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  • Original Paper
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Mnt transcriptional repressor is functionally regulated during cell cycle progression

Oncogene volume 24, pages 8326–8337 (2005)Cite this article

Abstract

The Myc/Max/Mad network of transcription factors regulates cell proliferation, differentiation, and transformation. Similar to other proteins of the network, Mnt forms heterodimers with Max and binds CACGTG E-Box elements. Transcriptional repression by Mnt is mediated through association with mSin3, and deletion of the mSin3-interacting domain (SID) converts Mnt to a transcriptional activator. Mnt is coexpressed with Myc in proliferating cells and has been suggested to be a modulator of Myc function. We report that Mnt is expressed both in growth-arrested and proliferating mouse fibroblasts and is phosphorylated when resting cells are induced to re-enter the cell cycle. Importantly, the interaction between Mnt and mSin3 is disrupted upon serum stimulation resulting in decreased Mnt-associated HDAC activity. Furthermore, we demonstrate that Mnt binds and recruits mSin3 to the Myc target gene cyclin D2 in quiescent mouse fibroblasts. Interference with Mnt expression by RNAi resulted in upregulation of cyclin D2 expression in growth-arrested fibroblasts, supporting the view that Mnt represses cyclin D2 transcription in quiescent cells. Our data suggest a model in which phosphorylation of Mnt at cell cycle entry results in disruption of Mnt–mSin3–HDAC1 interaction, which allows induction of Myc target genes by release of Mnt-mediated transcriptional repression.

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References

  • Amati B, Dalton S, Brooks MW, Littlewood TD, Evan GI and Land H . (1992). Nature, 359, 423–426.

  • Ayer DE and Eisenman RN . (1993). Genes Dev., 7, 2120–2129.

  • Ayer DE, Lawrence QA and Eisenman RN . (1995). Cell, 80, 767–776.

  • Barrera-Hernandez G, Cultrato CM, Pianetti S and Segal S . (2000). Mol. Cell. Biol., 20, 4253–4264.

  • Bejarano MT, Albihn A, Cornvik T, Brijker SO, Asker C, Osorio LM and Henriksson M . (2000). Exp. Cell Res., 260, 61–72.

  • Berberich SJ and Cole MD . (1992). Genes Dev., 6, 166–176.

  • Blackwood EM, Lüscher B and Eisenman RN . (1992). Genes Dev., 6, 71–80.

  • Bouchard C, Dittrich O, Kiermaier A, Dohmann K, Menkel A, Eilers M and Lüscher B . (2001). Genes Dev., 15, 2042–2047.

  • Bousset K, Henriksson M, Lüscher-Firzlaff JM, Litchfield DW and Lüscher B . (1993). Oncogene, 8, 3211–3220.

  • Cole MD . (1986). Annu. Rev. Genet., 20, 361–385.

  • Cvekl Jr A, Zavadil J, Birshtein BK, Gritzer MA and Cvekl A . (2004). Eur. J. Cancer, 40, 2525–2532.

  • Eberhardy SR, D’Cunha CA and Farnham PJ . (2000). J. Biol. Chem., 275, 33798–33805.

  • Ellenrieder V, Zhang JS, Kaczynski J and Urrutia R . (2002). EMBO J., 21, 2451–2460.

  • Fernandez PC, Frank SR, Wang L, Schroeder M, Liu S, Greene J, Cocito A and Amati B . (2003). Genes Dev., 17, 1115–1129.

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

  • Grynfeld Smith A, Popov N, Imreh M, Axelson H and Henriksson M . (2004). J. Cell Biochem., 92, 1282–1295.

  • Hassig CA, Fleischer TC, Billin AN, Schreiber SL and Ayer DE . (1997). Cell, 89, 341–347.

  • Henriksson M and Lüscher B . (1996). Adv. Cancer Res., 68, 109–182.

  • Hurlin PJ, Quéva C and Eisenman RN . (1997a). Genes Dev., 11, 44–58.

  • Hurlin PJ, Quéva C and Eisenman RN . (1997b). Curr. Top Microbiol. Immunol., 224, 115–121.

  • Hurlin PJ, Quéva C, Koskinen PJ, Steingrimsson E, Ayer DE, Copeland NG, Jenkins NA and Eisenman RN . (1995). EMBO J., 14, 5646–5659.

  • Hurlin PJ, Steingrimsson E, Copeland NG, Jenkins NA and Eisenman RN . (1999). EMBO J., 18, 7019–7028.

  • Hurlin PJ, Zhou ZQ, Toyo-oka K, Ota S, Walker WL, Hirotsune S and Wynshaw-Boris A . (2003). EMBO J., 22, 4584–4596.

  • Hurlin PJ, Zhou ZQ, Toyo-oka K, Ota S, Walker WL, Hirotsune S and Wynshaw-Boris A . (2004). Cell Cycle, 3, 97–99.

  • Imai YI, Kurokawa M, Yamaguchi Y, Izutsu K, Nitta E, Mitani K, Satake M, Noda T, Ito Y and Hirai H . (2004). Mol. Cell. Biol., 24, 1033–1043.

  • Kretzner L, Blackwood EM and Eisenman RN . (1992). Nature, 359, 426–429.

  • Laherty CD, Yang WM, Sun JM, Davie JR, Seto E and Eisenman RN . (1997). Cell, 89, 349–356.

  • Larsson LG, Pettersson M, Öberg F, Nilsson K and Lüscher B . (1994). Oncogene, 9, 1247–1252.

  • 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.

  • McMahon SB, Van Buskirk HA, Dugan KA, Copeland TD and Cole MD . (1998). Cell, 94, 363–374.

  • Meroni G, Reymond A, Alcalay M, Borsani G, Tanigami A, Tonlorenzi R, Lo Nigro C, Messali S, Zollo M, Ledbetter DH, Brent R, Ballabio A and Carrozo R . (1997). EMBO J., 16, 2892–2906.

  • Nigro CL, Venesio T, Reymond A, Meroni G, Alberici P, Cainarca S, Enrico F, Stack M, Ledbetter DH, Liscia DS, Ballabio A and Carrozzo R . (1998). Genomics, 49, 275–282.

  • Nilsson JA and Cleveland JL . (2004). Cell cycle, 3, 588–590.

  • Nilsson JA, Maclean KH, Keller UB, Pendeville H, Baudino TA and Cleveland JL . (2004). Mol. Cell. Biol., 24, 1560–1569.

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

  • Orian A, Van Steensel B, Delrow J, Bussemaker HJ, Li L, Sawado T, Williams E, Loo LW, Cowley SM, Yost C, Pierce S, Edgar BA, Parkhurst SM and Eisenman RN . (2003). Genes Dev., 17, 1101–1114.

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

  • Park J, Kunjibettu S, McMahon SB and Cole MD . (2001). Genes Dev., 15, 1619–1624.

  • Peyrefitte S, Kahn D and Haenlin M . (2001). Mech. Dev., 104, 99–104.

  • Quéva C, Hurlin PJ, Foley KP and Eisenman RN . (1998). Oncogene, 16, 967–977.

  • Sage J, Miller AL, Perez-Mancer PA, Wysocki JM and Jacks T . (2003). Nature, 424, 223–228.

  • Schreiber-Agus N, Chin L, Chen R, Torres G, Guida P, Skoultchi AI and DePinho R . (1995). Cell, 80, 777–786.

  • Shang Y, Hu X, diRenzo J, Lazar MA and Brown M . (2000). Cell, 103, 843–852.

  • Sommer A, Hilfenhaus S, Menkel A, Kremmer E, Seiser C, Loidl P and Lüscher B . (1997). Curr. Biol., 7, 357–365.

  • Sommer A, Waha A, Tonn J, Sorensen N, Hurlin PJ, Eisenman RN, Lüscher B and Pietsch T . (1999). Int. J. Cancer, 82, 810–816.

  • 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., 4, 392–399.

  • Takahashi T, Konishi H, Kozaki K-I, Osada H, Saji S, Takahashi T and Takahashi T . (1998). Jpn. J. Cancer Res., 89, 347–351.

  • Toyo-Oka K, Hirotsune S, Gambello MJ, Zhou ZQ, Olson L, Rosenfeld MG, Eisenman R, Hurlin P and Wynshaw-Boris A . (2004). Hum. Mol. Genet., 13, 1057–1067.

  • Walker W, Zhou Z-Q, Ota S, Wynshaw-Boris A and Hurlin PJ . (2005). J. Cell Biol., 169, 405–413.

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

  • Wolffe AP . (1997). Nature, 387, 16–17.

  • Xu D, Popov N, Hou M, Wang Q, Björkholm M, Gruber A, Menkel AR and Henriksson M . (2001). Proc. Natl. Acad. Sci. USA, 98, 3826–3831.

  • Zervos AS, Gyuris J and Brent R . (1993). Cell, 72, 223–232.

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Acknowledgements

We are grateful to A Drapier for initial RNAi experiments, J Marijsse for help with immunoprecipitations, R Bernarnds, D Ayer, and RN Eisenman for plasmids, RN Eisenman for the Mnt polyclonal antibody, M Eilers, M Masucci, A-K Östlund-Farrants, G Klein, and members of our laboratory for fruitful discussions, and M Masucci for critical reading of the manuscript. This work was supported by Karolinska Institutet, the Robert Lundberg's Research Fund, the Swedish Cancer Society, the Swedish Research Council, and the King Gustaf V Jubilee Foundation. N Popov and T Wahlström were recipients of stipends from the Cancer Research Institute and Concern Foundation (USA). N Popov was also supported by a training grant from the Karolinska Institutet.

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  1. Nikita Popov and Therese Wahlström: These two authors contributed equally to this work

Authors and Affiliations

  1. Microbiology and Tumor Biology Center, Karolinska Institutet, Box 280, SE-171 77, Stockholm, Sweden

    Nikita Popov, Therese Wahlström & Marie Henriksson

  2. Shriners Hospitals for Children and Department of Cell and Developmental Biology, Oregon Health Sciences University, Portland, OR, USA

    Peter J Hurlin

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  1. Nikita Popov
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Correspondence to Marie Henriksson.

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Popov, N., Wahlström, T., Hurlin, P. et al. Mnt transcriptional repressor is functionally regulated during cell cycle progression. Oncogene 24, 8326–8337 (2005). https://doi.org/10.1038/sj.onc.1208961

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