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Transcriptional repression of the E2F-1 gene by interferon-α is mediated through induction of E2F-4/pRB and E2F-4/p130 complexes

Oncogene volume 18, pages 2003–2014 (1999)Cite this article

Abstract

E2F is a heterodimeric transcription factor composed of one of five E2F subunits (E2F-1 to E2F-5) and a DP subunit. E2F regulates the expression of several growth-promoting genes, and thus, can be a target of antiproliferative action of interferons (IFNs). In this study, we investigated the mechanisms whereby IFN-α suppresses transcription of the E2F-1 gene. Transfection studies revealed that E2F-1 promoter was functionally divided into two parts: upstream activation sequences (UAS) and a downstream negative-regulatory element (E2F-binding sites). When cells were proliferating, transcription of the E2F-1 gene was primarily driven by the UAS, while E2F sites were not involved in activation. IFN-α markedly reduced E2F-1 promoter activity, but introduction of non-binding mutation at the E2F sites completely abrogated the inhibition. Free E2F-4 was found to be the predominant species bound to the E2F sites in proliferating cells. IFN-α induced up-regulation of E2F-4 along with dephosphorylation of pRB and p130, which resulted in the formation of E2F-4/pRB and E2F-4/p130 complexes on the E2F-1 promoter. These complexes function as transcriptional repressors to inhibit E2F-1 mRNA expression. Our findings indicate that E2F-4 is a critical regulator of E2F-1, which offer an excellent paradigm for understanding functional diversity within the E2F family.

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References

  • Baeuerle PA and Baltimore D. . 1988 Cell 53: 211–217.

  • Beijersbergen RL, Carlée L, Krekhoven RM and Bernards R. . 1995 Gene Dev. 9: 1340–1353.

  • Beijersbergen RL and Bernards R. . 1996 Biochim. Biophy. Acta 1287: 103–120.

  • Bradford MM. . 1976 Anal. Biochem. 72: 248–254.

  • Chin YE, Kitagawa M, Su WC, You ZH, Iwamoto Y and Fu XY. . 1996 Science 272: 719–722.

  • Chow KN and Dean DC. . 1996 Mol. Cell. Biol. 16: 4862–4868.

  • Cress WD and Nevins JR. . 1996 Mol. Cell. Biol. 16: 2119–2127.

  • Dalton S. . 1992 EMBO J. 11: 1797–1804.

  • DeGregori J, Kowalik T and Nevins JR. . 1995 Mol. Cell. Biol. 15: 4215–4224.

  • Einat M, Resnitzky D and Kimchi A. . 1985 Nature 313: 597–600.

  • Einhorn S and Grander D. . 1996 J. Interferon. Cytokine. Res. 16: 275–281.

  • Furukawa Y, Uenoyama S, Ohta M, Tsunoda A, Griffin JD and Saito M. . 1992 J. Biol. Chem. 267: 17121–17127.

  • Furukawa Y, Terui Y, Sakoe K, Ohta M and Saito M. . 1994 J. Biol. Chem. 269: 26249–26258.

  • Furukawa Y, Iwase S, Terui Y, Kikuchi J, Sakai T, Nakamura M, Kitagawa S and Kitagawa M. . 1996 J. Biol. Chem. 271: 28469–28477.

  • Geng Y, Eaton EN, Picon M, Roberts JM, Lundberg AS, Gifford A, Sardet C and Weinberg RA. . 1996 Oncogene 12: 1173–1180.

  • Gutterman JU. . 1994 Proc. Natl. Acad. Sci. USA 95: 1198–1205.

  • Henglein B, Chenivesse X, Wang J, Eick D and Brechot C. . 1994 Proc. Natl. Acad. Sci. USA 92: 5490–5494.

  • Hijmans EM, Noorhoeve PM, Beijersbergen RL, van't Veer LJ and Bernards R. . 1995 Mol. Cell. Biol. 15: 3082–3089.

  • Hofmann F, Martelli F, Livingston DM and Wang Z. . 1996 Gene. Dev. 10: 2949–2959.

  • Huber HE, Goodhart PJ and Huang PS. . 1994 J. Biol. Chem. 269: 6999–7005.

  • Iwase S, Furukawa Y, Kikuchi J, Nagai M, Terui Y, Nakamura M and Yamada H. . 1997 J. Biol. Chem. 272: 12406–12414.

  • Johnson DG, Ohtani K and Nevins JR. . 1994 Gene. Dev. 8: 1514–1525.

  • Kaelin Jr WG, Krek W, Sellers WR, DeCaprio JA, Ajchenbaum F, Fuchs CS, Chittenden T, Li Y, Farnham PJ, Blanar MA, Livingston DM and Flemington EK. . 1992 Cell 70: 351–364.

  • Kitagawa M, Higashi H, Suzuki-Takahashi I, Segawa K, Hanks SK, Taya Y, Nishimura S and Okuyama A. . 1995 Oncogene 10: 229–236.

  • Krämer A, Carstens C-P and Fahl WE. . 1996 J. Biol. Chem. 271: 6579–6582.

  • Lam EW and Watson RJ. . 1993 EMBO J. 12: 2705–2713.

  • Landt O, Grunert H-P and Hahn U. . 1990 Gene. (Amst.) 96: 125–128.

  • Lengyel P. . 1993 Proc. Natl. Acad. Sci. USA 90: 5893–5895.

  • Li J-M, Hu PP, Shen X, Yu Y and Wang X-F. . 1997 Proc. Natl. Acad. Sci. USA 94: 4948–4953.

  • Lucibello FC, Truss M, Zwicker J, Ehlert F, Beato M and Müller R. . 1995 EMBO J. 14: 132–142.

  • Melamed D, Tiefenbrun N, Yarden A and Kimchi A. . 1993 Mol. Cell. Biol. 13: 5255–5265.

  • Moberg K, Starz MA and Lees JA. . 1996 Mol. Cell. Biol. 16: 1436–1449.

  • Neuman E, Flemington EK, Sellers WR and Kaelin Jr WG. . 1994 Mol. Cell. Biol. 14: 6607–6615.

  • Nevins JR. . 1992 Science 258: 424–429.

  • Ohtani K, DeGregori J, Leone G, Herendeen DR, Kelly TJ and Nevins JR. . 1996 Mol. Cell. Biol. 16: 6977–6984.

  • Resnitzky D, Tiefenbrun N, Berissi H and Kimchi A. . 1992 Proc. Natl. Acad. Sci. USA 89: 402–406.

  • Sangfelt O, Erickson S, Einhorn S and Grander D. . 1997 Oncogene 14: 415–423.

  • Sardet C, Vidal M, Cobrinik D, Geng Y, Onufryk C, Chen A and Weinberg RA. . 1995 Proc. Natl. Acad. Sci. USA 92: 2403–2407.

  • Seed B and Sheen J-Y. . 1988 Gene. (Amst.) 67: 271–277.

  • Selleri C, Maciejewski JP, Sato T and Young NS. . 1996 Blood 87: 4149–4157.

  • Sen GC and Lengyel P. . 1992 J. Biol. Chem. 267: 5017–5020.

  • Slansky JE and Farnham PJ. . 1996 Curr. Top. Microbiol. Immunol. 208: 1–30.

  • Smith EJ, Leone G, DeGregori J, Jakoi L and Nevins JR. . 1996 Mol. Cell. Biol. 16: 6965–6976.

  • Tao Y, Kassatly RF, Cress WD and Horowitz JM. . 1997 Mol. Cell. Biol. 17: 6994–7007.

  • Thomas NSB. . 1988 J. Biol. Chem. 264: 13697–13700.

  • Tommasi S and Pfeifer GP. . 1995 Mol. Cell. Biol. 15: 6901–6913.

  • Vairo G, Livingston DM and Ginsberg D. . 1995 Gene. Dev. 9: 869–881.

  • Weintraub SJ, Chow KN, Luo RX, Zhang SH, He S and Dean DC. . 1995 Nature 375: 812–815.

  • Williams CD, Linch DC, Sørensen TS, LaThangue NB and Thomas NSB. . 1997a Br. J. Haematol. 96: 688–696.

  • Williams CD, Linch DC, Watts MJ and Thomas NSB. . 1997b Blood 90: 194–203.

  • Xu J, Rockow S, Kim S, Xiong W and Li W. . 1994 Mol. Cell. Biol. 14: 8018–8027.

  • Yamada H, Ochi K, Nakada S, Nemoto T and Horiguchi-Yamada J. . 1994 Mol. Cell. Biochem. 136: 117–123.

  • Zwicker J, Lucibello FC, Wolfraim LA, Gross C, Truss M, Engeland K and Müller R. . 1995 EMBO J. 14: 4514–4522.

  • Zwicker J, Liu N, Engeland K, Lucibello FC and Müller R. . 1996 Science 271: 1595–1597.

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Acknowledgements

We are grateful to Ms Yukiko Fukuda and Ms Taeko Inegeda for their technical assistance. This work was supported in part by Grants-in-Aid from the Ministry of Education Science and Culture of Japan (P07269220, C09680701) and by a grant from the Ichiro Kanehara Foundation (to YF).

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Authors and Affiliations

  1. Division of Molecular Hemopoiesis, the Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan

    Yusuke Furukawa, Mitsuru Nakamura & Michio Matsuda

  2. Department of Hematology, Jichi Medical School, Tochigi, 329-0498, Japan

    Yusuke Furukawa, Mitsuru Nakamura & Michio Matsuda

  3. Katsuta Research Laboratory, Hitachi Koki Company, Ltd., 312, Ibaraki, Japan

    Jiro Kikuchi

  4. Department of Internal Medicine (Aoto), DNA Research Institute, Jikei University School of Medicine, Tokyo, 105, Japan

    Satsuki Iwase & Hisashi Yamada

  5. Department of Genetics, the DNA Research Institute, Jikei University School of Medicine, Tokyo, 105, Japan

    Satsuki Iwase & Hisashi Yamada

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Furukawa, Y., Iwase, S., Kikuchi, J. et al. Transcriptional repression of the E2F-1 gene by interferon-α is mediated through induction of E2F-4/pRB and E2F-4/p130 complexes. Oncogene 18, 2003–2014 (1999). https://doi.org/10.1038/sj.onc.1202500

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