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Endocrinology Vol. 144, No. 10 4276-4279
Copyright © 2003 by The Endocrine Society

BRIEF COMMUNICATION

The WT1 Wilms’ Tumor Suppressor Gene: A Novel Target for Insulin-Like Growth Factor-I Action

Itay Bentov, Derek LeRoith and Haim Werner

Department of Clinical Biochemistry (I.B., H.W.), Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; and Diabetes Branch, National Institute of Diabetes, Digestive, and Kidney Diseases (D.L.), National Institutes of Health, Bethesda, Maryland 20892-1758

Address all correspondence and requests for reprints to: Haim Werner, Ph.D., Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. E-mail: hwerner{at}post.tau.ac.il.

Abstract

IGF-I stimulates cell division in numerous cell types after activation of the IGF-I receptor, a transmembrane heterotetramer linked to the ras-raf-MAPK and phosphatidylinositol 3-kinase signaling pathways. The WT1 Wilms’ tumor suppressor is a zinc finger-containing transcription factor that is involved in a number of developmental processes, as well as in the etiology of certain neoplasias. In the present study, we demonstrated that IGF-I reduced WT1 expression in osteosarcoma-derived Saos-2 cells in a time- and dose-dependent manner. This effect was mediated through the MAPK signaling pathway, as shown by the ability of the specific inhibitor UO126 to abrogate IGF-I action. Furthermore, the effect of IGF-I involved repression of transcription from the WT1 gene promoter, as demonstrated using transient transfection assays. Taken together, our results suggest that the WT1 gene is a novel downstream target for IGF-I action. Reduced levels of WT1 may facilitate IGF-I-stimulated cell cycle progression. Most importantly, inhibition of WT1 gene expression by IGF-I may have significant implications in terms of cancer initiation and/or progression.

THE IGF-I AND IGF-II are a family of polypeptide hormones that regulate growth, differentiation, and the maintenance of differentiated functions in numerous tissues and cell types (1, 2). Most of the biological actions of the IGFs are mediated by the IGF-I receptor (IGF-IR), a transmembrane heterotetramer coupled to several intracellular second messenger pathways, including the ras-raf-MAPK and phosphatidylinositol 3-kinase (PI3K) signaling cascades (3, 4). During the cell cycle, IGF-I functions as a progression factor able to control cellular division by modulating specific events that occur mainly at the G1 phase (5). IGF-I has been shown to stimulate the expression of a number of growth-regulated genes, including c-fos, cyclin-D1, twist, and others (6, 7, 8). Many growth processes, however, have been associated with decreased expression of negative regulators, or tumor suppressors.

The WT1 gene encodes a transcription factor whose mutation or deletion has been linked to the etiology of Wilms’ tumor, a pediatric kidney cancer (9, 10). Accordingly, WT1 has been classified as a tumor suppressor. The WT1 gene product is a nuclear protein of 52–54 kDa that contains an N-terminal transcriptional regulatory and self-association domain, and a C-terminal DNA and RNA binding domain that comprises four zinc fingers of the C2-H2 class (11, 12). Consistent with its tumor suppressor role, we have previously demonstrated that WT1 represses IGF-IR promoter activity in transient transfection assays, binding to consensus sequences in both the 5' flanking and 5' untranslated regions of the IGF-IR gene. In addition, stable expression of WT1 in the kidney tumor cell line G401 resulted in significant reduction in the endogenous levels of IGF-IR mRNA and protein, and inhibition of IGF-I-stimulated growth and colony formation in soft agar (13, 14). Loss of WT1 function (as a result of mutation, deletion, chromosomal rearrangement, or underexpression) may lead to transcriptional derepression of a specific set of target genes, including the IGF-IR. Aberrant expression of some of these genes may constitute a key step in the etiology of Wilms’ tumor, benign prostatic hyperplasia, breast carcinoma, and other malignancies (15, 16, 17).

In addition to its central role in neoplastic events, WT1 participates in a number of cell cycle regulatory mechanisms. Thus, WT1 has been shown to induce G1 arrest and apoptosis in myeloblastic leukemia M1 (18) and osteosarcoma (19) cells; this effect is preceded by induction of the cyclin-dependent kinase inhibitor p21. Paradoxically, WT1 was also demonstrated to induce the expression of antiapoptotic genes such as bcl-2, suggesting that, in certain cellular contexts, WT1 may exhibit oncogenic potential (20). Little information, however, is available regarding the molecular mechanisms responsible for regulating the expression of the WT1 gene itself. Transcription factor Sp1 fulfills an important role in controlling WT1 gene expression (21). Additional transcription factors involved in activation of the WT1 gene are nuclear factor-{kappa}B, PAX2, and PAX8 (22, 23, 24). Furthermore, WT1 is capable of autoregulating expression of its own gene in a negative manner (25). Finally, phosphorylation of WT1 interferes with its nuclear translocation, as well as with DNA binding, thus providing an additional level of regulation of WT1 action (26).

In light of the important role of IGF-I as an antiapoptotic agent, we hypothesized that at least part of the biological activities of IGF-I may be achieved by down-regulating the expression of the proapoptotic WT1 gene product. The results obtained indicate that IGF-I suppressed transcription of the WT1 gene in a dose- and time-dependent manner, via a mechanism that involves the MAPK pathway. Taken together, our data suggest that the WT1 gene is a novel downstream target for IGF-I action. Reduced levels of WT1 may facilitate IGF-I-stimulated cell cycle progression.

Materials and Methods

Cell cultures
The human osteogenic sarcoma-derived cell line Saos-2 was obtained from the American Type Culture Collection (Manassas, VA). Saos-2 cultures were maintained in DMEM with 10% fetal calf serum, 2 mM glutamine, and 50 µg/ml gentamicin sulfate.

Western immunoblots
Cells were serum-starved overnight and then incubated with IGF-I for the indicated periods of time. After incubation, cells were harvested, and lysates were prepared as described previously (27). Protein content of the lysates was determined using the Bradford reagent (Bio-Rad Laboratories, Hercules, CA). Samples were subjected to 10% SDS-PAGE, followed by electrophoretic transfer of the proteins to nitrocellulose membranes. After blocking with 3% BSA in T-TBS [20 mM Tris-HCl (pH 7.5), 135 mM NaCl, and 0.1% Tween 20], blots were incubated with a polyclonal antibody against WT1 (C19, Santa Cruz Biotechnology, Santa Cruz, CA), washed extensively with T-TBS, and incubated with a horseradish peroxidase-conjugated secondary antibody. Proteins were detected using the SuperSignal West Pico Chemiluminescent Substrate (Pierce, Rockford, IL). In addition, blots were probed with antibodies against Erk1, phospho-Erk1/2 (Thr202/Tyr204), Akt, phospho-Akt (Ser473), and actin. The MAPK kinase 1/2-specific inhibitor U0126 was obtained from Calbiochem (San Diego, CA), and the PI3K inhibitor LY294002 was from Sigma (St. Louis, MO).

DNA transfections
For transient transfection experiments, a WT1 promoter-luciferase reporter plasmid, pGLWTpS-P, including nucleotides -873 to +425 (relative to the major transcription site), was used (23). The WT1 construct was kindly provided by Dr. Mike Eccles (University of Otago, Dunedin, New Zealand). Cells were seeded in six-well plates the day before transfection, and transfected with 0.8 µg of the WT1 promoter construct, along with 0.2 µg of a ß-galactosidase expression plasmid (pCMVß, Clontech, Palo Alto, CA), using the Fugene-6 reagent (Roche Molecular Biochemicals, Indianapolis, IN). After transfection, cells were incubated in the absence or presence of IGF-I for 48 h, after which cells were harvested and luciferase and ß-galactosidase were measured as previously described (28).

Results

WT1 has been identified as a transcription factor with tumor suppressor activity (11). Deletion of the WT1 gene has been associated with the etiology of a number of malignancies, including pediatric solid tumors. To investigate whether the biological actions of IGF-I are associated with modulation of WT1 gene expression, human osteosarcoma-derived Saos-2 cells were serum-starved overnight and then stimulated with IGF-I (20 ng/ml) for various time periods, after which WT1 expression was assessed by Western immunoblotting using a specific human WT1 antibody. As shown in Fig. 1Go, IGF-I caused a significant decrease in WT1 levels at 1, 2, and 4 h, whereas at 24 h there was no noticeable effect. Maximal effect was detected after 1 h (~45% decrease). No change was seen in the levels of tubulin.



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  		FIG. 1. Regulation of WT1 levels by IGF-I. Serum-starved Saos-2 cells were incubated with IGF-I (20 ng/ml) for the indicated times. After incubation, cells were lysed as indicated in Materials and Methods, and equal amounts of protein (50 µg) were separated by 10% SDS-PAGE and transferred onto nitrocellulose membranes. Levels of WT1 were determined using a polyclonal antibody against WT1, followed by incubation with an horseradish peroxidase-conjugated secondary antibody. The position of the 52- to 54-kDa WT1 protein is indicated. Membranes were reprobed with a tubulin antibody. The figure shows the result of a typical experiment, repeated between two and four times.

 
To assess the dose dependency of this effect, Saos-2 cells were incubated with increasing concentrations of IGF-I for 4 h. Maximal reduction in WT1 levels was achieved at doses of 10–20 ng/ml of IGF-I (Fig. 2Go).



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  		FIG. 2. Dose-dependent effect of IGF-I on WT1 levels. Serum-starved Saos-2 cells were stimulated with increasing concentrations of IGF-I for 4 h. Cells were lysed and processed as described in the legend to Fig. 1Go and in Materials and Methods. The figure shows the results of a typical experiment, repeated twice.

 
To begin to examine the signaling pathways involved in IGF-I suppression of WT1 expression, we measured the phosphorylation of Erk1/2 and Akt after IGF-I treatment. As shown in Fig. 3Go, IGF-I induced the phosphorylation of Erk1/2 and Akt in a time-dependent fashion, with maximal phosphorylation observed after 20 min and 1 h. Phosphorylation of both proteins was still detected after 6-h incubation. No changes in total levels of Erk1/2 and Akt proteins were noticed. Likewise, no change was seen in actin levels.



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  		FIG. 3. IGF-I-induced phosphorylation of Erk1/2 and Akt. Serum-starved Saos-2 cells were incubated in the presence or absence of IGF-I (20 ng/ml) for the indicated times, after which equal amounts of protein were electrophoresed through 10% SDS-PAGE and blotted onto nitrocellulose membranes. Erk1/2 and Akt phosphorylation were detected with phospho-specific antibodies as described in Materials and Methods. Membranes were then stripped and reprobed with antibodies that detect the total amount of the specific proteins. WT1 was detected using antibody C19. Actin was used as a loading control.

 
To identify the particular pathway(s) responsible for this effect, inhibitors specific for Erk1/2 and PI3K were used. As shown in Fig. 4AGo, increasing concentrations of the Erk1/2 inhibitor UO126 suppressed the IGF-I-induced Erk1/2 phosphorylation in a dose-dependent manner. Suppression of Erk1/2 phosphorylation was associated with abrogation of the IGF-I-induced reduction in WT1 levels (Fig. 4BGo, compare lanes 2 and 3). A scanning densitometry analysis of three independent experiments is presented in Fig. 4CGo. These results indicate that 0.5 µM of UO126 completely abrogated the effect of IGF-I, whereas lower concentrations of the inhibitor (0.12–0.25 µM) had a partial effect. The PI3K inhibitor LY294002 was unable to inhibit the effect of IGF-I on WT1 expression (data not shown). Thus, in Saos-2 cells, the IGF-I-induced reduction in WT1 expression is apparently mediated through the MAPK pathway.



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  		FIG. 4. Determination of the intracellular signaling pathway involved in the IGF-I-induced WT1 down-regulation. Serum-starved cells were pretreated with the MAPK kinase 1/2 inhibitor UO126 for 2 h at the indicated concentrations and then incubated with or without IGF-I (20 ng/ml) for 1 h. Cell lysates were electrophoresed, transferred to membranes, and probed with antibodies against phospho- (pErk1/2) and total Erk1/2 (A), WT1 and actin (B). Bands corresponding to WT1 and actin were quantified by densitometry. Relative intensities are expressed in arbitrary units (A.U.) of absorbance of WT1 normalized for actin (C). The bars represent the mean ± SD of three independent experiments.

 
To assess whether the reduction in WT1 expression was mediated at the level of transcription, Saos-2 cells were transiently transfected with a luciferase reporter gene under the control of the WT1 promoter. The WT1 promoter construct, extending from -873 to +425 relative to the major human transcription start site, has been shown to contain all the cis-elements required for transcriptional activity in 293 cells (29). Transfected cells were incubated in the absence or presence of IGF-I (20 and 200 ng/ml) for 48 h, after which cells were harvested and luciferase and ß-galactosidase activities were measured. Results obtained showed that IGF-I induced a dose-dependent decrease in WT1 promoter activity (50.1 ± 10.2% inhibition at 20 ng/ml of IGF-I and 79.7 ± 7.9% inhibition at 200 ng/ml) (Fig. 5Go).



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  		FIG. 5. Suppression of WT1 gene promoter activity by IGF-I. Saos-2 cells were transfected with 0.8 µg of a WT1 promoter-luciferase reporter plasmid, along with 0.2 µg of a ß-galactosidase control vector, using the Fugene-6 reagent. Transfected cells were incubated with 0, 20, or 200 ng/ml of IGF-I. After 48 h, cells were harvested, and the levels of luciferase and ß-galactosidase were measured. Promoter activities are expressed as luciferase values normalized for ß-galactosidase levels. A value of 100% was given to the promoter activity in the absence of IGF-I. Results are mean ± SD of three independent experiments, performed in duplicate dishes.

 
Discussion

The role of IGF-I as a progression factor during the cell cycle has been firmly established. Similarly well documented is the fact that the vast majority of IGF-I actions are mediated via the IGF-IR. Activation of the IGF-IR has been associated with increased expression of several genes, including c-fos, twist, cyclin D1, and others. The present study was undertaken to examine the hypothesis that some of the biological effects of IGF-I maybe correlated with down-regulation of negative growth regulators.

WT1 was originally identified as a tumor suppressor on the basis of genetic analyses, showing that loss of WT1 function can initiate (or promote) tumorigenesis, as well as functional studies showing that expression of wild-type WT1 is usually associated with inhibition of cellular proliferation (9, 10, 30). Consistent with this notion, we have previously proposed that during normal kidney ontogeny WT1 suppresses the IGF-II/IGF-IR autocrine loop, with ensuing induction of renal differentiation. Inactivation of WT1 relieves inhibition of the IGF mitogenic loop, thus contributing to Wilms’ tumor progression (14).

In the present study, we have demonstrated that IGF-I can reduce the expression of WT1 in a time- and dose-dependent manner and that this effect is mediated through the MAPK signaling pathway, as shown by the ability of the specific inhibitor UO126 to abrogate IGF-I action. The inhibitory effect of IGF-I was seen at incubation periods of 1–4 h, whereas we were unable to see any repressive effect at incubation periods of 6–24 h. Furthermore, the effect of IGF-I involves repression of WT1 promoter activity, although the IGF-I-induced transcription factors involved are yet to be identified. Other mechanisms, such as a decrease in WT1 mRNA stability or translational efficiency, may also contribute to the decrease in WT1 expression. Because the WT1 protein is involved in multiple (and sometimes opposing) biological pathways, we may speculate that regulation of WT1 gene expression by IGF-I can provide a further level of control and that it is important for WT1 to exert its effects in a timely and spatially coordinated manner.

In conclusion, the data presented here demonstrate that the WT1 Wilms’ tumor suppressor gene is a novel downstream target for IGF-I action. Suppression of WT1 promoter activity by IGF-I, with ensuing reduction in nuclear WT1 levels, may impair the ability of the tumor suppressor to inhibit particular WT1 target genes. Increased expression of positive growth regulatory proteins may, in turn, allow cells to progress through the cell cycle. Most importantly, inhibition of WT1 gene expression by IGF-I may have profound implications in terms of cancer initiation and/or progression. Further studies are required to assess whether repression of tumor suppressors constitutes a common mechanism of action of IGF-I.

Acknowledgments

We thank Dr. Mike Eccles for providing the WT1 reporter construct.

Footnotes

This work was performed in partial fulfillment of the requirements for a Ph.D. degree by I.B. in the Sackler Faculty of Medicine, Tel Aviv University. I.B. was supported, in part, by a fellowship from the Combined Program of the NIH and the Sackler Faculty of Medicine, Tel Aviv University, in Women’s Health.

Abbreviations: IGF-IR, IGF-I receptor; PI3K, phosphatidylinositol 3-kinase.

Received March 31, 2003.

Accepted for publication July 2, 2003.

References

  1. Werner H, Adamo M, Roberts Jr CT, LeRoith D 1994 Molecular and cellular aspects of insulin-like growth factor action. In: Litwack G, ed. Vitamins and hormones. Vol 48. San Diego: Academic Press; 1–58
  2. Daughaday W, Rotwein P 1989 Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr Rev 10:68–91[Abstract]
  3. Werner H 1999 Molecular biology of the type 1 IGF receptor. In: Rosenfeld RG, Roberts Jr CT, eds. The IGF system: molecular biology, physiology and clinical applications. Totowa, NJ: Humana Press; 63–88
  4. LeRoith D, Werner H, Beitner-Johnson D, Roberts Jr CT 1995 Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev 16:143–163[CrossRef][Medline]
  5. Baserga R, Rubin R 1993 Cell cycle and growth control. Crit Rev Eukar Gene Exp 3:47–61[Medline]
  6. Furlanetto RW, Harwell SE, Frick KK 1994 Insulin-like growth factor-I induces cyclin-D1 expression in MG63 human osteosarcoma cells in vitro. Mol Endocrinol 8:510–517[Abstract]
  7. Heidenreich KA, Zeppelin T, Robinson LJ 1993 Insulin and insulin-like growth factor I induce c-fos expression in postmitotic neurons by a protein kinase C-dependent pathway. J Biol Chem 268:14663–14670[Abstract/Free Full Text]
  8. Dupont J, Fernandez AM, Glackin CA, Helman L, LeRoith D 2001 Insulin-like growth factor I (IGF-I)-induced twist expression is involved in the anti-apoptotic effects of the IGF-I receptor. J Biol Chem 276:26699–26707[Abstract/Free Full Text]
  9. Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH, Jones C, Housman DE 1990 Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms’ tumor locus. Cell 60:509–520[CrossRef][Medline]
  10. Gessler M, Poustka A, Cavence W, Neve RL, Orkin SH, Bruns GAP 1990 Homozygous deletion in Wilms’ tumors of a zinc-finger gene identified by chromosome jumping. Nature 343:774–778[CrossRef][Medline]
  11. Rauscher III FJ 1993 The WT1 Wilms tumor gene product: a developmentally regulated transcription factor in the kidney that functions as a tumor suppressor. FASEB J 7:896–903[Abstract]
  12. Morris JF, Madden SL, Tournay OE, Cook DM, Sukhatme VP, Rauscher III FJ 1991 Characterization of the zinc finger protein encoded by the WT1 Wilms’ tumor locus. Oncogene 6:2339–2348[Medline]
  13. Werner H, Re GG, Drummond IA, Sukhatme VP, Rauscher III FJ, Sens DA, Garvin AJ, LeRoith D, Roberts Jr CT 1993 Increased expression of the insulin-like growth factor-I receptor gene, IGFIR, in Wilms’ tumor is correlated with modulation of IGFIR promoter activity by the WT1 Wilms’ tumor gene product. Proc Natl Acad Sci USA 90:5828–5832[Abstract/Free Full Text]
  14. Werner H, Shen-Orr Z, Rauscher III FJ, Morris JF, Roberts Jr CT, LeRoith D 1995 Inhibition of cellular proliferation by the Wilms’ tumor suppressor WT1 is associated with suppression of insulin-like growth factor I receptor gene expression. Mol Cell Biol 15:3516–3522[Abstract]
  15. Karnieli E, Werner H, Rauscher III FJ, Benjamin LE, LeRoith D 1996 The IGF-I receptor gene promoter is a molecular target for the Ewings’ sarcoma-Wilms’ tumor 1 fusion protein. J Biol Chem 271:19304–19309[Abstract/Free Full Text]
  16. Dong G, Rajah R, Vu T, Hoffman A, Rosenfeld R, Roberts Jr CT, Peehl DM, Cohen P 1997 Decreased expression of the Wilms’ tumor gene WT-1 and elevated expression of the IGF-II and the IGF-II and IGF-IR genes in prostatic stromal cells from patients with benign prostatic hyperplasia. J Clin Endocrinol Metab 83:2198–2203
  17. Silberstein GB, Van Horn K, Strickland P, Roberts Jr CT, Daniel CW 1997 Altered expression of the WT1 Wilms tumor suppressor gene in human breast cancer. Proc Natl Acad Sci USA 94:8132–8137[Abstract/Free Full Text]
  18. Murata Y, Kudoh T, Sugiyama H, Toyoshima K, Akiyama T 1997 The Wilms tumor suppressor gene WT1 induces G1 arrest and apoptosis in myeloblastic leukemia M1 cells. FEBS Lett 409:41–45[CrossRef][Medline]
  19. Englert C, Maheswaran S, Garvin AJ, Kreidberg J, Haber DA 1997 Induction of p21 by the Wilms’ tumor suppressor gene WT1. Cancer Res 57:1429–1434[Abstract/Free Full Text]
  20. Mayo MW, Wang C-Y, Drouin SS, Madrid LV, Marshall AF, Reed JC, Weissman BE, Baldwin AS 1999 WT1 modulates apoptosis by transcriptionally upregulating the bcl-2 proto-oncogene. EMBO J 18:3990–4003[CrossRef][Medline]
  21. Cohen HT, Bossone SA, Zhu G, McDonald GA, Sukhatme VP 1997 Sp1 is a critical regulator of the Wilms’ tumor-1 gene. J Biol Chem 272:2901–2913[Abstract/Free Full Text]
  22. Dehbi M, Hiscott J, Pelletier J 1998 Activation of the wt1 Wilms’ tumor suppressor gene by NF-{kappa}B. Oncogene 16:2033–2039[CrossRef][Medline]
  23. McConnell MJ, Cunliffe HE, Chua LJ, Ward TA, Eccles MR 1997 Differential regulation of the human Wilms tumour suppressor gene (WT1) promoter by two isoforms of PAX2. Oncogene 14:2689–2700[CrossRef][Medline]
  24. Fraizer GC, Shimamura R, Zhang X, Saunders GF 1997 PAX8 regulates human WT1 transcription through a novel DNA binding site. J Biol Chem 272:30678–30687[Abstract/Free Full Text]
  25. Rupprecht HD, Drummond IA, Madden SL, Rauscher III FJ, Sukhatme VP 1994 The Wilms’ tumor suppressor gene WT1 is negatively autoregulated. J Biol Chem 269:6198–6206[Abstract/Free Full Text]
  26. Ye Y, Raychaudhuri B, Gurney A, Campbell CE, Williams BR 1996 Regulation of WT1 by phosphorylation: inhibition of DNA binding, alteration of transcriptional activity and cellular translocation. EMBO J 15:5606–5615[Medline]
  27. Idelman G, Glaser T, Roberts Jr CT, Werner H 2003 WT1-p53 interactions in IGF-I receptor gene regulation. J Biol Chem 278:3474–3482[Abstract/Free Full Text]
  28. Werner H, Bach MA, Stannard B, Roberts Jr CT, LeRoith D 1992 Structural and functional analysis of the insulin-like growth factor I receptor gene promoter. Mol Endocrinol 6:1545–1558[Abstract]
  29. Campbell CE, Huang A, Gurney AL, Kessler PM, Hewitt JA, Williams BRG 1994 Antisense transcripts and protein binding motifs within the Wilms tumour (WT1) locus. Oncogene 9:583–595[Medline]
  30. Madden SL, Cook DM, Morris JF, Gashler A, Sukhatme VP, Rauscher III FJ 1991 Transcriptional repression mediated by the WT1 Wilms’ tumor gene product. Science 253:1550–1553[Abstract/Free Full Text]




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