It has been over a decade since the identification of the Id protein family, and to paraphrase a familiar phrase, ‘Id’s come a long way baby’. Originally identified as dominant negative antagonists of the basic helix–loop–helix transcription factor family, as described within this review other key cell cycle regulatory and transcription factors may be under Id control thus expanding its sphere of influence significantly. In addition to roles in normal developmental processes, strong genetic and cell biological data suggest that Id may play a crucial role in tumor progression and in the formation of blood vessels that support their growth.
Three sets of proteins have been identified most convincingly as being primary targets for the Id proteins: the ubiquitously expressed basic helix–loop–helix (bHLH) E-protein family, Rb and Ets family members. Genetic, reverse genetic and biochemical data all suggest interactions of various Id family members with these proteins in certain cell types at certain times. Id proteins interact avidly with E-proteins in vitro and in vivo and inhibit their binding to DNA and other members of the bHLH family. Loss of E2A proteins is partially compensated by loss of Id1 and over expression of Id inhibits E-protein mediated transcription activation consistent with E-proteins being a primary cellular target for Id. Since E-proteins are obligate partners for tissue specific bHLH proteins, this allows for a common biochemical mechanism to regulate the transcription and cell fate decisions in multiple cell types. More recently, strong genetic data support the notion that Id2 is restrained by Rb family members since phenotypes in Rb null embryos are partially surprised by loss of Id2. In addition, it has been shown that Id2 is required for myc mediated transformation as myc directly activates the Id2 enhancer and loss of Id2 blocks myc mediated transformation. Finally, while control of p16 by Id1,3 was suggested from the analysis of Id1,3 knockout mice which display elevated levels of p16, the work of E Hara and colleagues demonstrate that this effect is being mediated by an interaction of Id1 with Ets proteins which transactivate the p16 enhancer.
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