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Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins

A Corrigendum to this article was published on 23 November 2000

Abstract

In mammalian cells, Id proteins coordinate proliferation and differentiation. Id2 is a dominant-negative antagonist of basic helix–loop–helix transcription factors and proteins of the retinoblastoma (Rb) family. Here we show that Id2Rb double knockout embryos survive to term with minimal or no defects in neurogenesis and haematopoiesis, but they die at birth from severe reduction of muscle tissue. In neuroblastoma, an embryonal tumour derived from the neural crest, Id2 is overexpressed in cells carrying extra copies of the N-myc gene. In these cells, Id2 is in molar excess of the active form of Rb. The overexpression of Id2 results from transcriptional activation by oncoproteins of the Myc family. Cell-cycle progression induced by Myc oncoproteins requires inactivation of Rb by Id2. Thus, a dual connection links Id2 and Rb: during normal cell-cycle, Rb prohibits the action of Id2 on its natural targets, but oncogenic activation of the Myc–Id2 transcriptional pathway overrides the tumour-suppressor function of Rb.

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Figure 1: Abnormal myogenesis in Id2-/- Rb-/- neonates.
Figure 2: Normal neurogenesis and erythropoiesis in Id2-/- Rb-/- neonates.
Figure 3: Cell-cycle analysis of complexes of Id2 with pocket proteins.
Figure 4: Id2 expression in neuroblastoma cell lines.
Figure 5: Id2 is an N-Myc target gene.
Figure 6: Id2 is a c-Myc target gene.
Figure 7: Binding and transactivation of Id2 promoter by Myc transcription factors.
Figure 8: Functional analysis of the Id2–Rb pathway in Myc-induced proliferation, transformation and apoptosis.

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References

  1. Norton, J. D., Deed, R. W., Craggs, G. & Sablitzky, F. Id helix-loop-helix proteins in cell growth and differentiation. Trends Cell Biol. 8, 58–65 (1998 ).

    CAS  PubMed  Google Scholar 

  2. Massari, M. E. & Murre, C. Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms. Mol. Cell. Biol. 20, 429–440 (2000).

    Article  CAS  Google Scholar 

  3. Iavarone, A., Garg, P., Lasorella, A., Hsu, J. & Israel, M. A. The helix-loop-helix protein Id-2 enhances cell proliferation and binds to the retinoblastoma protein. Genes Dev. 8, 1270–1284 (1994).

    Article  CAS  Google Scholar 

  4. Lasorella, A., Iavarone, A. & Israel, M. A. Id2 specifically alters regulation of the cell cycle by tumor suppressor proteins. Mol. Cell. Biol. 16, 2570–2578 (1996).

    Article  CAS  Google Scholar 

  5. Clarke, A. R. et al. Requirement for a functional Rb-1 gene in murine development. Nature 359, 328–330 (1992).

    Article  ADS  CAS  Google Scholar 

  6. Jacks, T. et al. Effects of an Rb mutation in the mouse. Nature 359, 295–300 (1992).

    Article  ADS  CAS  Google Scholar 

  7. Lee, E. Y. -H. P. et al. Mice deficient for Rb are nonviable and show defects in neurogenesis and hematopoesis. Nature 359, 288– 294 (1992).

    Article  ADS  CAS  Google Scholar 

  8. Zacksenhaus, E. et al. pRb controls proliferation, differentiation, and death of skeletal muscle cells and other lineages during embryogenesis. Genes Dev. 10, 3051–3064 (1996).

    Article  CAS  Google Scholar 

  9. Lee, E. Y. et al. Dual roles of the retinoblastoma protein in cell cycle regulation and neuron differentiation. Genes Dev. 8, 2008–2021 (1994).

    Article  CAS  Google Scholar 

  10. Jen, Y., Manova, K. & Benezra, R. Each member of the Id gene family exhibits a unique expression pattern in mouse gastrulation and neurogenesis. Dev. Dyn. 208, 92–106 ( 1997).

    Article  CAS  Google Scholar 

  11. Neuman, T. et al. Neuronal expression of regulatory helix-loop-helix factor Id2 gene in mouse. Dev. Biol. 160, 186– 195 (1993).

    Article  CAS  Google Scholar 

  12. Zhu, W. et al. Id gene expression during development and molecular cloning of the human Id-1 gene. Brain Res. Mol. Brain Res. 30, 312–326 (1995).

    Article  CAS  Google Scholar 

  13. Sherr, C. J. Cancer cell cycles. Science 274, 1672– 1677 (1996).

    Article  ADS  CAS  Google Scholar 

  14. Weinberg, R. A. The retinoblastoma protein and cell cycle control. Cell 81, 323–330 (1995).

    Article  CAS  Google Scholar 

  15. Martinsen, B. J. & Bronner-Fraser, M. Neural crest specification regulated by the helix-loop-helix repressor Id2. Science 281, 988–991 ( 1998).

    Article  ADS  CAS  Google Scholar 

  16. Maris, J. M. & Matthay, K. K. Molecular biology of neuroblastoma. J. Clin. Oncol. 17, 2264– 2279 (1999).

    Article  CAS  Google Scholar 

  17. Easton, J., Wei, T., Lahti, J. M. & Kidd, V. J. Disruption of the cyclin D/cyclin-dependent kinase/INK4/retinoblastoma protein regulatory pathway in human neuroblastoma. Cancer Res. 58, 2624–2632 (1998).

    CAS  PubMed  Google Scholar 

  18. Beltinger, C. P., White, P. S., Sulman, E. P., Maris, J. M. & Brodeur, G. M. No CDKN2 mutations in neuroblastomas. Cancer Res. 55, 2053-2055 ( 1995).

    Google Scholar 

  19. Diccianni, M. B., Chau, L. S., Batova, A., Vu, T. Q. & Yu, A. L. The p16 and p18 tumor suppressor genes in neuroblastoma: implications for drug resistance. Cancer Lett. 104, 183–192 (1996).

    Article  CAS  Google Scholar 

  20. Diccianni, M. B. et al. Frequent deregulation of p16 and the p16/G1 cell cycle-regulatory pathway in neuroblastoma. Int. J. Cancer 80, 145–154 (1999).

    Article  CAS  Google Scholar 

  21. Castresana, J. S., Gomez, L., Garcia-Miguel, P., Queizan, A. & Pestana, A. Mutational analysis of the p16 gene in human neuroblastomas. Mol. Carcinog. 18, 129–133 (1997).

    Article  CAS  Google Scholar 

  22. Kawamata, N., Seriu, T., Koeffler, H. P. & Bartram, C. R. Molecular analysis of the cyclin-dependent kinase inhibitor family: p16(CDKN2/MTS1/INK4A), p18(INK4C) and p27(Kip1) genes in neuroblastomas. Cancer 77, 570–575 (1996).

    Article  CAS  Google Scholar 

  23. Fan, X., Gomez, L., Nistal, M., Sierrasesumaga, L. & Castresana, J. S. Lack of gene amplification as a mechanism of CDK4 activation in human neuroblastoma. Oncol. Rep. 6, 647–650 (1999).

    CAS  PubMed  Google Scholar 

  24. Alevizopoulos, K., Vlach, J., Hennecke, S. & Amati, B. Cyclin E and c-Myc promote cell proliferation in the presence of p16INK4a and of hypophosphorylated retinoblastoma family proteins. EMBO J. 16, 5322–5333 (1997).

    Article  CAS  Google Scholar 

  25. Goodrich, D. W. & Lee, W. H. Abrogation by c-Myc of G1 phase arrest induced by RB protein but not by p53 [published erratum: Nature 360, 491 ( 1992)]. Nature 360, 177– 179 (1992).

    Article  ADS  CAS  Google Scholar 

  26. Amati, B., Alevizopoulos, K. & Vlach, J. Myc and the cell cycle. Front Biosci. 3, D250–268 (1998).

    Article  CAS  Google Scholar 

  27. Slack, R. S., El-Bizri, H., Wong, J., Belliveau, D. J. & Miller, F. D. A critical temporal requirement for the retinoblastoma protein family during neuronal determination. J. Cell Biol. 140, 1497–1509 (1998).

    Article  CAS  Google Scholar 

  28. Iavarone, A. & Massague, J. Repression of the CDK activator Cdc25A and cell-cycle arrest by cytokine TGF-beta in cells lacking the CDK inhibitor p15. Nature 387, 417– 422 (1997).

    Article  ADS  CAS  Google Scholar 

  29. Pietenpol, J. A. et al. TGF-β1 Inhibition of c-Myc transcription and growth in keratinocytes is abrogated by viral transforming protein with pRB binding domeins. Cell 61, 777–785 (1990).

    Article  CAS  Google Scholar 

  30. Neuman, K., Nornes, H. O. & Neuman, T. Helix-loop-helix transcription factors regulate Id2 gene promoter activity. FEBS Lett. 374, 279–283 (1995).

    Article  CAS  Google Scholar 

  31. Boyd, K. E., Wells, J., Gutman, J., Bartley, S. M. & Farnham, P. J. c-Myc target gene specificity is determined by a post-DNA-binding mechanism. Proc. Natl Acad. Sci. USA 95, 13887–13892 (1998).

    Article  ADS  CAS  Google Scholar 

  32. Morrow, M. A., Mayer, E. W., Perez, C. A., Adlam, M. & Siu, G. Overexpression of the Helix-Loop-Helix protein Id2 blocks T cell development at multiple stages. Mol. Immunol. 36, 491–503 ( 1999).

    Article  CAS  Google Scholar 

  33. Florio, M. et al. Id2 promotes apoptosis by a novel mechanism independent of dimerization to basic helix-loop-helix factors. Mol. Cell. Biol. 18, 5435–5444 ( 1998).

    Article  CAS  Google Scholar 

  34. Cooper, C. L., Brady, G., Bilia, F., Iscove, N. N. & Quesenberry, P. J. Expression of the Id family helix-loop-helix regulators during growth and development in the hematopoietic system. Blood 89, 3155–3165 ( 1997).

    CAS  PubMed  Google Scholar 

  35. Tsai, K. Y. et al. Mutation of E2f-1 suppresses apoptosis and inappropriate S phase entry and extends survival of Rb-deficient mouse embryos. Mol. Cell 2, 293–304 ( 1998).

    Article  CAS  Google Scholar 

  36. Jen, Y., Manova, K. & Benezra, R. Expression patterns of Id1, Id2, and Id3 are highly related but distinct from that of Id4 during mouse embryogenesis. Dev. Dyn. 207, 235–252 ( 1996).

    Article  CAS  Google Scholar 

  37. Yokota, Y. et al. Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2. Nature 397, 702–706 (1999).

    Article  ADS  CAS  Google Scholar 

  38. Lufkin, T. et al. Homeotic transformation of the occipital bones of the skull by ectopic expression of a homeobox gene. Nature 359 , 835–841 (1992).

    Article  ADS  CAS  Google Scholar 

  39. Jacobs, J. J., Kieboom, K., Marino, S., DePinho, R. A. & van Lohuizen, M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397, 164–168 ( 1999).

    Article  ADS  CAS  Google Scholar 

  40. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 ( 1997).

    Article  CAS  Google Scholar 

  41. Iavarone, A. & Massague, J. E2F and histone deacetylase mediate transforming growth factor beta repression of cdc25A during keratinocyte cell cycle arrest. Mol. Cell. Biol. 19, 916– 922 (1999).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Y. Yokota and T. Jacks for providing us with Id2+/- and Rb+/- mice, respectively; R. Russell for support in the preparation of pathological specimens and histological consultation; J. Massague for the Mv1Lu cell line expressing tetracycline-inducible c-Myc; E. Latres for p15-/- MEFs; C. Thiele for human neuroblastoma cell lines; R. Pestell for c-MycER cDNA; N. Schreiber-Agus for N-myc cDNA; M. van Lohuizen for LZRS-GFP retroviruses; and S. Lowe for retroviral vectors encoding activated ras and E1A. This work was supported by a grant from AIRC (Associazione Italiana per la Ricerca sul Cancro) to A.L., a grant from NIH (R01 to A.I.) and an institutional research grant from the American Cancer Society (A.I.). A.I. is recipient of a Sinsheimer Scholar award and M.N. is supported by a fellowship from Fondazione Beatrice Angelini.

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Correspondence to Antonio Iavarone.

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Lasorella, A., Noseda, M., Beyna, M. et al. Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins. Nature 407, 592–598 (2000). https://doi.org/10.1038/35036504

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