Transforming Growth Factor β-Mediated Transcriptional Repression of c-myc Is Dependent on Direct Binding of Smad3 to a Novel Repressive Smad Binding Element

REFERENCE

• Abdollah, S., Macias-Silva M., Tsukazaki T., Hayashi H., Attisano L., and Wrana J. L.. 1997. TβRI phosphorylation of Smad2 on Ser465 and Ser467 is required for Smad2-Smad4 complex formation and signaling. J. Biol. Chem. 272:27678–27685.
   PubMed Web of Science ®Google Scholar
• Akiyoshi, S., Inoue H., Hanai J., Kusanagi K., Nemoto N., Miyazono K., and Kawabata M.. 1999. c-Ski acts as a transcriptional co-repressor in transforming growth factor-beta signaling through interaction with smads. J. Biol. Chem. 274:35269–35277.
   PubMed Web of Science ®Google Scholar
• Alexandrow, M. G., Kawabata M., Aakre M., and Moses H. L.. 1995. Overexpression of the c-Myc oncoprotein blocks the growth-inhibitory response but is required for the mitogenic effects of transforming growth factor beta 1. Proc. Natl. Acad. Sci. USA 92:3239–3243.
   PubMedGoogle Scholar
• Attisano, L., and Wrana J. L.. 2000. Smads as transcriptional co-modulators. Curr. Opin. Cell Biol. 12:235–243.
   PubMed Web of Science ®Google Scholar
• Baker, J. C., and Harland R. M.. 1997. From receptor to nucleus: the Smad pathway. Curr. Opin. Genet. Dev. 7:467–473.
   PubMed Web of Science ®Google Scholar
• Bandara, L. R., Buck V. M., Zamanian M., Johnston L. H., and La Thangue N. B.. 1993. Functional synergy between DP-1 and E2F-1 in the cell cycle-regulating transcription factor DRTF1/E2F. EMBO J. 12:4317–4324.
   PubMed Web of Science ®Google Scholar
• Bieche, I., Laurendeau I., Tozlu S., Olivi M., Vidaud D., Lidereau R., and Vidaud M.. 1999. Quantitation of MYC gene expression in sporadic breast tumors with a real-time reverse transcription-PCR assay. Cancer Res. 59:2759–2765.
   PubMed Web of Science ®Google Scholar
• Blobe, G. C., Schiemann W. P., and Lodish H. F.. 2000. Role of transforming growth factor beta in human disease. N. Engl. J. Med. 342:1350–1358.
   PubMed Web of Science ®Google Scholar
• Bonilla, M., Ramirez M., Lopez-Cueto J., and Gariglio P.. 1988. In vivo amplification and rearrangement of c-myc oncogene in human breast tumors. J. Natl. Cancer Inst. 80:665–671.
   PubMedGoogle Scholar
• Chen, C. R., Kang Y., and Massague J.. 2001. Defective repression of c-myc in breast cancer cells: a loss at the core of the transforming growth factor beta growth arrest program. Proc. Natl. Acad. Sci. USA 98:992–999.
   PubMed Web of Science ®Google Scholar
• Chen, C. R., Kang Y., Siegel P. M., and Massague J.. 2002. E2F4/5 and p107 as Smad cofactors linking the TGFβ receptor to c-myc repression. Cell 110:19–32.
   PubMed Web of Science ®Google Scholar
• Claassen, G. F., and Hann S. R.. 2000. A role for transcriptional repression of p21CIP1 by c-Myc in overcoming transforming growth factor beta-induced cell-cycle arrest. Proc. Natl. Acad. Sci. USA 97:9498–9503.
   PubMed Web of Science ®Google Scholar
• Coffey, R. J., Jr., Bascom C. C., Sipes N. J., Graves-Deal R., Weissman B. E., and Moses H. L.. 1988. Selective inhibition of growth-related gene expression in murine keratinocytes by transforming growth factor beta. Mol. Cell. Biol. 8:3088–3093.
   PubMed Web of Science ®Google Scholar
• Datto, M. B., Frederick J. P., Pan L., Borton A. J., Zhuang Y., and Wang X. F.. 1999. Targeted disruption of Smad3 reveals an essential role in transforming growth factor beta-mediated signal transduction. Mol. Cell. Biol. 19:2495–2504.
   PubMed Web of Science ®Google Scholar
• Datto, M. B., Li Y., Panus J. F., Howe D. J., Xiong Y., and Wang X. F.. 1995. Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc. Natl. Acad. Sci. USA 92:5545–5549.
   PubMed Web of Science ®Google Scholar
• de Caestecker, M. P., Piek E., and Roberts A. B.. 2000. Role of transforming growth factor-beta signaling in cancer. J. Natl. Cancer Inst. 92:1388–1402.
   PubMed Web of Science ®Google Scholar
• DeGregori, J., Kowalik T., and Nevins J. R.. 1995. Cellular targets for activation by the E2F1 transcription factor include DNA synthesis- and G1/S-regulatory genes. Mol. Cell. Biol. 15:4215–4224.
   PubMed Web of Science ®Google Scholar
• DeGregori, J., Leone G., Miron A., Jakoi L., and Nevins J. R.. 1997. Distinct roles for E2F proteins in cell growth control and apoptosis. Proc. Natl. Acad. Sci. USA 94:7245–7250.
   PubMed Web of Science ®Google Scholar
• Dennler, S., Itoh S., Vivien D., ten Dijke P., Huet S., and Gauthier J. M.. 1998. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J. 17:3091–3100.
   PubMed Web of Science ®Google Scholar
• Derynck, R., and Zhang Y.. 1996. Intracellular signalling: the mad way to do it. Curr. Biol. 6:1226–1229.
   PubMedGoogle Scholar
• Dyson, N. 1998. The regulation of E2F by pRB-family proteins. Genes Dev. 12:2245–2262.
   PubMed Web of Science ®Google Scholar
• Eisenman, R. N. 2001. Deconstructing myc. Genes Dev. 15:2023–2030.
   PubMed Web of Science ®Google Scholar
• Eppert, K., Scherer S. W., Ozcelik H., Pirone R., Hoodless P., Kim H., Tsui L. C., Bapat B., Gallinger S., Andrulis I. L., Thomsen G. H., Wrana J. L., and Attisano L.. 1996. MADR2 maps to 18q21 and encodes a TGFβ-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Cell 86:543–552.
   PubMed Web of Science ®Google Scholar
• Erisman, M. D., Rothberg P. G., Diehl R. E., Morse C. C., Spandorfer J. M., and Astrin S. M.. 1985. Deregulation of c-myc gene expression in human colon carcinoma is not accompanied by amplification or rearrangement of the gene. Mol. Cell. Biol. 5:1969–1976.
   PubMed Web of Science ®Google Scholar
• Erisman, M. D., Scott J. K., Watt R. A., and Astrin S. M.. 1988. The c-myc protein is constitutively expressed at elevated levels in colorectal carcinoma cell lines. Oncogene 2:367–378.
   PubMedGoogle Scholar
• Goto, D., Yagi K., Inoue H., Iwamoto I., Kawabata M., Miyazono K., and Kato M.. 1998. A single missense mutant of Smad3 inhibits activation of both Smad2 and Smad3, and has a dominant negative effect on TGF-beta signals. FEBS Lett. 430:201–204.
   PubMedGoogle Scholar
• Grandori, C., Cowley S. M., James L. P., and Eisenman R. N.. 2000. The Myc/Max/Mad network and the transcriptional control of cell behavior. Annu. Rev. Cell. Dev. Biol. 16:653–699.
   PubMed Web of Science ®Google Scholar
• Hannon, G. J., and Beach D.. 1994. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 371:257–261.
   PubMed Web of Science ®Google Scholar
• He, T. C., Sparks A. B., Rago C., Hermeking H., Zawel L., da Costa L. T., Morin P. J., Vogelstein B., and Kinzler K. W.. 1998. Identification of c-MYC as a target of the APC pathway. Science 281:1509–1512.
   PubMed Web of Science ®Google Scholar
• Heldin, C. H., Miyazono K., and ten Dijke P.. 1997. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390:465–471.
   PubMed Web of Science ®Google Scholar
• Helin, K., Wu C. L., Fattaey A. R., Lees J. A., Dynlacht B. D., Ngwu C., and Harlow E.. 1993. Heterodimerization of the transcription factors E2F-1 and DP-1 leads to cooperative trans-activation. Genes Dev. 7:1850–1861.
   PubMed Web of Science ®Google Scholar
• Henriksson, M., and Luscher B.. 1996. Proteins of the Myc network: essential regulators of cell growth and differentiation. Adv. Cancer Res. 68:109–182.
   PubMed Web of Science ®Google Scholar
• Hiebert, S. W., Lipp M., and Nevins J. R.. 1989. E1A-dependent trans-activation of the human MYC promoter is mediated by the E2F factor. Proc. Natl. Acad. Sci. USA 86:3594–3598.
   PubMed Web of Science ®Google Scholar
• Huber, H. E., Edwards G., Goodhart P. J., Patrick D. R., Huang P. S., Ivey-Hoyle M., Barnett S. F., Oliff A., and Heimbrook D. C.. 1993. Transcription factor E2F binds DNA as a heterodimer. Proc. Natl. Acad. Sci. USA 90:3525–3529.
   PubMed Web of Science ®Google Scholar
• Iavarone, A., and Massague J.. 1999. E2F and histone deacetylase mediate transforming growth factor β repression of cdc25A during keratinocyte cell cycle arrest. Mol. Cell. Biol. 19:916–922.
   PubMedGoogle Scholar
• Iavarone, A., and Massague J.. 1997. Repression of the CDK activator Cdc25A and cell-cycle arrest by cytokine TGF-beta in cells lacking the CDK inhibitor p15. Nature 387:417–422.
   PubMedGoogle Scholar
• Janknecht, R., Wells N. J., and Hunter T.. 1998. TGF-beta-stimulated cooperation of smad proteins with the coactivators CBP/p300. Genes Dev. 12:2114–2119.
   PubMedGoogle Scholar
• Keeton, M. R., Curriden S. A., van Zonneveld A. J., and Loskutoff D. J.. 1991. Identification of regulatory sequences in the type 1 plasminogen activator inhibitor gene responsive to transforming growth factor beta. J. Biol. Chem. 266:23048–23052.
   PubMedGoogle Scholar
• Kerr, L. D., Miller D. B., and Matrisian L. M.. 1990. TGF-beta 1 inhibition of transin/stromelysin gene expression is mediated through a Fos binding sequence. Cell 61:267–278.
   PubMed Web of Science ®Google Scholar
• Kim, J., Johnson K., Chen H. J., Carroll S., and Laughon A.. 1997. Drosophila Mad binds to DNA and directly mediates activation of vestigial by Decapentaplegic. Nature 388:304–308.
   PubMedGoogle Scholar
• Kim, R. H., Wang D., Tsang M., Martin J., Huff C., de Caestecker M. P., Parks W. T., Meng X., Lechleider R. J., Wang T., and Roberts A. B.. 2000. A novel smad nuclear interacting protein, SNIP1, suppresses p300-dependent TGF-beta signal transduction. Genes Dev. 14:1605–1616.
   PubMed Web of Science ®Google Scholar
• Krek, W., Livingston D. M., and Shirodkar S.. 1993. Binding to DNA and the retinoblastoma gene product promoted by complex formation of different E2F family members. Science 262:1557–1560.
   PubMed Web of Science ®Google Scholar
• Lagna, G., Hata A., Hemmati-Brivanlou A., and Massague J.. 1996. Partnership between DPC4 and SMAD proteins in TGF-beta signalling pathways. Nature 383:832–836.
   PubMed Web of Science ®Google Scholar
• Lefstin, J. A., and Yamamoto K. R.. 1998. Allosteric effects of DNA on transcriptional regulators. Nature 392:885–888.
   PubMedGoogle Scholar
• Leone, G., Sears R., Huang E., Rempel R., Nuckolls F., Park C. H., Giangrande P., Wu L., Saavedra H. I., Field S. J., Thompson M. A., Yang H., Fujiwara Y., Greenberg M. E., Orkin S., Smith C., and Nevins J. R.. 2001. Myc requires distinct E2F activities to induce S phase and apoptosis. Mol. Cell 8:105–113.
   PubMedGoogle Scholar
• Letterio, J. J., and Roberts A. B.. 1997. TGF-beta: a critical modulator of immune cell function. Clin. Immunol. Immunopathol. 84:244–250.
   PubMedGoogle Scholar
• Liberati, N. T., Datto M. B., Frederick J. P., Shen X., Wong C., Rougier-Chapman E. M., and Wang X. F.. 1999. Smads bind directly to the Jun family of AP-1 transcription factors. Proc. Natl. Acad. Sci. USA 96:4844–4849.
   PubMed Web of Science ®Google Scholar
• Liberati, N. T., Moniwa M., Borton A. J., Davie J. R., and Wang X. F.. 2001. An essential role for Mad homology domain 1 in the association of Smad3 with histone deacetylase activity. J. Biol. Chem. 276:22595–22603.
   PubMedGoogle Scholar
• Liu, F., Pouponnot C., and Massague J.. 1997. Dual role of the Smad4/DPC4 tumor suppressor in TGFβ-inducible transcriptional complexes. Genes Dev. 11:3157–3167.
   PubMed Web of Science ®Google Scholar
• Luo, K., Stroschein S. L., Wang W., Chen D., Martens E., Zhou S., and Zhou Q.. 1999. The Ski oncoprotein interacts with the Smad proteins to repress TGFβ signaling. Genes Dev. 13:2196–2206.
   PubMed Web of Science ®Google Scholar
• Macias-Silva, M., Abdollah S., Hoodless P. A., Pirone R., Attisano L., and Wrana J. L.. 1996. MADR2 is a substrate of the TGFβ receptor and its phosphorylation is required for nuclear accumulation and signaling. Cell 87:1215–1224.
   PubMed Web of Science ®Google Scholar
• Massagué, J., Blain S. W., and Lo R. S.. 2000. TGFβ signaling in growth control, cancer, and heritable disorders. Cell 103:295–309.
   PubMed Web of Science ®Google Scholar
• Massague, J., and Wotton D.. 2000. Transcriptional control by the TGF-beta/Smad signaling system. EMBO J. 19:1745–1754.
   PubMed Web of Science ®Google Scholar
• Miyazono, K. 2000. TGF-beta signaling by Smad proteins. Cytokine Growth Factor Rev. 11:15–22.
   PubMedGoogle Scholar
• Miyazono, K. 2000. TGF-beta/SMAD signaling and its involvement in tumor progression. Biol. Pharm. Bull. 23:1125–1130.
   PubMed Web of Science ®Google Scholar
• Moses, H. L. 1992. TGF-beta regulation of epithelial cell proliferation. Mol. Rep. Dev. 32:179–184.
   PubMed Web of Science ®Google Scholar
• Muller, H., Bracken A. P., Vernell R., Moroni M. C., Christians F., Grassilli E., Prosperini E., Vigo E., Oliner J. D., and Helin K.. 2001. E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis. Genes Dev. 15:267–285.
   PubMed Web of Science ®Google Scholar
• Nakao, A., Imamura T., Souchelnytskyi S., Kawabata M., Ishisaki A., Oeda E., Tamaki K., Hanai J., Heldin C. H., Miyazono K., and ten Dijke P.. 1997. TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4. EMBO J. 16:5353–5362.
   PubMed Web of Science ®Google Scholar
• Nishihara, A., Hanai J. I., Okamoto N., Yanagisawa J., Kato S., Miyazono K., and Kawabata M.. 1998. Role of p300, a transcriptional coactivator, in signalling of TGF-beta. Genes Cells 3:613–623.
   PubMed Web of Science ®Google Scholar
• Padgett, R. W. 1999. Intracellular signaling: fleshing out the TGFβ pathway. Curr. Biol. 9:R408–R411.
   PubMedGoogle Scholar
• Pietenpol, J. A., Holt J. T., Stein R. W., and Moses H. L.. 1990. Transforming growth factor beta 1 suppression of c-myc gene transcription: role in inhibition of keratinocyte proliferation. Proc. Natl. Acad. Sci. USA 87:3758–3762.
   PubMed Web of Science ®Google Scholar
• Pouponnot, C., Jayaraman L., and Massague J.. 1998. Physical and functional interaction of SMADs and p300/CBP. J. Biol. Chem. 273:22865–22868.
   PubMed Web of Science ®Google Scholar
• Qing, J., Zhang Y., and Derynck R.. 2000. Structural and functional characterization of the transforming growth factor-beta-induced Smad3/c-Jun transcriptional cooperativity. J. Biol. Chem. 275:38802–38812.
   PubMed Web of Science ®Google Scholar
• Reynisdottir, I., Polyak K., Iavarone A., and Massague J.. 1995. Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta. Genes Dev. 9:1831–1845.
   PubMed Web of Science ®Google Scholar
• Rich, J., Borton A., and Wang X.. 2001. Transforming growth factor-beta signaling in cancer. Microsc. Res. Tech. 52:363–373.
   PubMedGoogle Scholar
• Roberts, A. B. 1999. TGF-beta signaling from receptors to the nucleus. Microbes Infect. 1:1265–1273.
   PubMedGoogle Scholar
• Roussel, M. F., Davis J. N., Cleveland J. L., Ghysdael J., and Hiebert S. W.. 1994. Dual control of myc expression through a single DNA binding site targeted by ets family proteins and E2F-1. Oncogene 9:405–415.
   PubMedGoogle Scholar
• Seoane, J., Pouponnot C., Staller P., Schader M., Eilers M., and Massague J.. 2001. TGFβ influences Myc, Miz-1, and Smad to control the CDK inhibitor p15INK4b. Nat. Cell Biol. 3:400–408.
   PubMed Web of Science ®Google Scholar
• Shen, X., Hu P. P., Liberati N. T., Datto M. B., Frederick J. P., and Wang X. F.. 1998. TGF-beta-induced phosphorylation of Smad3 regulates its interaction with coactivator p300/CREB-binding protein. Mol. Biol. Cell 9:3309–3319.
   PubMed Web of Science ®Google Scholar
• Shi, Y., Wang Y. F., Jayaraman L., Yang H., Massague J., and Pavletich N. P.. 1998. Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling. Cell 94:585–594.
   PubMed Web of Science ®Google Scholar
• Sikora, K., Chan S., Evan G., Gabra H., Markham N., Stewart J., and Watson J.. 1987. c-myc oncogene expression in colorectal cancer. Cancer 59:1289–1295.
   PubMed Web of Science ®Google Scholar
• Smith, D. R., Myint T., and Goh H. S.. 1993. Over-expression of the c-myc proto-oncogene in colorectal carcinoma. Br. J. Cancer 68:407–413.
   PubMedGoogle Scholar
• Souchelnytskyi, S., Tamaki K., Engstrom U., Wernstedt C., ten Dijke P., and Heldin C. H.. 1997. Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-beta signaling. J. Biol. Chem. 272:28107–28115.
   PubMed Web of Science ®Google Scholar
• Staller, P., Peukert K., Kiermaier A., Seoane J., Lukas J., Karsunky H., Moroy T., Bartek J., Massague J., Hanel F., and Eilers M.. 2001. Repression of p15INK4b expression by Myc through association with Miz-1. Nat. Cell Biol. 3:392–399.
   PubMed Web of Science ®Google Scholar
• Stroschein, S. L., Wang W., and Luo K.. 1999. Cooperative binding of Smad proteins to two adjacent DNA elements in the plasminogen activator inhibitor-1 promoter mediates transforming growth factor beta-induced smad-dependent transcriptional activation. J. Biol. Chem. 274:9431–9441.
   PubMedGoogle Scholar
• Sun, Y., Liu X., Eaton E. N., Lane W. S., Lodish H. F., and Weinberg R. A.. 1999. Interaction of the Ski oncoprotein with Smad3 regulates TGF-beta signaling. Mol. Cell 4:499–509.
   PubMedGoogle Scholar
• Sun, Y., Liu X., Ng-Eaton E., Lodish H. F., and Weinberg R. A.. 1999. SnoN and Ski protooncoproteins are rapidly degraded in response to transforming growth factor beta signaling. Proc. Natl. Acad. Sci. USA 96:12442–12447.
   PubMed Web of Science ®Google Scholar
• Takahashi, Y., Rayman J. B., and Dynlacht B. D.. 2000. Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression. Genes Dev. 14:804–816.
   PubMed Web of Science ®Google Scholar
• ten Dijke, P., Miyazono K., and Heldin C. H.. 2000. Signaling inputs converge on nuclear effectors in TGF-beta signaling. Trends Biochem. Sci. 25:64–70.
   PubMedGoogle Scholar
• Vigo, E., Muller H., Prosperini E., Hateboer G., Cartwright P., Moroni M. C., and Helin K.. 1999. CDC25A phosphatase is a target of E2F and is required for efficient E2F-induced S phase. Mol. Cell. Biol. 19:6379–6395.
   PubMed Web of Science ®Google Scholar
• Warner, B. J., Blain S. W., Seoane J., and Massague J.. 1999. Myc downregulation by transforming growth factor beta required for activation of the p15Ink4b G1 arrest pathway. Mol. Cell. Biol. 19:5913–5922.
   PubMed Web of Science ®Google Scholar
• White, L. A., Mitchell T. I., and Brinckerhoff C. E.. 2000. Transforming growth factor beta inhibitory element in the rabbit matrix metalloproteinase-1 (collagenase-1) gene functions as a repressor of constitutive transcription. Biochim. Biophys. Acta 1490:259–268.
   PubMed Web of Science ®Google Scholar
• Wong, C., Rougier-Chapman E. M., Frederick J. P., Datto M. B., Liberati N. T., Li J. M., and Wang X. F.. 1999. Smad3-Smad4 and AP-1 complexes synergize in transcriptional activation of the c-Jun promoter by transforming growth factor beta. Mol. Cell. Biol. 19:1821–1830.
   PubMedGoogle Scholar
• Wotton, D., Lo R. S., Lee S., and Massague J.. 1999. A Smad transcriptional corepressor. Cell 97:29–39.
   PubMed Web of Science ®Google Scholar
• Wrana, J. L., Attisano L., Carcamo J., Zentella A., Doody J., Laiho M., Wang X. F., and Massague J.. 1992. TGF beta signals through a heteromeric protein kinase receptor complex. Cell 71:1003–1014.
   PubMed Web of Science ®Google Scholar
• Wrana, J. L., Attisano L., Wieser R., Ventura F., and Massague J.. 1994. Mechanism of activation of the TGF-beta receptor. Nature 370:341–347.
   PubMed Web of Science ®Google Scholar
• Wu, J. W., Hu M., Chai J., Seoane J., Huse M., Li C., Rigotti D. J., Kyin S., Muir T. W., Fairman R., Massague J., and Shi Y.. 2001. Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling. Mol. Cell 8:1277–1289.
   PubMedGoogle Scholar
• Xu, W., Angelis K., Danielpour D., Haddad M. M., Bischof O., Campisi J., Stavnezer E., and Medrano E. E.. 2000. Ski acts as a co-repressor with Smad2 and Smad3 to regulate the response to type beta transforming growth factor. Proc. Natl. Acad. Sci. USA 97:5924–5929.
   PubMedGoogle Scholar
• Yagi, K., Furuhashi M., Aoki H., Goto D., Kuwano H., Sugamura K., Miyazono K., and Kato M.. 2002. c-myc is a downstream target of the Smad pathway. J. Biol. Chem. 277:854–861.
   PubMed Web of Science ®Google Scholar
• Yingling, J. M., Datto M. B., Wong C., Frederick J. P., Liberati N. T., and Wang X. F.. 1997. Tumor suppressor Smad4 is a transforming growth factor β-inducible DNA binding protein. Mol. Cell. Biol. 17:7019–7028.
   PubMed Web of Science ®Google Scholar
• Zawel, L., Dai J. L., Buckhaults P., Zhou S., Kinzler K. W., Vogelstein B., and Kern S. E.. 1998. Human Smad3 and Smad4 are sequence-specific transcription activators. Mol. Cell 1:611–617.
   PubMed Web of Science ®Google Scholar
• Zhang, Y., Musci T., and Derynck R.. 1997. The tumor suppressor Smad4/DPC 4 as a central mediator of Smad function. Curr. Biol. 7:270–276.
   PubMed Web of Science ®Google Scholar
• Zheng, N., Fraenkel E., Pabo C. O., and Pavletich N. P.. 1999. Structural basis of DNA recognition by the heterodimeric cell cycle transcription factor E2F-DP. Genes Dev. 13:666–674.
   PubMed Web of Science ®Google Scholar
• Zimmerman, C. M., and Padgett R. W.. 2000. Transforming growth factor beta signaling mediators and modulators. Gene 249:17–30.
   PubMedGoogle Scholar