Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency

Article metrics

Abstract

The Myc oncogene regulates the expression of several components of the protein synthetic machinery, including ribosomal proteins, initiation factors of translation, RNA polymerase III and ribosomal DNA1,2. Whether and how increasing the cellular protein synthesis capacity affects the multistep process leading to cancer remains to be addressed. Here we use ribosomal protein heterozygote mice as a genetic tool to restore increased protein synthesis in Eμ-Myc/+ transgenic mice to normal levels, and show that the oncogenic potential of Myc in this context is suppressed. Our findings demonstrate that the ability of Myc to increase protein synthesis directly augments cell size and is sufficient to accelerate cell cycle progression independently of known cell cycle targets transcriptionally regulated by Myc. In addition, when protein synthesis is restored to normal levels, Myc-overexpressing precancerous cells are more efficiently eliminated by programmed cell death. Our findings reveal a new mechanism that links increases in general protein synthesis rates downstream of an oncogenic signal to a specific molecular impairment in the modality of translation initiation used to regulate the expression of selective messenger RNAs. We show that an aberrant increase in cap-dependent translation downstream of Myc hyperactivation specifically impairs the translational switch to internal ribosomal entry site (IRES)-dependent translation that is required for accurate mitotic progression. Failure of this translational switch results in reduced mitotic-specific expression of the endogenous IRES-dependent form of Cdk11 (also known as Cdc2l and PITSLRE)3,4,5, which leads to cytokinesis defects and is associated with increased centrosome numbers and genome instability in Eμ-Myc/+ mice. When accurate translational control is re-established in Eμ-Myc/+ mice, genome instability is suppressed. Our findings demonstrate how perturbations in translational control provide a highly specific outcome for gene expression, genome stability and cancer initiation that have important implications for understanding the molecular mechanism of cancer formation at the post-genomic level.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Myc-induced increases in protein synthesis regulates B-lymphocyte size, division and apoptosis before lymphomagenesis.
Figure 2: The ability of Myc to augment protein synthesis is necessary for its oncogenic potential.
Figure 3: Myc hyperactivation impairs the translational switch from cap- to IRES-dependent translation control during mitosis and blocks mitotic translation of the Cdk11 kinase.
Figure 4: Aberrant translation control downstream of Myc activation underlies cytokinesis defects and genome instability.

References

  1. 1

    Gomez-Roman, N. et al. Activation by c-Myc of transcription by RNA polymerases I, II and III. Biochem. Soc. Symp. 73, 141–154 (2006)

  2. 2

    Ruggero, D. & Pandolfi, P. P. Does the ribosome translate cancer? Nature Rev. Cancer 3, 179–192 (2003)

  3. 3

    Cornelis, S. et al. Identification and characterization of a novel cell cycle-regulated internal ribosome entry site. Mol. Cell 5, 597–605 (2000)

  4. 4

    Petretti, C. et al. The PITSLRE/CDK11p58 protein kinase promotes centrosome maturation and bipolar spindle formation. EMBO Rep. 7, 418–424 (2006)

  5. 5

    Wilker, E. W. et al. 14-3-3σ controls mitotic translation to facilitate cytokinesis. Nature 446, 329–332 (2007)

  6. 6

    Boxer, L. M. & Dang, C. V. Translocations involving c-myc and c-myc function. Oncogene 20, 5595–5610 (2001)

  7. 7

    Pelengaris, S., Khan, M. & Evan, G. c-MYC: more than just a matter of life and death. Nature Rev. Cancer 2, 764–776 (2002)

  8. 8

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

  9. 9

    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)

  10. 10

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

  11. 11

    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)

  12. 12

    Oliver, E. R., Saunders, T. L., Tarle, S. A. & Glaser, T. Ribosomal protein L24 defect in belly spot and tail (Bst), a mouse Minute . Development 131, 3907–3920 (2004)

  13. 13

    Harris, A. W. et al. The Eμ-myc transgenic mouse. A model for high-incidence spontaneous lymphoma and leukemia of early B cells. J. Exp. Med. 167, 353–371 (1988)

  14. 14

    Iritani, B. M. & Eisenman, R. N. c-Myc enhances protein synthesis and cell size during B lymphocyte development. Proc. Natl Acad. Sci. USA 96, 13180–13185 (1999)

  15. 15

    Thomas, G. An encore for ribosome biogenesis in the control of cell proliferation. Nature Cell Biol. 2, E71–E72 (2000)

  16. 16

    Yang, W. et al. Repression of transcription of the p27Kip1 cyclin-dependent kinase inhibitor gene by c-Myc. Oncogene 20, 1688–1702 (2001)

  17. 17

    Wu, S. et al. Myc represses differentiation-induced p21CIP1 expression via Miz-1-dependent interaction with the p21 core promoter. Oncogene 22, 351–360 (2003)

  18. 18

    Bouchard, C. et al. Direct induction of cyclin D2 by Myc contributes to cell cycle progression and sequestration of p27. EMBO J. 18, 5321–5333 (1999)

  19. 19

    Pyronnet, S. & Sonenberg, N. Cell-cycle-dependent translational control. Curr. Opin. Genet. Dev. 11, 13–18 (2001)

  20. 20

    Hellen, C. U. & Sarnow, P. Internal ribosome entry sites in eukaryotic mRNAmolecules. Genes Dev. 15, 1593–1612 (2001)

  21. 21

    Dave, B. J. et al. Deletion of cell division cycle 2-like 1 gene locus on 1p36 in non-Hodgkin lymphoma. Cancer Genet. Cytogenet. 108, 120–126 (1999)

  22. 22

    Nelson, M. A. et al. Abnormalities in the p34cdc2-related PITSLRE protein kinase gene complex (CDC2L) on chromosome band 1p36 in melanoma. Cancer Genet. Cytogenet. 108, 91–99 (1999)

  23. 23

    Lahti, J. M. et al. Alterations in the PITSLRE protein kinase gene complex on chromosome 1p36 in childhood neuroblastoma. Nature Genet. 7, 370–375 (1994)

  24. 24

    Chandramouli, A. et al. Haploinsufficiency of the cdc2l gene contributes to skin cancer development in mice. Carcinogenesis 28, 2028–2035 (2007)

  25. 25

    Fujiwara, T. et al. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 437, 1043–1047 (2005)

  26. 26

    Wade, M. & Wahl, G. M. c-Myc, genome instability, and tumorigenesis: the devil is in the details. Curr. Top. Microbiol. Immunol. 302, 169–203 (2006)

  27. 27

    Amsterdam, A. et al. Many ribosomal protein genes are cancer genes in zebrafish. PLoS Biol. 2, e139 (2004)

  28. 28

    Ganem, N. J., Storchova, Z. & Pellman, D. Tetraploidy, aneuploidy and cancer. Curr. Opin. Genet. Dev. 17, 157–162 (2007)

  29. 29

    Svitkin, Y. V. et al. Eukaryotic translation initiation factor 4E availability controls the switch between cap-dependent and internal ribosomal entry site-mediated translation. Mol. Cell. Biol. 25, 10556–10565 (2005)

  30. 30

    Yoon, A. et al. Impaired control of IRES-mediated translation in X-linked dyskeratosis congenita. Science 312, 902–906 (2006)

  31. 31

    Ruggero, D. L. et al. The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nature Med. 10, 484–486 (2004)

  32. 32

    Lenahan, M. K. & Ozer, H. L. Induction of c-myc mediated apoptosis in SV40-transformed rat fibroblasts. Oncogene 12, 1847–1854 (1996)

  33. 33

    Ferguson, A. M., White, L. S., Donovan, P. J. & Piwnica-Worms, H. Normal cell cycle and checkpoint responses in mice and cells lacking Cdc25B and Cdc25C protein phosphatases. Mol. Cell Biol. 25, 2853–2860 (2005)

  34. 34

    Beretta, L., Gingras, A. C., Svitkin Y.V, M. N. & Sonenberg, N. Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation. Embo J. 15, 658–664 (1996)

  35. 35

    Kallioniemi, O. P. et al. Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumors. Genes Chromosom. Cancer 10, 231–243 (1994)

Download references

Acknowledgements

We thank F. McCormick, G. Evan and P. O’Farrell for critically reading the manuscript; J. Testa for support and critical discussion during early stages of this work; W. Xu and R. Adamo for technical assistance; J. Copley for editing the manuscript, S. Cornelis for the Cdk11 IRES bicistronic vector. This work was supported by the NIH (D.R.) and the Sandler Foundation (M.B.).

Author Contributions M.B. and D.R. conceived the experiments. M.B. designed and M.B., A.Y., O.Z., M.C. and N.K. performed experiments and collected data. E.R. analysed the lymphoid compartment of ribosomal protein heterozygote mice. P.H.R. designed, performed and interpreted CGH experiments. M.B. and D.R. analysed the data and wrote the manuscript.

Author information

Correspondence to Maria Barna or Davide Ruggero.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-7 with Legends. (PDF 6443 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Barna, M., Pusic, A., Zollo, O. et al. Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency. Nature 456, 971–975 (2008) doi:10.1038/nature07449

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.