The emerging role of APC/CCdh1 in controlling differentiation, genomic stability and tumor suppression

Wäsch, Ralph; Robbins, Jonathan A.; Cross, Frederick R.

doi:10.1038/onc.2009.325

Cited by 98 publications

(76 citation statements)

References 101 publications

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“…Consistent with such a significant phenotypic change it is not surprising that the APC/C is activated in its Cdh1 and not the Cdc20-bound form. First, the APC/C-Cdh1 has a much broader substrate specificity, including many crucial activators of cell division and DNA replication that are not targeted by APC/C-Cdc20 (Peters, 2006;Wa¨sch et al, 2010). Second, because p21 is a substrate of the APC/CCdc20 in mitosis (Amador et al, 2007) and of SCF Skp2 during interphase (Yu et al, 1998;Bornstein et al, 2003;Wang et al, 2005), APC/C-Cdh1-dependent degradation of Cdc20 (Pfleger and Kirschner, 2000) and Skp2 (Bashir et al, 2004;Wei et al, 2004;Liu et al, 2007) might reinforce the p53-dependent induction of p21 expression after DNA damage.…”

Section: Discussionmentioning

confidence: 99%

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p53- and p21-dependent premature APC/C–Cdh1 activation in G2 is part of the long-term response to genotoxic stress

2010

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The long-term cellular response to DNA damage is controlled by the tumor suppressor p53. It results in cellcycle arrest followed by DNA repair and, depending on the degree of damage inflicted, premature senescence or apoptotic cell death. Here we show that in normal diploid fibroblasts the ubiquitin ligase anaphase-promoting complex or cyclosome (APC/C)-Cdh1 becomes prematurely activated in G2 as part of the sustained long-term but not the rapid short-term response to genotoxic stress and results in the degradation of numerous APC/C substrates. Using HCT116 somatic knockout cells we show that mechanistically premature APC/C activation depends on p53 and its transcriptional target p21 that mediates the signal through downregulation of the APC/C inhibitor Emi1. Cdc14B is dispensable in this setting but might function redundantly. Our data suggest an unexpected role for the APC/C in executing a part of the p53-dependent DNA damage response that leads to premature senescence.

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Section: Discussionmentioning

confidence: 99%

“…It relies on Cdh1, the G 1 -phase-specific adaptor subunit (Wa¨sch et al, 2010), and goes hand in hand with marked decline of Emi1 expression, the main interphase inhibitor of the APC/C (Hsu et al, 2002). Importantly, activation of APC/C-Cdh1 is required for timely destruction of a broad range of APC/C substrates after DNA damage.…”

Section: Introductionmentioning

confidence: 99%

p53- and p21-dependent premature APC/C–Cdh1 activation in G2 is part of the long-term response to genotoxic stress

2010

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“…The RXXL motif, or D-box, at residues 29-32 of cyclin D1 is required for its degradation in response to gamma irradiation (24) and is a conserved motif of APC/C targets that is recognized by the Cdh1 coactivator (27,29). Mutation of this sequence to QXXA abolished degradation of cyclin D1 by C/EBPδ, and Cdc27 in cotransfection experiments in MCF-7 ( Fig.…”

Section: Cdc27-mediated Cyclin D1 Degradation Requires the D-box And Anmentioning

confidence: 99%

C/EBPδ targets cyclin D1 for proteasome-mediated degradation via induction of CDC27/APC3 expression

Pawar

Sarkar

Balamurugan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The transcription factor CCAAT/enhancer binding protein δ (C/EBPδ, CEBPD, NFIL-6β) has tumor suppressor function; however, the molecular mechanism(s) by which C/EBPδ exerts its effect are largely unknown. Here, we report that C/EBPδ induces expression of the Cdc27 (APC3) subunit of the anaphase promoting complex/cyclosome (APC/C), which results in the polyubiquitination and degradation of the prooncogenic cell cycle regulator cyclin D1, and also down-regulates cyclin B1, Skp2, and Plk-1. In C/EBPδ knockout mouse embryo fibroblasts (MEF) Cdc27 levels were reduced, whereas cyclin D1 levels were increased even in the presence of activated GSK-3β. Silencing of C/EBPδ, Cdc27, or the APC/C coactivator Cdh1 (FZR1) in MCF-10A breast epithelial cells increased cyclin D1 protein expression. Like C/EBPδ, and in contrast to cyclin D1, Cdc27 was down-regulated in several breast cancer cell lines, suggesting that Cdc27 itself may be a tumor suppressor. Cyclin D1 is a known substrate of polyubiquitination complex SKP1/CUL1/F-box (SCF), and our studies show that Cdc27 directs cyclin D1 to alternative degradation by APC/C. These findings shed light on the role and regulation of APC/C, which is critical for most cellular processes.

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“…Unlike F-box proteins that bind phosphorylated substrates, activators of APC/C recognize Destruction Box (D-Box) or KEN Box motifs [27,28]. Substrates of APC Cdh1 include proteins important for G1 stability (cyclin A, cyclin B1 and Skp2), DNA synthesis (Cdc6 and Geminin) and mitosis (Aurora A and Plk) [29][30][31][32]. Therefore, APC Cdh1 is a critical regulator of cell cycle progression.…”

Section: Introductionmentioning

confidence: 99%

Regulation of APCCdh1 E3 ligase activity by the Fbw7/cyclin E signaling axis contributes to the tumor suppressor function of Fbw7

et al. 2013

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Fbw7 and Cdh1 are substrate-recognition subunits of the SCF-and APC-type E3 ubiquitin ligases, respectively. There is emerging evidence suggesting that both Fbw7 and Cdh1 function as tumor suppressors by targeting oncoproteins for destruction. Loss of Fbw7, but not Cdh1, is frequently observed in various human tumors. However, it remains largely unknown how Fbw7 mechanistically functions as a tumor suppressor and whether there is a signaling crosstalk between Fbw7 and Cdh1. Here, we report that Fbw7-deficient cells not only display elevated expression levels of SCF Fbw7 substrates, including cyclin E, but also have increased expression of various APC Cdh1 substrates. We further defined cyclin E as the critical signaling link by which Fbw7 governs APC Cdh1 activity, as depletion of cyclin E in Fbw7-deficient cells results in decreased expression of APC Cdh1 substrates to levels comparable to those in wildtype (WT) cells. Conversely, ectopic expression of cyclin E recapitulates the aberrant APC Cdh1 substrate expression observed in Fbw7-deficient cells. More importantly, 4A-Cdh1 that is resistant to Cdk2/cyclin E-mediated phosphorylation, but not WT-Cdh1, reversed the elevated expression of various APC Cdh1 substrates in Fbw7-deficient cells. Overexpression of 4A-Cdh1 also resulted in retarded cell growth and decreased anchorage-independent colony formation. Altogether, we have identified a novel regulatory mechanism by which Fbw7 governs Cdh1 activity in a cyclin E-dependent manner. As a result, loss of Fbw7 can lead to aberrant increase in the expression of both SCF Fbw7 and APC Cdh1 substrates. Our study provides a better understanding of the tumor suppressor function of Fbw7, and suggests that Cdk2/cyclin E inhibitors could serve as effective therapeutic agents for treating Fbw7-deficient tumors.

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The emerging role of APC/CCdh1 in controlling differentiation, genomic stability and tumor suppression

Cited by 98 publications

References 101 publications

p53- and p21-dependent premature APC/C–Cdh1 activation in G2 is part of the long-term response to genotoxic stress

p53- and p21-dependent premature APC/C–Cdh1 activation in G2 is part of the long-term response to genotoxic stress

C/EBPδ targets cyclin D1 for proteasome-mediated degradation via induction of CDC27/APC3 expression

Regulation of APCCdh1 E3 ligase activity by the Fbw7/cyclin E signaling axis contributes to the tumor suppressor function of Fbw7

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