0.10
−0.18
−0.14
−0.26
−0.10
−0.16
−0.06
0.18

CD44/H-CAM
−0.07
0.16
−0.06
0.09
0.12
0.05
0.08
0.18
−0.05
−0.15

CD44/3E
−0.05
−0.08
0.13
0.14
0.01
−0.35
−0.11
0.38
0.19
−0.17

CD44/3s
−0.08
0.06
0.11
0.19
0.04
0.05
−0.14
0.32
0.32
−0.10

Jagged-1
0.09
0.06
0.18
−0.06
−0.08
0.29
−0.01
0.41
−0.39
−0.13

p94-WT
−0.12
−0.06
0.15
0.08
0.10
0.16
0.15
0.16
0.25
0.30

p94-mut
−0.03
−0.33
0.09
−0.17
0.07
0.16
0.30
−0.34
−0.02
0.11

E2F-High
−0.07
−0.23
0.35
0.12
0.37
0.12
0.20
−0.03
0.15
0.33

indicates data missing or illegible when filed

TABLE 10

caspase-3
caspase-2
cystatin al
cystatin E
u-calpain
m-calpain
calpain 30K
calpain 30K
calpastatin

E2F-Low
−0.04
−0.19
−0.07
0.20
0.06
−0.04
−0.06
0.27
0.19

FBRCA1-13
−0.04
0.02
−0.30
−0.14
0.01
−0.15
0.16
0.03
−0.01

FMDM2hwt-6
−0.39
−0.13
−0.19
−0.12
0.04
−0.24
0.07
−0.08
0.38

p27-3
0.29
0.05
−0.13
0.07
0.13
0.09
−0.51
0.18
−0.06

CAPN10-10
0.44
−0.01
0.37
0.32
0.21
0.18
−0.30
0.24
−0.28

c-myc-1
0.26
0.13
0.25
0.36
0.38
0.27
−0.55
0.15
−0.29

MSSP-10
−0.26
−0.23
−0.21
0.01
0.03
−0.22
−0.02
0.10
0.35

MM1
0.32
0.17
0.30
0.41
0.33
0.27
−0.25
0.26
−0.57

AMY1
0.35
−0.08
0.16
0.16
−0.05
0.32
−0.09
0.03
−0.19

Max
0.39
−0.10
0.34
0.18
−0.05
0.23
−0.14
0.15
−0.25

MDM2-hmut
0.61
0.26
0.40
0.31
0.36
0.41
−0.22
0.37
−0.48

MDM2-mWT
0.16
0.08
0.28
0.55
0.01
0.11
−0.15
0.07
−0.17

TERT-WT
−0.06
−0.08
−0.13
−0.05
−0.13
0.13
0.28
−0.21
0.00

TERT-DN
0.50
0.30
0.39
0.30
0.29
0.32
−0.09
0.38
−0.49

PTEN-WT
0.44
−0.06
0.22
−0.22
0.27
0.38
−0.22
−0.03
−0.21

PTEN-A3
0.32
−0.06
0.26
−0.08
−0.22
0.24
−0.07
−0.12
−0.42

PTEN-G129R
0.45
−0.08
0.29
0.11
0.16
0.24
−0.09
0.14
−0.17

Bcl-2
0.21
0.14
0.05
0.18
−0.01
0.24
−0.11
−0.01
−0.32

per2
0.23
0.15
0.21
0.18
0.24
0.42
−0.07
0.14
−0.18

per3
0.13
−0.02
0.20
0.11
0.18
0.41
−0.07
0.02
0.03

Cyclin D1-11
−0.25
−0.35
0.01
−0.24
−0.13
−0.07
0.05
0.00
0.25

STAT2-4
−0.18
−0.17
−0.08
−0.08
−0.20
0.15
−0.52
−0.36
0.30

TSC1-4
0.25
0.30
−0.19
0.07
0.23
0.39
0.31
0.16
−0.27

Bad-22
0.15
0.07
0.25
0.01
0.50
0.36
0.11
0.37
0.04

FAPP-4
−0.54
−0.21
−0.28
0.03
−0.12
−0.18
0.05
0.03
0.39

FHO-6
0.13
0.01
−0.01
−0.21
0.26
0.39
−0.17
0.03
−0.01

F25 + lactacystin
0.34
0.38
0.37
0.05
0.25
0.45
−0.23
0.10
−0.20

F25 + ONO5046
0.01
0.17
−0.07
−0.06
−0.02
−0.14
−0.17
−0.11
0.18

F25 + CA-074
−0.09
−0.17
−0.08
−0.06
−0.02
0.02
−0.30
−0.05
0.25

F25 + PQQ
−0.23
−0.36
−0.21
−0.21
−0.14
−0.08
−0.24
−0.14
0.30

F25 + PD98059
0.16
0.02
0.37
0.19
−0.04
0.06
−0.39
−0.07
−0.10

F25 + ALLN
0.32
0.41
0.26
0.08
0.16
0.22
−0.17
−0.09
−0.31

F25 + ONO3403
0.47
0.28
0.19
0.05
0.26
0.52
−0.41
0.17
−0.40

F25 + Y27632
0.40
0.17
0.30
0.39
0.28
0.25
−0.37
0.36
−0.08

CP-antisens
BH
DAN
Regucalc
CathL-mut
STAT1
CBP
P/CAF
HNF1

E2F-Low
0.01
0.24
0.02
0.27
0.17
0.09
0.14
−0.09
0.41

FBRCA1-13
0.09
−0.06
0.01
0.01
−0.14
−0.31
−0.03
−0.05
−0.09

FMDM2hwt-6
−0.15
0.19
−0.31
0.21
0.15
−0.26
−0.12
−0.33
−0.40

p27-3
0.33
0.23
0.26
−0.03
0.25
0.11
0.48
−0.09
0.33

CAPN10-10
0.07
−0.14
0.25
−0.10
−0.16
0.52
0.11
0.18
0.56

c-myc-1
0.10
0.09
0.20
0.03
0.15
0.35
0.10
−0.18
0.40

MSSP-10
0.01
0.35
−0.21
0.23
0.29
−0.23
0.13
−0.24
−0.21

MM1
0.22
0.01
0.47
0.08
−0.14
−0.01
0.13
0.19
0.32

AMY1
0.25
−0.07
0.17
0.06
0.11
0.29
0.22
0.26
0.45

Max
0.15
−0.24
0.26
−0.10
0.02
0.18
0.22
0.25
0.35

MDM2-hmut
0.43
0.01
0.55
0.17
−0.05
0.33
0.32
0.22
0.50

MDM2-mWT
0.27
0.05
0.16
0.16
0.03
0.22
−0.03
−0.14
0.44

TERT-WT
0.00
−0.18
−0.22
−0.06
0.11
0.00
−0.37
−0.14
0.05

TERT-DN
−0.02
−0.29
0.58
−0.19
−0.41
0.18
0.04
0.50
0.45

PTEN-WT
0.02
−0.21
0.23
−0.08
−0.34
0.26
0.06
0.22
0.42

PTEN-A3
−0.07
−0.37
0.15
−0.17
−0.12
0.07
0.13
0.22
0.02

PTEN-G129R
−0.05
−0.22
0.37
−0.01
−0.34
0.40
0.01
0.28
0.78

Bcl-2
0.20
−0.04
0.23
0.01
0.26
0.04
0.11
0.25
0.09

per2
−0.07
0.02
0.22
0.12
−0.09
0.34
0.16
0.44
0.21

per3
−0.23
0.16
0.03
0.24
−0.06
0.40
0.13
0.25
0.18

Cyclin D1-11
−0.38
0.11
−0.20
0.13
−0.16
0.05
0.00
0.07
0.04

STAT2-4
−0.18
0.20
−0.26
0.12
0.43
0.26
0.10
−0.35
0.04

TSC1-4
0.26
0.13
0.39
0.23
0.31
0.09
0.18
0.22
0.02

Bad-22
−0.02
0.07
0.30
0.27
0.16
0.05
0.20
0.30
0.22

FAPP-4
−0.20
0.26
−0.26
0.04
0.40
−0.09
−0.17
−0.04
−0.11

FHO-6
−0.02
0.03
0.00
0.29
0.12
0.27
0.22
0.14
0.18

F25 + lactacystin
0.10
0.14
0.41
0.13
0.08
0.10
0.30
0.28
0.28

F25 + ONO5046
0.09
0.31
0.17
0.02
0.34
0.02
0.09
−0.17
−0.09

F25 + CA-074
0.10
0.34
−0.11
0.20
0.42
−0.08
0.22
−0.19
−0.08

F25 + PQQ
0.05
0.24
−0.31
0.13
0.42
−0.17
0.18
−0.38
−0.12

F25 + PD98059
−0.10
−0.03
0.02
−0.17
0.00
0.34
−0.07
−0.14
0.31

F25 + ALLN
0.18
−0.21
0.29
−0.08
−0.07
−0.04
−0.15
0.06
0.04

F25 + ONO3403
0.41
0.15
0.39
0.22
0.10
0.12
0.45
0.20
0.24

F25 + Y27632
0.29
0.23
0.30
0.32
−0.02
0.30
0.40
0.16
0.54

indicates data missing or illegible when filed

TABLE 11

HNF3b
HNF4
coup
C/EBPa
C/EBPb
per-1
p33/ING1

HNF3b
1.00

HNF4
0.06
1.00

coup
0.01
0.17
1.00

C/EBPa
0.19
−0.11
0.20
1.00

C/EBPb
0.10
−0.02
0.34
0.40
1.00

per-1
0.47
0.11
−0.25
0.01
−0.06
1.00

p33/ING1
−0.29
−0.11
0.32
0.25
0.31
−0.31
1.00

T.Tn
0.02
0.17
−0.12
0.16
−0.04
−0.01
−0.10

CD44/H-CAM
−0.23
0.06
0.10
−0.06
0.09
−0.11
0.45

CD44/3E
−0.24
−0.11
−0.27
0.02
0.02
−0.10
0.16

CD44/3s
−0.01
−0.05
−0.10
0.08
0.11
−0.16
0.31

Jagged-1
−0.11
−0.02
0.09
0.04
−0.28
−0.12
−0.01

p94-WT
0.04
0.02
0.39
−0.01
0.22
−0.16
0.23

p94-mut
0.04
0.06
0.07
−0.26
0.06
0.02
−0.06

E2F-High
0.25
−0.02
0.12
−0.15
0.10
0.14
−0.06

T.Tn
CD44/H-CAM
CD44/3E
CD44/3s
Jagged-1
p94-WT
p94-mut
E2F-High

HNF3b

HNF4

coup

C/EBPa

C/EBPb

per-1

p33/ING1

T.Tn
1.00

CD44/H-CAM
−0.11
1.00

CD44/3E
0.10
0.18
1.00

CD44/3s
0.01
0.19
0.67
1.00

Jagged-1
0.01
−0.01
0.17
0.08
1.00

p94-WT
−0.27
−0.11
0.04
0.14
0.04
1.00

p94-mut
−0.24
0.00
−0.22
−0.20
−0.20
0.62
1.00

E2F-High
−0.10
−0.10
0.15
0.28
−0.13
0.39
0.36
1.00

TABLE 12

HNF3b
HNF4
coup
C/EBPa
C/EBPb
per-1
p33/ING1
T.Tn

E2F-Low
0.24
0.10
0.11
−0.09
−0.04
−0.14
−0.12
0.09

FBRCA1-13
0.04
0.10
−0.21
0.02
−0.09
0.06
0.03
−0.07

FMDM2hwt-6
0.11
0.03
−0.43
−0.17
−0.47
0.27
−0.27
−0.01

p27-3
0.13
0.29
0.52
−0.03
0.05
−0.27
0.14
−0.10

CAPN10-10
−0.06
0.02
0.47
0.32
0.46
−0.18
0.27
0.09

c-myc-1
−0.01
0.16
0.46
−0.08
0.24
0.07
−0.03
−0.07

MSSP-10
0.02
−0.12
−0.02
−0.23
−0.39
−0.18
−0.12
−0.10

MM1
−0.13
−0.01
0.42
0.23
0.45
−0.06
0.28
−0.23

AMY1
0.07
0.06
0.47
0.28
0.22
−0.28
0.37
0.01

Max
0.07
−0.08
0.30
0.34
0.24
−0.24
0.34
0.08

MDM2-hmut
0.18
0.04
0.61
0.45
0.56
0.08
0.26
−0.12

MDM2-mWT
0.26
−0.06
0.34
0.11
0.23
0.15
−0.22
0.02

TERT-WT
0.11
−0.07
−0.06
−0.19
−0.01
−0.04
−0.15
0.01

TERT-DN
−0.17
−0.16
0.22
0.55
0.62
−0.04
0.36
0.01

PTEN-WT
−0.21
−0.10
0.23
0.08
0.29
−0.29
0.18
0.14

PTEN-A3
−0.09
−0.10
−0.02
0.04
−0.06
−0.05
0.23
−0.10

PTEN-G129R
0.04
0.01
0.21
0.25
0.27
−0.11
0.22
0.19

Bcl-2
0.09
−0.02
0.28
0.14
0.24
−0.02
0.22
−0.05

per2
−0.27
0.02
0.32
0.16
0.14
−0.07
0.36
0.03

per3
−0.23
0.12
0.15
0.08
−0.18
−0.02
0.18
0.18

Cyclin D1-11
−0.13
−0.02
−0.34
−0.02
−0.30
−0.13
0.15
0.16

STAT2-4
−0.14
0.23
0.10
−0.30
−0.29
−0.17
−0.10
−0.05

TSC1-4
0.20
0.03
0.29
−0.05
0.04
0.14
0.17
−0.30

Bad-22
0.22
−0.03
0.19
0.24
0.16
0.11
0.33
0.10

FAPP-4
0.07
0.05
−0.02
−0.28
−0.18
−0.12
−0.16
0.06

FHO-6
0.05
0.03
0.32
−0.11
−0.01
0.14
0.17
−0.04

F25 + lactacystin
0.06
0.10
0.39
0.19
0.05
0.02
0.15
−0.12

F25 + ONO5046
0.18
0.00
0.21
0.12
−0.09
−0.05
0.00
−0.08

F25 + CA-074
−0.06
0.10
0.30
−0.02
−0.26
−0.30
0.04
−0.08

F25 + PQQ
−0.02
0.11
0.21
−0.28
−0.35
−0.24
−0.01
0.05

F25 + PD98059
−0.07
−0.01
0.26
0.12
0.16
−0.16
−0.04
0.04

F25 + ALLN
0.11
0.13
0.19
0.22
0.30
0.20
−0.06
−0.16

F25 + ONO3403
0.17
0.12
0.47
0.17
0.22
0.04
0.16
−0.30

F25 + Y27632
0.20
0.30
0.45
0.25
0.16
0.16
0.10
−0.06

CD44/H-CAM
CD44/3E
CD44/3s
Jagged-1
p94-WT
p94-mut
E2F-High

E2F-Low
−0.05
0.14
0.31
−0.03
0.06
−0.09
0.57

FBRCA1-13
0.03
0.22
0.22
0.12
0.02
−0.13
−0.12

FMDM2hwt-6
−0.11
0.17
0.01
0.47
−0.05
−0.06
−0.13

p27-3
0.16
0.05
0.19
0.33
0.39
−0.04
0.01

CAPN10-10
0.12
−0.23
−0.19
−0.24
0.26
0.32
0.13

c-myc-1
0.21
−0.25
−0.29
0.03
0.31
0.31
0.23

MSSP-10
−0.03
0.09
0.13
0.38
0.09
−0.08
0.17

MM1
0.31
−0.03
0.05
−0.12
0.16
0.00
0.16

AMY1
0.06
−0.23
−0.03
−0.20
0.10
−0.01
0.00

Max
0.11
0.01
0.18
−0.09
−0.07
−0.23
−0.03

MDM2-hmut
0.12
−0.12
0.12
−0.11
0.29
0.07
0.25

MDM2-mWT
−0.18
−0.14
−0.16
−0.15
−0.09
0.05
0.35

TERT-WT
−0.15
−0.17
0.08
−0.34
−0.09
0.17
0.09

TERT-DN
0.09
0.13
0.12
−0.35
0.01
−0.01
0.14

PTEN-WT
−0.06
−0.04
0.00
−0.33
0.12
0.03
0.06

PTEN-A3
−0.08
−0.30
−0.32
−0.33
0.04
0.14
−0.16

PTEN-G129R
−0.17
−0.11
0.03
−0.35
0.05
−0.01
0.10

Bcl-2
0.14
−0.05
0.08
−0.15
−0.08
0.03
−0.01

per2
0.28
−0.03
−0.13
−0.24
0.11
0.16
−0.03

per3
0.14
−0.01
−0.02
0.02
0.15
0.10
−0.08

Cyclin D1-11
0.00
0.37
0.20
0.10
−0.15
−0.14
0.06

STAT2-4
0.01
−0.17
−0.39
0.41
0.01
0.08
−0.12

TSC1-4
0.28
−0.19
0.13
−0.09
0.25
0.02
0.10

Bad-22
0.20
−0.04
0.33
0.03
0.22
−0.07
0.22

FAPP-4
0.05
−0.07
−0.05
0.01
−0.13
0.04
0.25

FHO-6
0.01
−0.16
−0.23
0.01
0.43
0.24
0.04

F25 + lactacystin
0.01
0.09
0.04
0.16
0.44
0.07
0.09

F25 + ONO5046
−0.01
−0.04
0.06
0.42
0.20
−0.01
−0.01

F25 + CA-074
0.21
−0.03
0.20
0.49
0.29
−0.03
0.00

F25 + PQQ
0.09
−0.13
0.01
0.53
0.20
−0.06
−0.18

F25 + PD98059
−0.03
−0.26
−0.36
−0.01
0.21
0.43
0.08

F25 + ALLN
0.00
−0.37
−0.50
−0.15
0.32
0.33
−0.08

F25 + ONO3403
0.06
0.02
0.15
−0.02
0.48
0.13
0.22

F25 + Y27632
0.01
0.00
−0.09
−0.06
0.25
0.03
0.20

TABLE 13

E2F-Low
FBRCA1-13
FMDM2hwt-6
p27-3
CAPN10-10
c-myc-1
MSSP-10
MM1

E2F-Low
1.00

FBRCA1-13
0.08
1.00

FMDM2hwt-6
−0.02
0.48
1.00

p27-3
0.26
0.22
−0.04
1.00

CAPN10-10
0.08
−0.57
−0.70
0.13
1.00

c-myc-1
0.05
−0.37
−0.38
0.36
0.60
1.00

MSSP-10
0.38
0.40
0.59
0.29
−0.47
−0.19
1.00

MM1
0.04
0.00
−0.38
0.23
0.32
0.42
−0.08
1.00

AMY1
0.21
−0.16
−0.57
0.21
0.49
0.16
−0.32
0.29

Max
0.14
0.03
−0.47
0.16
0.33
0.13
−0.23
0.25

MDM2-hmut
0.19
−0.19
−0.51
0.30
0.50
0.40
−0.31
0.47

MDM2-mWT
0.44
−0.14
−0.31
−0.05
0.25
0.34
−0.09
0.29

TERT-WT
0.02
0.10
−0.17
−0.26
−0.04
0.04
−0.22
0.01

TERT-DN
−0.03
−0.10
−0.60
−0.15
0.51
0.18
−0.49
0.53

PTEN-WT
0.10
−0.04
−0.46
0.11
0.33
0.18
−0.18
0.37

PTEN-A3
−0.24
−0.07
−0.39
−0.06
0.20
0.04
−0.21
0.01

PTEN-G129R
0.39
0.04
−0.48
0.21
0.55
0.21
−0.17
0.30

Bcl-2
−0.14
−0.08
−0.39
0.02
0.09
0.21
−0.26
0.19

per2
−0.19
−0.44
−0.56
−0.01
0.50
0.36
−0.48
0.24

per3
−0.16
−0.28
−0.20
0.04
0.23
0.21
−0.26
0.10

Cyclin D1-11
0.21
0.32
0.43
−0.18
−0.36
−0.55
0.30
−0.28

STAT2-4
−0.10
−0.15
0.23
0.16
−0.07
0.23
0.13
−0.20

TSC1-4
−0.09
0.04
−0.29
0.40
0.03
0.34
0.02
0.43

Bad-22
0.04
−0.21
−0.13
0.16
0.27
0.19
−0.08
0.24

FAPP-4
0.34
−0.22
0.08
0.01
−0.05
−0.03
0.28
−0.05

FHO-6
−0.12
0.00
0.09
0.25
0.02
0.14
0.08
0.06

F25 + lactacystin
−0.17
−0.09
−0.11
0.28
0.13
0.27
−0.07
0.39

F25 + ONO5046
−0.07
−0.07
0.14
0.37
−0.06
0.15
0.26
−0.01

F25 + CA-074
0.14
−0.01
0.20
0.43
−0.12
0.12
0.35
0.14

F25 + PQQ
0.03
0.10
0.40
0.52
−0.28
0.08
0.50
−0.03

F25 + PD98059
0.02
−0.56
−0.45
−0.08
0.61
0.45
−0.44
0.05

F25 + ALLN
−0.37
−0.07
−0.27
−0.04
0.29
0.40
−0.44
0.23

F25 + ONO3403
−0.09
0.06
−0.22
0.40
0.11
0.31
−0.05
0.29

F25 + Y27632
0.23
−0.04
−0.17
0.36
0.42
0.34
−0.11
0.10

AMY1
Max
MDM2-hmut
MDM2-mWT
TERT-WT
TERT-DN
PTEN-WT
PTEN-A3

E2F-Low

FBRCA1-13

FMDM2hwt-6

p27-3

CAPN10-10

c-myc-1

MSSP-10

MM1

AMY1
1.00

Max
0.56
1.00

MDM2-hmut
0.54
0.46
1.00

MDM2-mWT
0.36
0.16
0.52
1.00

TERT-WT
0.30
0.37
0.02
0.32
1.00

TERT-DN
0.28
0.48
0.43
0.22
0.06
1.00

PTEN-WT
0.46
0.45
0.27
0.00
0.27
0.44
1.00

PTEN-A3
0.29
0.42
0.11
−0.14
−0.06
0.18
0.16
1.00

PTEN-G129R
0.48
0.48
0.43
0.36
0.09
0.54
0.55
0.18

Bcl-2
0.37
0.64
0.45
0.30
0.38
0.31
0.16
0.40

per2
0.49
0.37
0.29
−0.08
−0.10
0.42
0.32
0.36

per3
0.30
0.16
0.12
−0.19
−0.14
0.05
0.18
0.14

Cyclin D1-11
−0.25
0.19
−0.34
−0.25
−0.02
−0.06
−0.09
−0.07

STAT2-4
0.03
−0.02
−0.28
−0.14
0.06
−0.32
−0.09
−0.10

TSC1-4
0.21
0.15
0.31
−0.06
0.01
0.05
0.18
0.29

Bad-22
0.04
−0.01
0.28
−0.22
−0.21
0.16
0.06
−0.13

FAPP-4
0.10
−0.22
−0.31
0.13
0.07
−0.16
−0.11
−0.31

FHO-6
0.13
−0.02
0.13
−0.15
−0.17
−0.12
0.26
0.16

F25 + lactacystin
0.21
0.08
0.33
0.11
−0.06
0.14
0.13
−0.02

F25 + ONO5046
−0.18
−0.05
0.08
−0.10
−0.24
−0.28
−0.28
−0.16

F25 + CA-074
0.02
0.00
0.06
−0.15
−0.11
−0.41
−0.12
−0.24

F25 + PQQ
−0.13
−0.06
−0.11
−0.24
−0.16
−0.62
−0.16
−0.15

F25 + PD98059
0.21
0.09
0.19
0.28
0.06
0.29
0.03
0.06

F25 + ALLN
0.03
−0.08
0.14
−0.02
0.01
0.27
0.12
0.29

F25 + ONO3403
0.28
0.20
0.55
0.11
0.00
0.08
0.20
0.32

F25 + Y27632
0.27
0.19
0.47
0.25
−0.25
0.13
−0.05
0.12

TABLE 14

PTEN-G129R
Bcl-2
per2
per3
Cyclin D1-
STAT2-4
TSC1-4
Bad-22
FAPP-4

PTEN-G129R
1.00

Bcl-2
0.04
1.00

per2
0.19
0.34
1.00

per3
0.10
0.05
0.78
1.00

Cyclin D1-11
0.04
−0.13
−0.17
0.04
1.00

STAT2-4
−0.28
0.05
0.13
0.30
0.16
1.00

TSC1-4
0.00
0.32
0.32
0.30
−0.42
0.01
1.00

Bad-22
0.18
−0.19
0.16
0.27
−0.13
−0.16
0.37
1.00

FAPP-4
−0.11
−0.16
−0.01
−0.09
0.02
0.28
−0.03
−0.01
1.00

FHO-6
0.03
−0.06
0.33
0.45
0.03
0.25
0.35
0.24
0.11

F25 + lactacystin
0.09
0.13
0.25
0.35
−0.13
0.15
0.37
0.32
−0.05

F25 + ONO5046
−0.29
0.14
−0.15
−0.01
−0.05
0.30
0.26
0.12
0.03

F25 + CA-074
−0.34
−0.01
−0.04
0.23
0.06
0.43
0.24
0.21
0.12

F25 + PQQ
−0.30
−0.07
−0.20
0.09
0.11
0.44
0.14
0.08
0.12

F25 + PD98059
0.15
0.02
0.22
0.06
−0.21
0.15
−0.23
0.01
−0.02

F25 + ALLN
−0.09
0.05
0.24
0.04
−0.55
−0.02
0.28
0.03
−0.22

F25 + ONO3403
0.03
0.35
0.17
0.14
−0.25
0.05
0.57
0.18
−0.32

F25 + Y27632
0.35
0.08
0.28
0.23
−0.01
0.04
0.07
0.12
−0.29

FHO-6

+lactacystin
+ONO5046

+ CA-074
F25 + PQQ

PD98059
F25 + ALLN

+ONO3403

+Y27632

PTEN-G129R

Bcl-2

per2

per3

Cyclin D1-11

STAT2-4

TSC1-4

Bad-22

FAPP-4

FHO-6
1.00

F25 + lactacystin
0.46
1.00

F25 + ONO5046
0.12
0.22
1.00

F25 + CA-074
0.20
0.24
0.62
1.00

F25 + PQQ
0.30
0.10
0.56
0.79
1.00

F25 + PD98059
−0.13
0.04
0.13
0.08
−0.17
1.00

F25 + ALLN
0.16
0.28
0.00
−0.13
−0.27
0.34
1.00

F25 + ONO3403
0.33
0.58
0.17
0.24
0.10
−0.07
0.29
1

F25 + Y27632
0.10
0.25
0.03
0.04
0.00
0.06
0.04
0.46
1

indicates data missing or illegible when filed

From the result of the Tables 3 to 14, there were identified 71 pairs of genes showing positive correlations (r>0.5) and 17 pairs of genes showing negative correlations (r<−0.5). A part of those gene combinations and functional relationship thereof is shown in Table 15.

TABLE 15

r values

1. Combinations of genes belonging to the same family

where correlation is naturally expected

Ha-ras
v.s.
Ki-ras
0.71

Ha-ras
v.s.
N-ras
0.56

Ki-ras
v.s.
N-ras
0.56

v-src
v.s.
erbB2
0.66

cystatin α
v.s.
cystatin E
0.54

PKCα-KN
v.s.
PKCε-KN
0.68

ERK-DN
v.s.
p38-DN
0.63

JNK-DN
v.s.
p38-DN
0.54

caspase-1
v.s.
caspase-3
0.49

Hsdj
v.s.
DnaJ-61
0.40

2. Combination of a transcription factor and the target gene

p53
v.s.
p21
0.56

3. Presence of a product at the downstream of the signal of

another product

Ha-las
->
RhoA-DN
−0.55

N-ras
->
ERK-DN
−0.51

Ras-DN
->
Akt-DN
0.40

IKK-DN
->
IkB-SR
0.75

PDGFR-Δ
->
ERK-DN
0.62

CaMKIIα-active
->
coup
0.56

p53
->
caspase-3
0.52

IkB-SR
->
p53
0.52

IKK-DN
->
p21
0.62

glucocorticoid-R
->
STAT1
0.78

4. Protease and its substrate

m-calpain
->
PDGFR-Δ
0.54

5. Simultaneous expression

p16
v.s.
Bax
0.56

hsp90
v.s.
caspase-3
0.63

JNK-DN
v.s.
μ-calpain
0.48

6. Binding protein

p53
v.s.
MDM2-WT
−0.56

p53
v.s.
MDM2-mutated
0.62

hsp90
v.s.
TERT-DN
0.53

As a result of the above method, there was constructed a gene function database where correlation among the genes having known functions was made clear. By referring to the database, it is now possible to easily elucidate the functions of the gene having unknown functions.

INDUSTRIAL APPLICABILITY

As mentioned in details hereinabove, the invention of this application provides a novel method of analysis of functions of function-unknown genes useful as a genetic material for the Pharmacogenomics and for the manufacture of various useful proteins by means of genetic engineering and also provides a gene function database to be used for the analysis as well as a method for constructing the database.

Number	Date	Country	Kind
2000-378047	Dec 2000	JP	national
2001-375565	Dec 2001	JP	national

	Number	Date	Country
Parent	10450118	Jul 2003	US
Child	12149434		US

Database for analyzing gene function and method of analyzing gene function by DSPA

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