To stop the cell cycle, tumour suppressors such as the retinoblastoma protein ( Rb) apply the brakes. A Nature paper by Anna Lasorella and colleagues describes how Id2 — a dominant-negative inhibitor of helix–loop–helix DNA-binding proteins — gets the wheels turning again.
Retinoblastoma protein is essential for mammalian development: knockouts die during embryogenesis. Lasorella et al. report that knocking out Id2 rescues Rb−/− embryos. Defective myogenesis kills Id2−/−Rb−/− mice shortly after birth (they also have a 'hunchback' posture, see picture), but they show none of the hallmarks of Rb−/− mice — too much proliferation and apoptosis in the haematopoietic and nervous systems. Id2 therefore perpetrates the Rb−/−phenotype; but how? Immunoprecipitates revealed that active, hypophosphorylated Rb binds Id2 and, to tip the balance against tumour suppression, Id2 has to be in molar excess of Rb.
An intact Rb pathway is needed to prevent tumorigenesis, so Lasorella and colleagues asked whether Id2 is overexpressed in neuroblastoma cell lines, in which N-myc amplification typically bypasses Rb. Remarkably, Id2 expression correlated with N-myc amplification. What's more, Myc's effect on Id2 expression (which also extends to c-myc) is direct, owing to two high-affinity Myc-binding sites in the Id2 promoter. Deletion of these sites abolished Id2 expression in response to Myc.
References
ORIGINAL RESEARCH PAPER
Lasorella, A. et al. Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins. Nature 407, 592–598 (2000) [ PubMed]
FURTHER READING
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) [ PubMed]
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Brooksbank, C. Tampering with the cell cycle's brakes. Nat Rev Mol Cell Biol 1, 88 (2000). https://doi.org/10.1038/35040034
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DOI: https://doi.org/10.1038/35040034