Disruption of cyclin D1 nuclear export and proteolysis accelerates mammary carcinogenesis

Lin, Douglas I.; Lessie, Matthew D.; Gladden, Andrew B.; Bassing, Craig H.; Wagner, Kay Uwe; Diehl, J. Alan

doi:10.1038/sj.onc.1210738

Cited by 68 publications

(74 citation statements)

References 34 publications

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“…6,7 Furthermore, transgenic mice overexpressing the same mutant, driven by mouse mammary tumor virus (MMTV) promoter (MMTV-D1T286A), developed mammary adenocarcinoma with a shorter latency relative to mice overexpressing wild-type (WT) cyclin D1 (MMTV-D1). 8 These observations support the notion that the subcellular localization of cyclin D1 is critical in controlling its tumorigenicity. Identifying the molecular mechanisms that regulate the nuclear localization of cyclin D1 is, therefore, vital for our better understanding of tumor development.…”

supporting

confidence: 78%

SUMO-modified nuclear cyclin D1 bypasses Ras-induced senescence

et al. 2010

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Oncogene-induced senescence represents a key tumor suppressive mechanism. Here, we show that Ras oncogene-induced senescence can be mediated by the recently identified haploinsufficient tumor suppressor apoptosis-stimulating protein of p53 (ASPP) 2 through a novel and p53/p19 Arf /p21 waf1/cip1 -independent pathway. ASPP2 suppresses Ras-induced small ubiquitin-like modifier (SUMO)-modified nuclear cyclin D1 and inhibits retinoblastoma protein (Rb) phosphorylation. The lysine residue, K33, of cyclin D1 is a key site for this newly identified regulation. In agreement with the fact that its nuclear localization is required for its oncogenic activity, we show that nuclear cyclin D1 is far more potent than wild-type (WT) cyclin D1 in bypassing Ras-induced senescence. Thus, this study identifies SUMO modification as a positive regulator of nuclear cyclin D1, and reveals a new way by which cell cycle entry and senescence are regulated. Cell Death and Differentiation (2011) 18, 304-314; doi:10.1038/cdd.2010; published online 27 August 2010Cellular senescence is an irreversible cell cycle arrest and one of the major cellular processes that suppress tumor growth. Cyclin-dependent kinases (CDKs) are among the main regulators of cellular senescence, predominantly achieved through their phosphorylation of the retinoblastoma protein (Rb), preventing it from binding and inhibiting the E2F family of transcription factors that are involved in cell cycle progression. Deregulation of CDK pathways is common in the development of human cancers. Amplification and overexpression of cyclin D1, a regulatory subunit of CDK4/CDK6, has been observed in around 50% of human breast and esophageal cancers. 1,2 Interestingly, however, elevation of cyclin D1 alone is not sufficient to induce tumor growth in vivo, 3,4 partly owing to the fact that the cyclin D1/CDK4 or cyclin D1/CDK6 complex needs to locate in the nucleus to phosphorylate Rb during S-phase to promote cell proliferation. 5,6 Nuclear export, coupled with ubiquitin-dependent destruction of cyclin D1 in the cytoplasm during S-phase, is one of the best known mechanisms of cyclin D1/CDK4 kinase activity control. Hence, nuclear accumulation of cyclin D1 may be a key mechanism by which cyclin D1 exerts its oncogenic effects. In agreement with this, overexpression of mutant cyclin D1 (D1T286A), defective in phosphorylation-mediated nuclear export and subsequent proteolysis, induces cell transformation in vitro and triggers B-cell lymphoma in vivo. 6,7 Furthermore, transgenic mice overexpressing the same mutant, driven by mouse mammary tumor virus (MMTV) promoter (MMTV-D1T286A), developed mammary adenocarcinoma with a shorter latency relative to mice overexpressing wild-type (WT) cyclin D1 (MMTV-D1). 8 These observations support the notion that the subcellular localization of cyclin D1 is critical in controlling its tumorigenicity. Identifying the molecular mechanisms that regulate the nuclear localization of cyclin D1 is, therefore, vital for our better understanding of tumor development....

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confidence: 78%

SUMO-modified nuclear cyclin D1 bypasses Ras-induced senescence

et al. 2010

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“…Overexpression of wild-type cyclin D1 is shown to be insufficient in inducing transformation of cells, because nuclear export and subsequent cytoplasmic proteolysis reduce the oncogenic capability of the protein (Quelle et al, 1993;Alt et al, 2000). In contrast, overexpression of cyclin D1-T286A results in tumorigenesis in transgenic mice (Alt et al, 2000;Gladden and Diehl, 2005;Benzeno et al, 2006;Lin et al, 2008). In our study, long-term FR resulted in nuclear accumulation of cyclin D1 by deregulating GSK3b-mediated cyclin D1 phosphorylation for nuclear export.…”

Section: Discussionmentioning

confidence: 51%

Acquired radioresistance of human tumor cells by DNA-PK/AKT/GSK3β-mediated cyclin D1 overexpression

et al. 2010

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Recurrence is frequently associated with the acquisition of radioresistance by tumors and resulting failures in radiotherapy. We report, in this study, that long-term fractionated radiation (FR) exposures conferred radioresistance to the human tumor cells, HepG2 and HeLa with cyclin D1 overexpression. A positive feedback loop was responsible for the cyclin D1 overexpression in which constitutively active AKT was involved. AKT is known to inactivate glycogen synthase kinase-3b (GSK3b), which is essential for the proteasomal degradation of cyclin D1. The resulting cyclin D1 overexpression led to the forced progression of S-phase with the induction of DNA double strand breaks. Cyclin D1-dependent DNA damage activated DNA-dependent protein kinase (DNA-PK), which in turn activated AKT and inactivated GSK3b, thus completing a positive feedback loop of cyclin D1 overproduction. Cyclin D1 overexpression led to the activation of DNA damage response (DDR) consisted of ataxia telangiectasia mutated (ATM)-and Chk1-dependent DNA damage checkpoint and homologous recombination repair (HRR). Long-term FR cells repaired radiation-induced DNA damage faster than non-FR cells. Thus, acquired radioresistance of long-term FR cells was the result of alterations in DDR mediated by cyclin D1 overexpression. Inhibition of the AKT/GSK3b/cyclin D1/ Cdk4 pathway by the AKT inhibitor, Cdk4 inhibitor or cyclin D1 targeting small interfering RNA (siRNA) suppressed the radioresistance. Present observations give a mechanistic insight for acquired radioresistance of tumor cells by cyclin D1 overexpression, and provide novel therapeutic targets for recurrent radioresistant tumors.

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“…The oncogenic activity of cyclin D1 overexpression is thought to rely on its localization in the nucleus (30), and previous studies have shown that the transfected D1b protein exhibits increased nuclear localization relative to D1a (17,18). We therefore examined the localization of endogenous cyclin D1 isoforms in EwSa cell lines.…”

Section: Expression and Biological Significance Of The Cyclin D1b Isomentioning

confidence: 99%

Alteration of cyclin D1 transcript elongation by a mutated transcription factor up-regulates the oncogenic D1b splice isoform in cancer

Sanchez

Bittencourt

Laud

et al. 2008

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

110

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Pre-mRNA splicing and polyadenylation are tightly connected to transcription, and transcriptional stimuli and elongation dynamics can affect mRNA maturation. However, whether this regulatory mechanism has a physio/pathological impact is not known. In cancer, where splice variant expression is often deregulated, many mutated oncogenes are transcriptional regulators. In particular, the Ewing sarcoma (EwSa) oncogene, resulting from a fusion of the EWS and FLI1 genes, encodes a well characterized transcription factor. EWS-FLI1 directly stimulates transcription of the CCND1 protooncogene encoding cyclin D1a and a less abundant but more oncogenic splice isoform, D1b. We show that, although both EWS and EWS-FLI1 enhance cyclin D1 gene expression, they regulate the D1b/D1a transcript ratio in an opposite manner. Detailed analyses of RNA polymerase dynamics along the gene and of the effects of an inhibitor of elongation show that EWS-FLI1 favors D1b isoform expression by decreasing the elongation rate, whereas EWS has opposite effects. As a result, the D1b/D1a ratio is elevated in EwSa cell lines and tumors. The endogenous D1b protein is enriched in nuclei, where the oncogenic activity of cyclin D1 is known to occur, and depleting D1b in addition to D1a results in a stronger reduction of EwSa cell growth than depleting D1a only. These data show that elevated expression of a splice isoform in cancer can be due to an alteration of the transcription process by a mutated transcriptional regulator and provide evidence for a physio/pathological impact of the coupling between transcription and mRNA maturation.coregulator ͉ Ewing sarcoma ͉ EWS-FLI1 ͉ polyadenylation ͉ splicing G ene expression in cancer cells is altered at the transcriptional level by many mutated oncogenes acting as transcriptional regulators. A second level of gene expression that is often altered in cancer cells is pre-mRNA splicing. Indeed, most human genes give rise to several transcripts with different exon content because of alternative splicing and alternative cleavage/ polyadenylation sites (1). Genes involved in major cellular programs often give rise to splice isoforms with distinct biological activities and deregulated expression in cancer (2, 3). In some cases, cancer-associated deregulation of alternative splicing arises from mutations within splicing regulatory sequences or from alterations of the expression of splicing factors involved in splicing regulation (2, 3). However, only few splicing factors have been found to be altered in cancer. Moreover, the role of another level of splicing regulation that involves transcriptional regulators has not been investigated yet.It is now widely accepted that pre-mRNA splicing and 3Ј-end maturation are tightly connected to transcription in Metazoans and that transcription impacts RNA processing (4, 5). It has been shown that the recruitment of processing factors and the maturation of pre-mRNAs occur at least in part cotranscriptionally and are enhanced by RNA polymerase II (Pol II) and its phosphorylation (...

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Disruption of cyclin D1 nuclear export and proteolysis accelerates mammary carcinogenesis

Cited by 68 publications

References 34 publications

SUMO-modified nuclear cyclin D1 bypasses Ras-induced senescence

SUMO-modified nuclear cyclin D1 bypasses Ras-induced senescence

Acquired radioresistance of human tumor cells by DNA-PK/AKT/GSK3β-mediated cyclin D1 overexpression

Alteration of cyclin D1 transcript elongation by a mutated transcription factor up-regulates the oncogenic D1b splice isoform in cancer

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