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Mnt: A Novel Max-interacting Protein and Myc Antagonist

  • P. J. Hurlin
  • C. Qúeva
  • R. N. Eisenman
Chapter
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 224)

Summary

We have identified a novel Max-binding protein, Mnt, which belongs to neither the Myc nor the Mad families (Hurlin et al. 1997). Mnt interacts with Max in vivo and functions as a transcriptional repressor of reporter genes containing promoter-proximal CACGTG sites. Mnt:Max complexes also efficiently suppress Myc-dependent activation from the same promoter. Transcription repression by Mnt maps to a 13 amino acid N-terminal region related to the Sin3 interaction domain (SID) of Mad proteins. This region of Mnt mediates interaction with mSin3 corepressor proteins and its deletion converts Mnt from a repressor to an activator and from a suppressor of Myc-dependent transformation to a cooperating oncogene. This latter result suggests that Mnt and Myc regulate an overlapping set of target genes in vivo. Expression of mnt RNA is observed in many tissues and in both proliferating and differentiating cells. Likewise, Mnt protein is expressed in many proliferating cell types in culture where both Myc:Max and Mnt:Max complexes are detected. An exception is P19 embryonal carcinoma cells, where Mnt is expressed and in a complex with Max, but Myc proteins are not detected. Mnt is likely to be a key regulator of Myc activities in vivo and, in addition, may possess Myc-independent functions.

Keywords

High Stringency Condition Dependent Transformation Proliferate Cell Type Sin3 Interaction Domain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Amin, C, A.J. Wagner and N.Hay. 1993. Sequence-specific transcriptional activation by Myc and repression by Max. Mol Cell Biol 13: 383–390.PubMedCentralPubMedGoogle Scholar
  2. Ayer, D.E., L. Kretzner and R.N. Eisenman. 1993a. Mad: A heterodimeric partner for Max that antagonizes Myc transcriptional activity. Cell 72: 211–222.CrossRefGoogle Scholar
  3. Ayer, D.E. and R.N. Eisenman. 1993b. A switch from Myc:Max to Mad:Max heterocomplexes accompanies monocyte/macrophage differentiation. Genes & Dev. 7: 2110–2119.CrossRefGoogle Scholar
  4. Ayer, D.E., Q. A. Lawrence and R.N. Eisenman. 1995. Mad-Max transcriptional repression is mediated by ternary complex formation with mammalian homologs of the yeast repressor Sin3. Cell 80: 767–776.PubMedCrossRefGoogle Scholar
  5. Blackwell, T.K., L. Kretzner, E.M. Blackwood, R.N. Eisenman and H. Weintraub. 1990. Sequence-specific DNA-binding by the c-Myc protein. Science 250: 1149–1151.PubMedCrossRefGoogle Scholar
  6. Blackwood, E.M. and R.N. Eisenman. 1991. Max: A helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. Science 251: 1211–1217.PubMedCrossRefGoogle Scholar
  7. Blackwood, E.M., B. Lüscher and R.N. Eisenman. 1992. Myc and Max associate in vivo. Genes and Dev. 6:71–80.PubMedCrossRefGoogle Scholar
  8. Charron, J., B.A. Malynn, P. Fisher, V. Stewart, L. Jeanotte, S.P. Goff, E.J. Robertson and F.W. Alt. 1992. Embryonic lethality in mice homozygous for a targeted disruption of the N-myc gene. Genes Dev. 6:2248–2257.PubMedCrossRefGoogle Scholar
  9. Davis, A. C., M. Wims, G.D. Spotts, S.R. Hann and A. Bradley. 1993. A null c-myc mutation causes lethality before 10.5 days of gestation in homozygous and reduced fertility in heterozygous female mice. Genes Dev. 7: 671–682.PubMedCrossRefGoogle Scholar
  10. Gu, W., K. Cechova, V. Tassi and Dalla-Favera, R. 1993. Opposite regulation of gene transcription by c-Myc and Max. Proc. Natl Acad. Sci USA 90: 2935–2939.PubMedCentralPubMedCrossRefGoogle Scholar
  11. Henriksson, M. and B. Liischer. 1996. Proteins of the Myc network: essential regulators of cell growth and differentiation. Adv. Cancer Res. 68: 109–182.PubMedCrossRefGoogle Scholar
  12. Hurlin, PJ., Queva, C. and R.N. Eisenman. 1997. Mnt, a Novel Max-Interacting Protein is Coexpressed with Myc in Proliferating Cells and Mediates Repression at Myc Binding Sites. 1997. Genes & Dev. in press.Google Scholar
  13. Hurlin, P.J., D.A. Ayer, C. Grandori and R.E. Eisenman, 1994. The Max transcription network: involvement of Mad in differentiation and an approach to identification of target genes. Cold Spring Harbor Symposium, Cold Spring Harbor Press, NY.Google Scholar
  14. Hurlin, P.J., K.P. Foley, D.E. Ayer, R.N. Eisenman, D. Hanahan and J.M. Arbeit. 1995a. Regulation of Myc and Mad during epidermal differentiation and HPV-associated tumorigenesis. Oncogene 11: 2487–2501.Google Scholar
  15. Hurlin, P.J., C. Quéva, P.J. Koskinen, E. Steingrímsson, D.E. Ayer, N.G. Copeland, N.A. Jenkins and R.N. Eisenman. 1995b. Mad3 and Mad4: Novel Max-interacting transcriptional repressors that suppress c-Myc-dependent transformation and are expresed during neural and epidermal differentiation. EMBO J. 14: 5646–5659.Google Scholar
  16. Koskinen, P.J., D.G. Ayer and R.E. Eisenman. 1995. Repression of Myc-Ras cotransformation by Mad is mediated by multiple protein-protein interactions. Cell Growth and Differ. 6: 623–629.Google Scholar
  17. Kretzner, L., E.M. Blackwood, R.N. Eisenman. 1992. The Myc and Max proteins possess distinct transcriptional activities. Nature 359: 426–429.PubMedCrossRefGoogle Scholar
  18. Lahoz, E.G., L. Xu, N. Schreiber-Agus and R.A. DePinho. 1994. Suppression of Myc, but not Ela transformation activity by Max-associated proteins, Mad and Mxi1. Proc. Natl Acad. Sci. USA 91: 5503–5507.PubMedCentralPubMedCrossRefGoogle Scholar
  19. Moens, C.B., A.B. Auerbach, R.A. Conlon, A.L. Joyner and Rossant, J. 1992. A targeted mutation reveals a role for N-myc in branching morphogenesis in the embryonic mouse lung. Genes & Dev. 6:691–704.CrossRefGoogle Scholar
  20. Moens, C. B., B. R. Stanton, L. F. Parada and J. Rossant. 1993. Defects in heart and lung development in compund heterozygotes for two different targeted mutations at the N-myc locus. Development 119: 485–499.PubMedGoogle Scholar
  21. Prendergast, G. C., D. Lawe and E. B. Ziff. 1991. Association of Myn, the murine homolog of Max, with c-Myc stimulates methylation-sensitive DNA binding and Ras cotransformation. Cell 65: 395–407.PubMedCrossRefGoogle Scholar
  22. Sawai, S., A. Shimono, Y. Wakamatsu, C. Palmes, K. Hanaoka and H. Kondoh. 1993. Defects of embryonic organogenesis resulting from targeted disruption of the N-myc gene in the mouse. Development 117: 1445–1455.PubMedGoogle Scholar
  23. Schreiber-Agus, N., L. Chin, K. Chen, R. Torres, G. Rao, P. Guida, A.I. Skoultchi, and R. DePinho. 1995. An amino-terminal domain of Mxi1 mediates anti-Myc oncogenic activity and interacts with a homolog of the yeast transcriptional repressor SIN3. Cell 80: 777–786.PubMedCrossRefGoogle Scholar
  24. Stanton, B.R., A.S. Perkins, L. Tessarollo, D.A. Sassoon and L.F. Parada. 1992. Loss of N-myc function results in embryonic lethality and failure of the epithelial component of the embryo. Genes Dev. 6: 2235–2247.PubMedCrossRefGoogle Scholar
  25. Zervos, A. S., J. Gyuris, and R. Brent. 1993. Mxil, a protein that specifically interacts with Max to bind Myc-Max recognition sites. Cell 72: 223–232.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1997

Authors and Affiliations

  • P. J. Hurlin
    • 1
  • C. Qúeva
    • 1
  • R. N. Eisenman
    • 1
  1. 1.Division of Basic SciencesFred Hutchinson Cancer Research CenterSeattleUSA

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