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

ABSTRACT 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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Available from: Judith Stegmüller, Sep 26, 2015
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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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    ABSTRACT: Staufen1 (Stau1) is a ribonucleic acid (RNA)-binding protein involved in the post-transcriptional regulation of gene expression. Recent studies indicate that Stau1-bound messenger RNAs (mRNAs) mainly code for proteins involved in transcription and cell cycle control. Consistently, we report here that Stau1 abundance fluctuates through the cell cycle in HCT116 and U2OS cells: it is high from the S phase to the onset of mitosis and rapidly decreases as cells transit through mitosis. Stau1 down-regulation is mediated by the ubiquitin-proteasome system and the E3 ubiquitin ligase anaphase promoting complex/cyclosome (APC/C). Stau1 interacts with the APC/C co-activators Cdh1 and Cdc20 via its first 88 N-terminal amino acids. The importance of controlling Stau155 levels is underscored by the observation that its overexpression affects mitosis entry and impairs proliferation of transformed cells. Microarray analyses identified 275 Stau155-bound mRNAs in prometaphase cells, an early mitotic step that just precedes Stau1 degradation. Interestingly, several of these mRNAs are more abundant in Stau155-containing complexes in cells arrested in prometaphase than in asynchronous cells. Our results point out for the first time to the possibility that Stau1 participates in a mechanism of post-transcriptional regulation of gene expression that is linked to cell cycle progression in cancer cells.
    Nucleic Acids Research 06/2014; 42(12). DOI:10.1093/nar/gku506 · 9.11 Impact Factor
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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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    ABSTRACT: This review will consider the impact of compromised PTEN signaling in brain patterning. We approach understanding the contribution of PTEN to nervous system development by surveying the findings from the numerous genetic loss-of-function models that have been generated as well as other forms of PTEN inactivation. By exploring the developmental programs influenced by this central transduction molecule, we can begin to understand the molecular mechanisms that shape the developing brain. A wealth of data indicates that PTEN plays critical roles in a variety of stages during brain development. Many of them are considered here including: stem cell proliferation, fate determination, polarity, migration, process outgrowth, myelination and somatic hypertrophy. In many of these contexts, it is clear that PTEN phosphatase activity contributes to the observed effects of genetic deletion or depletion, however recent studies have also ascribed non-catalytic functions to PTEN in regulating cell function. We also explore the potential impact this alternative pool of PTEN may have on the developing brain. Together, these elements begin to form a clearer picture of how PTEN contributes to the emergence of brain structure and binds form and function in the nervous system.
    Frontiers in Molecular Neuroscience 04/2014; 7(35). DOI:10.3389/fnmol.2014.00035 · 4.08 Impact Factor
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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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    ABSTRACT: Vascularization of the placenta is a critical developmental process that ensures fetal viability. Although the vascular health of the placenta affects both maternal and fetal well being, relatively little is known about the early stages of placental vascular development. The ubiquitin ligase Ankyrin repeat, SOCS box-containing 4 (ASB4) promotes embryonic stem cell differentiation to vascular lineages and is highly expressed early in placental development. The transcriptional regulator Inhibitor of DNA binding 2 (ID2) negatively regulates vascular differentiation during development and is a target of many ubiquitin ligases. Due to their overlapping spatiotemporal expression pattern in the placenta and contrasting effects on vascular differentiation, we investigated whether ASB4 regulates ID2 through its ligase activity in the placenta and whether this activity mediates vascular differentiation. In mouse placentas, ASB4 expression is restricted to a subset of cells that express both stem cell and endothelial markers. Placentas that lack Asb4 display immature vascular patterning and retain expression of placental progenitor markers, including ID2 expression. Using JAR placental cells, we determined that ASB4 ubiquitinates and represses ID2 expression in a proteasome-dependent fashion. Expression of ASB4 in JAR cells and primary isolated trophoblast stem cells promotes the expression of differentiation markers. In functional endothelial co-culture assays, JAR cells ectopically expressing ASB4 increased endothelial cell turnover and stabilized endothelial tube formation, both of which are hallmarks of vascular differentiation within the placenta. Co-transfection of a degradation-resistant Id2 mutant with Asb4 inhibits both differentiation and functional responses. Lastly, deletion of Asb4 in mice induces a pathology that phenocopies human pre-eclampsia, including hypertension and proteinuria in late-stage pregnant females. These results indicate that ASB4 mediates vascular differentiation in the placenta via its degradation of ID2.
    PLoS ONE 02/2014; 9(2):e89451. DOI:10.1371/journal.pone.0089451 · 3.23 Impact Factor
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