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

Nature volume 407, pages 592–598 (2000)Cite this article

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 Id2–Rb 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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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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Authors and Affiliations

  1. Department of Neurology,

    Anna Lasorella, Michela Noseda, Mercedes Beyna & Antonio Iavarone

  2. Department of Developmental and Molecular Biology,

    Antonio Iavarone

  3. Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, 10461, New York, USA

    Anna Lasorella & Antonio Iavarone

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  1. Anna Lasorella
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  4. Antonio Iavarone
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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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