The ubiquitin ligase APCCdh1 is required to maintain genome integrity in primary human cells

Engelbert, Dirk; Schnerch, Dominik; Baumgarten, Axel; Wäsch, Ralph

doi:10.1038/sj.onc.1210703

Cited by 103 publications

(135 citation statements)

References 47 publications

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“…Loss of Cdh1 function in yeast and human cells results in genome instability, and Cdh1 haploinsufficiency predisposes mice to cancer. 3,40,41 We found that cdh1Δ cells exhibited a mild spindle morphology defect (compared with acm1Δ cells) and an increase in binucleate cells, consistent with a previous report in reference 15. The fact that similar phenotypes are observed upon either loss of Cdh1 function or failure to properly restrain Cdh1 function highlights the critical role that Cdh1 plays in maintaining genome stability and the requirement for a multifaceted and stringent regulatory system to precisely control Cdh1 expression and activity.…”

Section: Methodssupporting

confidence: 76%

Acm1 contributes to nuclear positioning by inhibiting Cdh1-substrate interactions

Martinez

Hall²,

Bartolowits³

et al. 2012

Cell Cycle

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Section: Methodssupporting

confidence: 76%

Acm1 contributes to nuclear positioning by inhibiting Cdh1-substrate interactions

Martinez

Hall²,

Bartolowits³

et al. 2012

Cell Cycle

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“…GarciaHiguera et al [26] demonstrated that heterozygous Cdh1 mice (Cdh1 +/− ) develop epithelial tumors, suggesting a haploinsufficient role of Cdh1 in tumor suppression. Moreover, reduced Cdh1 expression was observed in hematological neoplasias and solid tumors [33]. As loss of Cdh1 function can have multiple effects that predispose cells to transformation, it is critical to understand its regulatory pathways.…”

Section: Introductionmentioning

confidence: 99%

“…As aforementioned, aberrant cell cycle regulation can often lead to missegregation of chromosomes, resulting in aneuploidy. Not surprisingly, many reports have implicated Cdh1 function in maintaining proper genomic stability [26,[33][34][35]. In addition, multiple APC Cdh1 targets have also been documented for their oncogenic capabilities.…”

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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“…Recently, it was shown that APC/C is involved in the segregation of chromatides and is necessary for accurate DNA replication. 16,28 The temporally regulated degradation of its targets seems sufficient to enable genetic stability. Since our data suggest that CDC6 protein level is altered by CSN2 overexpression, we hypothesized that this could lead to genetic instability.…”

Section: Resultsmentioning

confidence: 99%

Regulation of the anaphase-promoting complex by the COP9 signalosome

Kob

Kelm²,

Posorski³

et al. 2009

Cell Cycle

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The COP9 complex (signalosome) is a known regulator of the proteasome/ubiquitin pathway. Furthermore it regulates the activity of the cullin-RING ligase (CRL) families of ubiquitin E3-complexes. Besides the CRL family, the anaphase-promoting complex (APC/C) is a major regulator of the cell cycle. To investigate a possible connection between both complexes we assessed interacting partners of COP9 using an in vivo protein-protein interaction assay. Hereby, we were able to show for the first time that CSN2, a subunit of the COP9 signalosome, interacts physically with APC/C. Furthermore, we detected a functional influence of the COP9 complex regarding the stability of several targets of the APC/C. Consistent with these data we showed a genetic instability of cells overexpressing CSN2.

show abstract

The ubiquitin ligase APCCdh1 is required to maintain genome integrity in primary human cells

Cited by 103 publications

References 47 publications

Acm1 contributes to nuclear positioning by inhibiting Cdh1-substrate interactions

Acm1 contributes to nuclear positioning by inhibiting Cdh1-substrate interactions

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

Regulation of the anaphase-promoting complex by the COP9 signalosome

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