Lasorella, A, Stegmüller, J, Guardavaccaro, D, Liu, G, Carro, MS, Rothschild, G et al.. Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth. Nature 442: 471-474

Institute for Cancer Genetics, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
Nature (Impact Factor: 41.46). 08/2006; 442(7101):471-4. DOI: 10.1038/nature04895
Source: PubMed


In the developing nervous system, Id2 (inhibitor of DNA binding 2, also known as inhibitor of differentiation 2) enhances cell proliferation, promotes tumour progression and inhibits the activity of neurogenic basic helix-loop-helix (bHLH) transcription factors. The anaphase promoting complex/cyclosome and its activator Cdh1 (APC/C(Cdh1)) restrains axonal growth but the targets of APC/C(Cdh1) in neurons are unknown. Id2 and other members of the Id family are very unstable proteins that are eliminated as cells enter the quiescent state, but how they are targeted for degradation has remained elusive. Here we show that Id2 interacts with the core subunits of APC/C and Cdh1 in primary neurons. APC/C(Cdh1) targets Id2 for degradation through a destruction box motif (D box) that is conserved in Id1 and Id4. Depletion of Cdh1 stabilizes Id proteins in neurons, whereas Id2 D-box mutants are impaired for Cdh1 binding and remain stable in cells that exit from the cell cycle and contain active APC/C(Cdh1). Mutants of the Id2 D box enhance axonal growth in cerebellar granule neurons in vitro and in the context of the cerebellar cortex, and overcome the myelin inhibitory signals for growth. Conversely, activation of bHLH transcription factors induces a cluster of genes with potent axonal inhibitory functions including the gene coding for the Nogo receptor, a key transducer of myelin inhibition. Degradation of Id2 in neurons permits the accumulation of the Nogo receptor, thereby linking APC/C(Cdh1) activity with bHLH target genes for the inhibition of axonal growth. These findings indicate that deregulated Id activity might be useful to reprogramme quiescent neurons into the axonal growth mode.

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    • "Through the cell cycle-dependent proteolysis of numerous substrates, APC/C is required for cell survival and proliferation. The list of its known targets not only includes important cell cycle regulators such as cyclins, mitotic kinases and organizers of the cytoskeleton, but also modulators of gene expression like transcription factors and components of E3 ubiquitin ligases complexes (45,68–72). In Arabidopsis, APC/C also targets DRB4 (dsRNA-binding protein 4) a protein involved in RNA silencing (73). "
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    • "This complex has been shown to regulate axon formation and outgrowth by targeting transcriptional components for degradation. As described earlier, PTEN could be contributing to the timing of axon specification/outgrowth by increasing the association of APC and CDH1 (Lasorella et al., 2006; Stegmuller et al., 2006). The related complex of APC/CDC20 has been implicated in axonal outgrowth (De La Torre-Ubieta and Bonni, 2011), but whether PTEN associates with this complex as well remains to be determined. "
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    • "Within these processes, there is significant, but not ubiquitous redundancy between the individual ID proteins [56]–[59]. Further, ID proteins, and ID2 specifically, are known to be tightly regulated by E3 ligases [47], [60], [61]. Therefore, ID2 was chosen for investigation in this study due to its involvement in differentiation [54], vascular development [62], and placental maturation [25]. "
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