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Max-independent functions of Myc in Drosophila melanogaster

Nature Genetics volume 40, pages 1084–1091 (2008)Cite this article

Abstract

Myc proteins are powerful proto-oncoproteins and important promoters of growth and proliferation during normal development. They are thought to exercise their effects upon binding to their partner protein Max, and their activities are largely antagonized by complexes of Max with Mnt or an Mxd family protein. Although the biological functions of Myc, Mxd and Mnt have been intensively studied, comparatively little is known about the in vivo role of Max. Here we generate Max loss-of-function and reduction-of-function mutations in Drosophila melanogaster to address the contribution of Max to Myc-dependent growth control. We find that many biological activities of Myc do not, or only partly, require the association with Max—for example, the control of endoreplication and cell competition—and that a Myc mutant that does not interact with Max retains substantial biological activity. We further show that Myc can control RNA polymerase III independently of Max, which explains some of Myc's observed biological activities. These studies show the ability of Myc to function independently of Max in vivo and thus change the current model of Max network function.

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Figure 1: Max null mutants are delayed in development and die before eclosion.
Figure 2: Loss of Max leads to milder defects than simultaneous loss of Myc and Mnt.
Figure 3: C-terminally truncated Myc does not interact with Max but retains partial function.
Figure 4: Max mutant mitotic clones grow better than dm Mnt double-mutant clones.
Figure 5: Myc overexpression in the eye induces growth and apoptosis in a largely Max-dependent and Max-independent manner, respectively.
Figure 6: Myc interacts with Brf and can induce RNA Pol III targets independently of Max.

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References

  1. Vita, M. & Henriksson, M. The Myc oncoprotein as a therapeutic target for human cancer. Semin. Cancer Biol. 16, 318 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Dang, C.V. et al. The c-Myc target gene network. Semin. Cancer Biol. 16, 253 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Wanzel, M., Herold, S. & Eilers, M. Transcriptional repression by Myc. Trends Cell Biol. 13, 146–150 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Kretzner, L., Blackwood, E.M. & Eisenman, R.N. Myc and Max proteins possess distinct transcriptional activities. Nature 359, 426–429 (1992).

    Article  CAS  PubMed  Google Scholar 

  5. Amati, B. et al. Transcriptional activation by the human c-Myc oncoprotein in yeast requires interaction with Max. Nature 359, 423–426 (1992).

    Article  CAS  PubMed  Google Scholar 

  6. Facchini, L.M., Chen, S.J., Marhin, W.W., Lear, J.N. & Penn, L.Z. The Myc negative autoregulation mechanism requires Myc-Max association and involves the c-Myc P2 minimal promoter. Mol. Cell. Biol. 17, 100–114 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mao, D.Y. et al. Analysis of Myc bound loci identified by CpG island arrays shows that Max is essential for Myc-dependent repression. Curr. Biol. 13, 882–886 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Amati, B. et al. Oncogenic activity of the c-Myc protein requires dimerization with Max. Cell 72, 233–245 (1993).

    Article  CAS  PubMed  Google Scholar 

  9. Amati, B., Littlewood, T.D., Evan, G.I. & Land, H. The c-Myc protein induces cell cycle progression and apoptosis through dimerization with Max. EMBO J. 12, 5083–5087 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Adhikary, S. & Eilers, M. Transcriptional regulation and transformation by Myc proteins. Nat. Rev. Mol. Cell Biol. 6, 635–645 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Hurlin, P.J. & Huang, J. The MAX-interacting transcription factor network. Semin. Cancer Biol. 16, 265 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Hurlin, P.J. et al. Deletion of Mnt leads to disrupted cell cycle control and tumorigenesis. EMBO J. 22, 4584–4596 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nilsson, J.A. et al. Mnt loss triggers Myc transcription targets, proliferation, apoptosis, and transformation. Mol. Cell. Biol. 24, 1560–1569 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shen-Li, H. et al. Essential role for Max in early embryonic growth and development. Genes Dev. 14, 17–22 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Gallant, P., Shiio, Y., Cheng, P.F., Parkhurst, S.M. & Eisenman, R.N. Myc and Max homologs in Drosophila. Science 274, 1523–1527 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Schreiber-Agus, N. et al. Drosophila Myc is oncogenic in mammalian cells and plays a role in the diminutive phenotype. Proc. Natl. Acad. Sci. USA 94, 1235–1240 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Johnston, L.A., Prober, D.A., Edgar, B.A., Eisenman, R.N. & Gallant, P. Drosophila myc regulates cellular growth during development. Cell 98, 779–790 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Pierce, S.B. et al. dMyc is required for larval growth and endoreplication in Drosophila. Development 131, 2317–2327 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Montero, L., Müller, N. & Gallant, P. Induction of apoptosis by Drosophila Myc. Genesis 46, 104–111 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. De La Cova, C., Abril, M., Bellosta, P., Gallant, P. & Johnston, L.A. Drosophila myc regulates organ size by inducing cell competition. Cell 117, 107–116 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Moreno, E. & Basler, K. dMyc transforms cells into super-competitors. Cell 117, 117–129 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Gallant, P. Myc, cell competition, and compensatory proliferation. Cancer Res. 65, 6485–6487 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Trumpp, A. et al. c-Myc regulates mammalian body size by controlling cell number but not cell size. Nature 414, 768–773 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Benassayag, C. et al. Human c-Myc isoforms differentially regulate cell growth and apoptosis in Drosophila melanogaster. Mol. Cell. Biol. 25, 9897–9909 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Orian, A. et al. Genomic binding by the Drosophila Myc, Max, Mad/Mnt transcription factor network. Genes Dev. 17, 1101–1114 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hulf, T. et al. Whole-genome analysis reveals a strong positional bias of conserved dMyc-dependent E-boxes. Mol. Cell. Biol. 25, 3401–3410 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Grandori, C. et al. c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I. Nat. Cell Biol. 7, 311–318 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Arabi, A. et al. c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription. Nat. Cell Biol. 7, 303–310 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Grewal, S.S., Li, L., Orian, A., Eisenman, R.N. & Edgar, B.A. Myc-dependent regulation of ribosomal RNA synthesis during Drosophila development. Nat. Cell Biol. 7, 295–302 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Loo, L.W. et al. The transcriptional repressor dMnt is a regulator of growth in Drosophila melanogaster. Mol. Cell. Biol. 25, 7078–7091 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gallant, P. Myc / Max / Mad in invertebrates - the evolution of the Max network. Curr. Top. Microbiol. Immunol. 302, 235–253 (2006).

    CAS  PubMed  Google Scholar 

  32. Pierce, S.B. et al. Drosophila growth and development in the absence of dMyc and dMnt. Dev. Biol. 315, 303 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Maines, J.Z., Stevens, L.M., Tong, X. & Stein, D. Drosophila dMyc is required for ovary cell growth and endoreplication. Development 131, 775–786 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Blackwood, E.M. & Eisenman, R.N. Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. Science 251, 1211–1217 (1991).

    Article  CAS  PubMed  Google Scholar 

  35. La Rocca, S.A., Crouch, D.H. & Gillespie, D.A. c-Myc inhibits myogenic differentiation and myoD expression by a mechanism which can be dissociated from cell transformation. Oncogene 9, 3499–3508 (1994).

    CAS  PubMed  Google Scholar 

  36. Nair, S.K. & Burley, S.K. X-ray structures of Myc-Max and Mad-Max recognizing DNA. Molecular bases of regulation by proto-oncogenic transcription factors. Cell 112, 193–205 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Newsome, T.P., Asling, B. & Dickson, B.J. Analysis of Drosophila photoreceptor axon guidance in eye-specific mosaics. Development 127, 851–860 (2000).

    CAS  PubMed  Google Scholar 

  38. Secombe, J., Li, L., Carlos, L. & Eisenman, R.N. The Trithorax group protein Lid is a trimethyl histone H3K4 demethylase required for dMyc-induced cell growth. Genes Dev. 21, 537–551 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Goodliffe, J.M., Wieschaus, E. & Cole, M.D. Polycomb mediates Myc autorepression and its transcriptional control of many loci in Drosophila. Genes Dev. 19, 2941–2946 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gomez-Roman, N., Grandori, C., Eisenman, R.N. & White, R.J. Direct activation of RNA polymerase III transcription by c-Myc. Nature 421, 290–294 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Isogai, Y., Takada, S., Tjian, R. & Keles, S. Novel TRF1/BRF target genes revealed by genome-wide analysis of Drosophila Pol III transcription. EMBO J. 26, 79–89 (2007).

    Article  PubMed  Google Scholar 

  42. Bellosta, P. et al. Myc interacts genetically with Tip48/Reptin and Tip49/Pontin to control growth and proliferation during Drosophila development. Proc. Natl. Acad. Sci. USA 102, 11799–11804 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wert, M., Kennedy, S., Palfrey, H.C. & Hay, N. Myc drives apoptosis in PC12 cells in the absence of Max. Oncogene 20, 3746–3750 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Cowling, V.H. & Cole, M.D. The Myc transactivation domain promotes global phosphorylation of the RNA polymerase II carboxy-terminal domain independently of direct DNA binding. Mol. Cell. Biol. 27, 2059–2073 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kleine-Kohlbrecher, D., Adhikary, S. & Eilers, M. Mechanisms of transcriptional repression by Myc. Curr. Top. Microbiol. Immunol. 302, 51–62 (2006).

    CAS  PubMed  Google Scholar 

  46. Bischof, J., Maeda, R.K., Hediger, M., Karch, F. & Basler, K. An optimized transgenesis system for Drosophila using germ-line-specific phiC31 integrases. Proc. Natl. Acad. Sci. USA 104, 3312–3317 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Stocker, H. et al. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat. Cell Biol. 5, 559–565 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Takada, S., Lis, J.T., Zhou, S. & Tjian, R.A. TRF1:BRF complex directs Drosophila RNA polymerase III transcription. Cell 101, 459 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Prober, D.A. & Edgar, B.A. Growth regulation by oncogenes–new insights from model organisms. Curr. Opin. Genet. Dev. 11, 19–26 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Prober, D.A. & Edgar, B.A. Ras1 promotes cellular growth in the Drosophila wing. Cell 100, 435–446 (2000).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank S. Pierce and R. Eisenman (Fred Hutchinson Cancer Research Center) for providing us with a dm Mnt recombinant chromosome before publication; K. Basler, J. Bischof (University of Zürich), E. Hafen, H. Stocker (ETH Zürich), S. Takada (MD Anderson) and D. Stein (University of Texas, Austin) for flies and antibodies; H. Stocker and C. Hugentobler for advice; N. Müller, R. Perez and other members of the lab for technical help and support; O. Carreño, L. Damerius, N. Arnold, N. Meier and S. Peterhans for help with fly work; and K. Basler and R. Eisenman for critical comments on the manuscript. This work was financially supported by a grant from the Schweizerische Nationalfonds (SNF).

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  1. Dominik Steiger

    Present address: Present address: Institut für Molekularbiologie, Universität Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.,

  2. Michael Furrer and Daniela Schwinkendorf: These authors contributed equally to this work.

Authors and Affiliations

  1. Zoologisches Institut, Universität Zürich, Winterthurerstrasse 190, Zürich, 8057, Switzerland

    Dominik Steiger, Michael Furrer, Daniela Schwinkendorf & Peter Gallant

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Correspondence to Peter Gallant.

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Steiger, D., Furrer, M., Schwinkendorf, D. et al. Max-independent functions of Myc in Drosophila melanogaster. Nat Genet 40, 1084–1091 (2008). https://doi.org/10.1038/ng.178

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