Genomic stability and tumour suppression by the APC/C cofactor Cdh1

García-Higuera, Irene; Manchado, Eusebio; Dubus, Pierre; Cañamero, Marta; Méndez, Juan Pablo; Moreno, Sergio; Malumbres, Marcos

doi:10.1038/ncb1742

Cited by 340 publications

(501 citation statements)

References 45 publications

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“…With Cdh1 playing such a vital role in mediating the degradation of major cell cycle regulators, it is not surprising that Cdh1 was recently characterized to be a bona fide tumor suppressor [26]. Therefore, understanding how the tumor suppressor function of Cdh1 is regulated becomes increasingly more important.…”

Section: Discussionmentioning

confidence: 99%

“…Although Cdh1 displays many characteristics of a bona fide tumor suppressor, only recently has this been established. 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].…”

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%

“…APC/C is a well-characterized E3 ligase important for genomic stability and a known tumor suppressor [26]. Cdh1 is an activator and a substrate-recognition subunit of the APC/C E3 ligase.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…APC/C is a well-characterized E3 ligase important for genomic stability and a known tumor suppressor [26]. Cdh1 is an activator and a substrate-recognition subunit of the APC/C E3 ligase.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…For example, tumor suppressor genes (eg, CDH1 and SYK) were transcriptionally activated and highly expressed, whereas the genes regulating cell proliferation (eg, uPAR, FN and EGFR) were significantly reduced in ERp29-transfected MDA-MB-231 cells (Supplementary Table 1, Figure 7). E-cadherin suppressed tumor formation by preventing genomic instability, 42 whereas SYK negatively regulated cell proliferation, invasion and tumor formation. 43 EGFR and uPAR were found to positively regulate cell migration, invasion and tumorigenesis.…”

mentioning

confidence: 99%

Overexpression of endoplasmic reticulum protein 29 regulates mesenchymal–epithelial transition and suppresses xenograft tumor growth of invasive breast cancer cells

Bambang

Zhou

et al. 2009

Laboratory Investigation

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Endoplasmic reticulum protein 29 (ERp29) is a novel endoplasmic reticulum (ER) secretion factor that facilitates the transport of secretory proteins in the early secretory pathway. Recently, it was found to be overexpressed in several cancers; however, little is known regarding its function in breast cancer progression. In this study, we show that the expression of ERp29 was reduced with tumor progression in clinical specimens of breast cancer, and that overexpression of ERp29 resulted in G 0 /G 1 arrest and inhibited cell proliferation in MDA-MB-231 cells. Importantly, overexpression of ERp29 in MDA-MB-231 cells led to a phenotypic change and mesenchymal-epithelial transition (MET) characterized by cytoskeletal reorganization with loss of stress fibers, reduction of fibronectin (FN), reactivation of epithelial cell marker E-cadherin and loss of mesenchymal cell marker vimentin. Knockdown of ERp29 by shRNA in MCF-7 cells reduced E-cadherin, but increased vimentin expression. Furthermore, ERp29 overexpression in MDA-MB-231 and SKBr3 cells decreased cell migration/invasion and reduced cell transformation, whereas silencing of ERp29 in MCF-7 cells enhanced cell aggressive behavior. Significantly, expression of ERp29 in MDA-MB-231 cells suppressed tumor formation in nude mice by repressing the cell proliferative index (Ki-67 positivity). Transcriptional profiling analysis showed that ERp29 acts as a central regulator by upregulating a group of genes with tumor suppressive function, for example, E-cadherin (CDH1), cyclin-dependent kinase inhibitor (CDKN2B) and spleen tyrosine kinase (SYK), and by downregulating a group of genes that regulate cell proliferation (eg, FN, epidermal growth factor receptor (EGFR) and plasminogen activator receptor (uPAR)). It is noteworthy that ERp29 significantly attenuated the overall ERK cascade, whereas the ratio of p-ERK1 to p-ERK2 was highly increased. Taken together, our results showed that ERp29 is a novel regulator leading to cell growth arrest and cell transition from a proliferative to a quiescent state, and reprogramming molecular portraits to suppress the tumor growth of MDA-MB-231 breast cancer cells.

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Chromosome Instability ( CIN ), Aneuploidy and Cancer

Yuen

2010

Encyclopedia of Life Sciences

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Chromosome instability (CIN) describes an increased rate of chromosome missegregation in mitosis resulting in a failure to maintain the correct chromosomal complement (euploidy). The aberrant chromosomal state of a cell can be classified based on the changes in ploidy, gain or loss of whole chromosomes (aneuploidy) or gross chromosomal rearrangements (GCR), all of which are hallmarks of solid cancers. CIN can be caused by multiple mechanisms involved in chromosome segregation, including a weakened or overactivated mitotic spindle assembly checkpoint, sister chromatid cohesion defects, increased merotelic kinetochore‐microtubule attachments or the presence of extra centrosomes. CIN occurs early in cancer development, and is associated with poor prognosis. CIN has long been proposed to contribute to tumour progression. However, recent studies suggest that CIN can either promote or suppress tumour progression, depending on the contexts. Targeting characteristics specific to tumour cells, such as CIN, is an attractive therapeutic avenue. Key Concepts: Stable aneuploidy can occur without CIN (e.g. Down syndrome patients with trisomy chromosome 21), but aneuploidy observed in cancer is often caused by CIN. CIN is a hallmark of solid cancers, occurring early in tumorigenesis, and is associated with poor prognosis. CIN can arise from defects that affect different steps of chromosome segregation, including the spindle checkpoint, kinetochore‐microtubule attachments, sister chromatid cohesion, centrosome duplication and bipolar spindle assembly. Mutations and misregulation of genes functioning at the spindle checkpoint, at the kinetochore, sister chromatid cohesion and centrosomes are associated with various cancer types. Germline biallelic mutations in spindle checkpoint gene BUB1B are associated with mosaic variegated aneuploidy (MVA) and predispositions to various types of cancer, strongly supporting a causal link between CIN and cancer development. However, only low frequency of somatic mutations in spindle checkpoint components has been found in spontaneous cancers. Either a weakened spindle checkpoint or a prolonged activated checkpoint can cause chromosome missegregation, presumably due to premature sister chromatid separation or increased frequency of uncorrected merotelic attachments, respectively. Extra centrosomes usually cluster to form bipolar spindles, but they undergo a transient multipolar stage, increasing the frequency of merotelic attachments and lagging chromosomes. Animal models with CIN can either promote or suppress cancers, depending on the genetic background and contexts. Stable aneuploidy per se does not cause CIN, and is antiproliferative. CIN can be exploited as a cancer‐specific target for selective killing of tumours.

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Genomic stability and tumour suppression by the APC/C cofactor Cdh1

Cited by 340 publications

References 45 publications

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

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

Overexpression of endoplasmic reticulum protein 29 regulates mesenchymal–epithelial transition and suppresses xenograft tumor growth of invasive breast cancer cells

Chromosome Instability ( CIN ), Aneuploidy and Cancer

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