Cyclin gene amplification and overexpression in breast and ovarian cancers: Evidence for the selection of cyclin D1 in breast and cyclin E in ovarian tumors

Courjal, Frank; Louason, Geneviève; Speiser, Paul; Katsaros, Dionisios; Zeillinger, Robert; Theillet, Charles

doi:10.1002/(sici)1097-0215(19960822)69:4<247::aid-ijc1>3.3.co;2-q

Cited by 71 publications

(109 citation statements)

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“…29) Levels of cyclin E are elevated in many types of human cancer 9,10) ; our evidence that hCDC4 expression is directly regulated by p53 might account for this observation, because p53 is very often inactivated in a wide range of human cancers. 30) Loss of p53 should result in down-regulation of hCDC4b and up-regulation of cyclin E. Hence, investigations of the relationship between the status of p53 and expression of cyclin E in tumor cells would be interesting.…”

Section: Discussionmentioning

confidence: 79%

“…7,8) The proper timing and amplitude of cyclin E expression is pivotal for cell-cycle control, and elevated levels of cyclin E have been associated with a variety of malignancies. 9,10) Human CDC4, recently identified as an F-box protein containing seven WD repeats, is responsible for degradation of cyclin E protein. [11][12][13] This protein is one of four subunits of the SCF complex that forms a ubiquitin protein ligase; the other three subunits are Skp1, Rbx1 and Cul1.…”

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confidence: 99%

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hCDC4b, a regulator of cyclin E, as a direct transcriptional target of p53

et al. 2003

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To identify p53-target genes we have been using a cDNA-microarray system to assess gene expression in a p53-mutated glioblastoma cell line (U373MG) after adenovirus-mediated transfer of wild-type p53 into the p53-deficient cells. In the work reported here, expression of hCDC4b, which encodes one of the four subunits of the SCF (ubiquitin ligase) complex responsible for degradation of cyclin E, was dramatically up-regulated by infection with Ad-p53. An electrophoretic mobility-shift assay and a chromatin immunoprecipitation assay indicated that a potential p53-binding site (p53BS) present in exon 1b of the hCDC4 gene was able to bind to p53, and a reporter assay confirmed that this p53BS had p53-dependent transcriptional activity. Expression of endogenous hCDC4b, but not the alternative transcript of this gene, hCDC4a, was induced in a p53-dependent manner in response to genotoxic stresses caused by UV irradiation and adriamycin treatment, suggesting that each transcript has a different functional role. These results suggest that hCDC4b is a previously unrecognized transcriptional target of the p53 protein, and that by negatively regulating cyclin E through induction of hCDC4b, p53 might stop cell-cycle progression at G0-G1. This would represent a novel mechanism for p53-dependent control of the cell cycle, in addition to the well-known p21 rogression through the cell-cycle is controlled by cyclin-dependent kinases (Cdks) 1,2) ; the activities of Cdks are regulated positively by cyclins and negatively by Cdk inhibitors. 3)Cyclin E, a regulatory subunit of Cdk2, controls the transition from G1 to S phase, a rate-limiting factor for proliferation. [4][5][6] Cyclin E is tightly regulated by ubiquitin-mediated proteolysis in a phosphorylation-dependent manner. 7,8) The proper timing and amplitude of cyclin E expression is pivotal for cell-cycle control, and elevated levels of cyclin E have been associated with a variety of malignancies.9, 10) Human CDC4, recently identified as an F-box protein containing seven WD repeats, is responsible for degradation of cyclin E protein. [11][12][13] This protein is one of four subunits of the SCF complex that forms a ubiquitin protein ligase; the other three subunits are Skp1, Rbx1 and Cul1.14, 15) The CDC4 component binds to Skp1 through the F-box motif, 16) and determines the substrate-specificity of SCF complexes by interacting with substrates through its WD40 domains.The DNA-damage checkpoint plays a critical role in preventing genomic instability by regulating the cell cycle and DNA repair.17) p53 is stabilized and activated by a variety of cellular stresses such as heat shock, hypoxia, osmotic shock, and DNA damage, and it exerts a tumor-suppressing function [18][19][20] by activating transcription of multiple target genes including p21 WAF1 ,21) p53R2, 22)p53AIP1, 23)BAX, 24)MDM2, 25) and p53DINP1.26) Among the known transcriptional targets of p53, p21 WAF1 has long been considered the most important, as a mediator of the signaling pathway that induces cell-cycle arrest at ...

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Section: Discussionmentioning

confidence: 79%

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confidence: 99%

hCDC4b, a regulator of cyclin E, as a direct transcriptional target of p53

et al. 2003

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“…No significant comparison can be drawn with the literature, which, to the best of our knowledge, contains only three studies [42][43][44] without any assessment of the correlations of interest in our study.…”

Section: Discussionmentioning

confidence: 99%

Flow cytometry and quantitative immunohistochemical study of cell cycle regulation proteins in invasive breast carcinoma

Michels

Duigou

Marescaux

et al. 2003

Cancer

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BACKGROUNDBetween January 11, 1991 and January 8, 1992, 104 patients with previously untreated, invasive, primitive breast carcinoma were admitted to the authors' hospital.METHODSFor each patient, flow cytometry DNA analyses on frozen samples and on immunohistochemical staining were performed, including Ki‐67, cyclin A, p53, and p21waf1 (p21), with assessment of the percentages of positive nuclei were assessed. Correlations with classic clinicopathologic data and survival (overall, metastasis free, or recurrence free) and a multivariate analysis were performed.RESULTSAfter a multivariate analysis according to a Cox model that was stratified by age, tumor size, tumor grade, lymph node status, and receptor status, among the factors studied, the presence of p21 was the unique remaining prognostic factor for patients with invasive breast carcinoma. Because of the lack of a correlation between p21 and proliferative factors (Ki‐67, S‐phase, and cyclin A), the authors combined p21 with those markers and found that, for the different combinations, after statistical analysis, only p21 combined with S‐phase or with cyclin A and lymph node status were salient survival prognostic factors.CONCLUSIONSImmunohistochemical study of proteins involved in the cell cycle and assessment of proliferative activity using flow cytometric DNA analysis aided the authors in singling out correlations of cyclin A and S‐phase, along with p21, with metastasis free survival and overall survival in patients with invasive breast carcinoma. These promising results will require confirmation in a larger series of patients. Cancer 2003;97:1376–86. © 2003 American Cancer Society.DOI 10.1002/cncr.11209

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“…Amplification of CCND1 in ovarian tumours is infrequent (Courjal et al, 1996;Masciullo et al, 1997); however, in these studies cyclin D1 protein levels were not measured. We examined CCND1 amplification in tumours overexpressing cyclin D1 protein as determined by IHC; 28/29 of these tumours did not demonstrate amplification of CCND1.…”

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confidence: 84%

Expression and subcellular localization of cyclin D1 protein in epithelial ovarian tumour cells

Dhar

Branigan

Parkes³

et al. 1999

Br J Cancer

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SummaryThe expression of cyclin D1 protein in tumour sections from 81 patients with epithelial ovarian cancer was analysed using immunohistochemistry. The tumours that overexpressed cyclin D1 in more than 10% of neoplastic cells were considered positive. Thus overexpression of cyclin D1 was observed in 72/81 (89%) of the cases examined. Protein was detected in both the nucleus and the cytoplasm in 24/81 (30%) and localized exclusively in the cytoplasm in 48/81 (59%) of the tumours. Cyclin D1 was overexpressed in both borderline and invasive tumours. There was no association between protein overexpression and tumour stage and differentiation. Furthermore, no correlation between cyclin D1 expression and clinical outcome was observed. However, in tumours overexpressing cyclin D1 (n = 72), the proportion displaying exclusively cytoplasmic localization of protein was higher in those with serous compared with non-serous histology (P = 0.004, odds ratio 4.8, 95% confidence interval 1.4-19.1). Western analysis using a monoclonal antibody to cyclin D1 identified a 36 kDa protein in homogenates from seven tumours displaying cytoplasmic only and one tumour demonstrating both nuclear and cytoplasmic immunostaining. Using restriction fragment length polymorphism polymerase chain reaction and PCR-multiplex analysis, amplification of the cyclin D1 gene (CCNDI) was detected in 1/29 of the tumours demonstrating overexpression of cyclin D1 protein. We conclude that deregulation of CCND1 expression leading to both cytoplasmic and nuclear protein localization is a frequent event in ovarian cancer and occurs mainly in the absence of gene amplification.

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Cyclin gene amplification and overexpression in breast and ovarian cancers: Evidence for the selection of cyclin D1 in breast and cyclin E in ovarian tumors

Cited by 71 publications

References 5 publications

hCDC4b, a regulator of cyclin E, as a direct transcriptional target of p53

hCDC4b, a regulator of cyclin E, as a direct transcriptional target of p53

Flow cytometry and quantitative immunohistochemical study of cell cycle regulation proteins in invasive breast carcinoma

Expression and subcellular localization of cyclin D1 protein in epithelial ovarian tumour cells

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