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c-Myc represses the proximal promoters of GADD45a and GADD153 by a post-RNA polymerase II recruitment mechanism

Abstract

The c-Myc cellular oncogene has diverse activities, including transformation, proliferation, and apoptosis. These activities are dependent on the ability of c-Myc to regulate gene transcription. c-Myc downregulates the GADD45a and GADD153 (DDTI3) genes that are induced in response to genotoxic stresses and that encode protein products with antiproliferative activities. We show that c-Myc represses the expression of GADD45a and GADD153 in response to thapsigargin, a nongenotoxic stress, as well as other endoplasmic reticulum (ER) stress agents. c-Myc represses both the basal expression and the magnitude of ER stress induction of GADD gene transcription. This repression requires the minimal promoter region of GADD45a and GADD153 and is not dependent on the ER stress element or p53-binding sites in the regulatory regions of these genes. Further analysis by chromatin immunoprecipitation shows that c-Myc binds to the minimal promoter region of GADD45a and GADD153 in vivo. c-Myc-associated protein X (Max) is also bound to both GADD gene promoters, whereas c-Myc interacting zinc-finger protein 1 (Miz-1) is bound to the GADD153, but not GADD45a, promoter. RNA polymerase II (RNAPII) is recruited to the GADD gene promoters in the presence and absence of c-Myc, which suggests that c-Myc represses these genes through a post-RNAPII recruitment mechanism.

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References

  • Abcouwer SF, Schwarz C and Meguid RA . (1999). J. Biol. Chem., 274, 28645–28651.

  • Amundson SA, Zhan Q, Penn LZ and Fornace Jr AJ . (1998). Oncogene, 17, 2149–2154.

  • Bowen H, Lapham A, Phillips E, Yeung I, Alter-Koltunoff M, Levi BZ, Perry VH, Mann DA and Barton CH . (2003). J. Biol. Chem., 278, 36017–36026.

  • Bush A, Mateyak M, Dugan K, Obaya A, Adachi S, Sedivy J and Cole M . (1998). Genes Dev., 12, 3797–3802.

  • Carrier F, Georgel PT, Pourquier P, Blake M, Kontny HU, Antinore MJ, Gariboldi M, Myers TG, Weinstein JN, Pommier Y and Fornace Jr AJ . (1999). Mol. Cell. Biol., 19, 1673–1685.

  • Chen C, Nussenzweig A, Guo M, Kim D, Li GC and Ling CC . (1996). Oncogene, 13, 1659–1665.

  • Cheng C and Sharp PA . (2003). Mol. Cell. Biol., 23, 1961–1967.

  • Claassen GF and Hann SR . (2000). Proc. Natl. Acad. Sci., USA, 97, 9498–9503.

  • Corey LL, Weirich CS, Benjamin IJ and Kingston RE . (2003). Genes Dev., 17, 1392–1401.

  • Dang CV . (1999). Mol. Cell. Biol., 19, 1–11.

  • Eberhardy SR and Farnham PJ . (2001). J. Biol. Chem., 276, 48562–48571.

  • Eberhardy SR and Farnham PJ . (2002). J. Biol. Chem., 277, 40156–40162.

  • Facchini LM, Chen S, Marhin WW, Lear JN and Penn LZ . (1997). Mol. Cell. Biol., 17, 100–114.

  • Feng XH, Liang YY, Liang M, Zhai W and Lin X . (2002). Mol. Cell, 9, 133–143.

  • Fornace Jr AJ, Alamo Jr I and Hollander MC . (1988). Proc. Natl. Acad. Sci., USA, 85, 8800–8804.

  • Frank SR, Schroeder M, Fernandez P, Taubert S and Amati B . (2001). Genes Dev., 15, 2069–2082.

  • Gartel AL and Shchors K . (2003). Exp. Cell Res., 283, 17–21.

  • Gartel AL, Ye X, Goufman E, Shianov P, Hay N, Najmabadi F and Tyner AL . (2001). Proc. Natl. Acad. Sci., USA, 98, 4510–4515.

  • Grandori C, Cowley SM, James LP and Eisenman RN . (2000). Annu. Rev. Cell Dev. Biol., 16, 653–699.

  • Graunke DM, Fornace Jr AJ and Pieper RO . (1999). Nucleic Acids Res., 27, 3881–3890.

  • Herold S, Wanzel M, Beuger V, Frohme C, Beul D, Hillukkala T, Syvaoja J, Saluz HP, Haenel F and Eilers M . (2002). Mol. Cell, 10, 509–521.

  • Hollander MC, Sheikh MS, Bulavin DV, Lundgren K, Augeri-Henmueller L, Shehee R, Molinaro TA, Kim KE, Tolosa E, Ashwell JD, Rosenberg MP, Zhan Q, Fernandez-Salguero PM, Morgan WF, Deng CX and Fornace Jr AJ . (1999). Nat. Genet., 23, 176–184.

  • Izumi H, Molander C, Penn LZ, Ishisaki A, Kohno K and Funa K . (2001). J. Cell Sci., 114, 1533–1544.

  • Kime L and Wright SC . (2003). Biochem. J., 370, 291–298.

  • Krumm A, Meulia T, Brunvand M and Groudine M . (1992). Genes Dev., 6, 2201–2213.

  • Lee LA, Dolde C, Barrett J, Wu CS and Dang CV . (1996). J. Clin. Invest., 97, 1687–1695.

  • Li Z, Van Calcar S, Qu C, Cavenee WK, Zhang MQ and Ren B . (2003). Proc. Natl. Acad. Sci., USA, 100, 8164–8169.

  • Mai S and Jalava A . (1994). Nucleic Acids Res., 22, 2264–2273.

  • Mao DY, Watson JD, Yan PS, Barsyte-Lovejoy D, Khosravi F, Wong WW, Farnham PJ, Huang TH and Penn LZ . (2003). Curr. Biol., 13, 882–886.

  • Marhin WW, Chen S, Facchini LM, Fornace Jr AJ and Penn LZ . (1997). Oncogene, 14, 2825–2834.

  • Maytin EV and Habener JF . (1998). J. Invest. Dermatol., 110, 238–246.

  • O’Connell BC, Cheung AF, Simkevich CP, Tam W, Ren X, Mateyak MK and Sedivy JM . (2003). J. Biol. Chem., 278, 12563–12573.

  • Oster SK, Ho CS, Soucie EL and Penn LZ . (2002). Adv. Cancer Res., 84, 81–154.

  • Oster SK, Mao DY, Kennedy J and Penn LZ . (2003). Oncogene, 22, 1998–2010.

  • Outinen PA, Sood SK, Pfeifer SI, Pamidi S, Podor TJ, Li J, Weitz JI and Austin RC . (1999). Blood, 94, 959–967.

  • Penn LJ, Brooks MW, Laufer EM, Littlewood TD, Morgenstern JP, Evan GI, Lee WM and Land H . (1990). Mol. Cell. Biol., 10, 4961–4966.

  • Peukert K, Staller P, Schneider A, Carmichael G, Hanel F and Eilers M . (1997). EMBO J., 16, 5672–5686.

  • Piluso D, Bilan P and Capone JP . (2002). J. Biol. Chem., 277, 46799–46808.

  • Price BD and Calderwood SK . (1992). Cancer Res., 52, 3814–3817.

  • Ron D and Habener JF . (1992). Genes Dev., 6, 439–453.

  • Seoane J, Le HV and Massague J . (2002). Nature, 419, 729–734.

  • Seoane J, Pouponnot C, Staller P, Schader M, Eilers M and Massague J . (2001). Nat. Cell Biol., 3, 400–408.

  • Staller P, Peukert K, Kiermaier A, Seoane J, Lukas J, Karsunky H, Moroy T, Bartek J, Massague J, Hanel F and Eilers M . (2001). Nat. Cell Biol., 3, 392–399.

  • Takekawa M and Saito H . (1998). Cell, 95, 521–530.

  • Ubeda M and Habener JF . (2000). Nucleic Acids Res., 28, 4987–4997.

  • Vairapandi M, Azam N, Balliet AG, Hoffman B and Liebermann DA . (2000). J. Biol. Chem., 275, 16810–16819.

  • Wanzel M, Herold S and Eilers M . (2003). Trends Cell Biol., 13, 146–150.

  • Watson JD, Oster SK, Shago M, Khosravi F and Penn LZ . (2002). J. Biol. Chem., 277, 36921–36930.

  • Wu S, Cetinkaya C, Munoz-Alonso MJ, von der Lehr N, Bahram F, Beuger V, Eilers M, Leon J and Larsson LG . (2003). Oncogene, 22, 351–360.

  • Xiao Q, Claassen G, Shi J, Adachi S, Sedivy J and Hann S R . (1998). Genes Dev., 12, 3803–3808.

  • Ziegelbauer J, Shan B, Yager D, Larabell C, Hoffmann B and Tjian R . (2001). Mol. Cell, 8, 339–349.

  • Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT, Remotti H, Stevens JL and Ron D . (1998). Genes Dev., 12, 982–995.

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Acknowledgements

We thank members of the Penn laboratory for helpful discussions. We also thank Dr A Fornace for providing GADD45a cDNA and p53−/− MEFs, Dr R Tjian for human Miz-1 antibody and Dr A Lee for the GRP78 and GRP94 cDNAs. This work was supported by an operating grant from the National Cancer Institute of Canada with funds from the Canadian Cancer Society. DB-L is a recipient of CIHR fellowship and DYLM holds an NSERC PGS-B studentship.

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Barsyte-Lovejoy, D., Mao, D. & Penn, L. c-Myc represses the proximal promoters of GADD45a and GADD153 by a post-RNA polymerase II recruitment mechanism. Oncogene 23, 3481–3486 (2004). https://doi.org/10.1038/sj.onc.1207487

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