D-type cyclins in adult human testis and testicular cancer: relation to cell type, proliferation, differentiation, and malignancy

Bártková, Jiřina; Meyts, Ewa Rajpert‐De; Skakkebæk, Niels E.; Bártek, Jiří

doi:10.1002/(sici)1096-9896(199904)187:5<573::aid-path289>3.0.co;2-h

Cited by 70 publications

(45 citation statements)

References 24 publications

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“…6c). Our expression data also correlate well with published protein data, e.g., the induction of cyclin D2 in testis tumors, 20 the expression of cyclin B1 in mitotic and of cyclin B2 in meiotic testis cells. 34 The microarray approach comprised several advantages.…”

Section: Discussionsupporting

confidence: 89%

“…D-type cyclins were the only induced cyclins in testis tumors corroborating previous data. 20 D-type cyclins were highly expressed in most histologic subtypes except mature teratoma. Thus, D-type cyclins seem to be FIGURE 7 -Cyclin expression in normal and malignant testis tissue.…”

Section: Discussionmentioning

confidence: 99%

“…19 Overall, no clear mechanistic model including different layers of cell cycle regulation in mitosis and meiosis has been derived. Cancerous aberrations in germ cells often affect cell cycle regulation, e.g., overexpression of cyclins 20 or loss of CDK inhibitors. 21 The deeper understanding of the regulatory mechanisms governing mitosis will have a clear impact on cancer biology in all tumor entities.…”

mentioning

confidence: 99%

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Expression patterns of mitotic and meiotic cell cycle regulators in testicular cancer and development

Diederichs

Bäumer

Schultz

et al. 2005

Intl Journal of Cancer

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Mitotic and meiotic cell cycle regulation is essential for normal development and tumor prevention. The underlying molecular mechanisms are not completely characterized. The aim of our analysis was to derive a global expression map of cell cycle regulators in mitosis and meiosis. First, the expression of cyclins, CDKs and CDK inhibitors was determined during postnatal testis maturation in mice using microarrays and quantitative RT-PCR. The abundance of cyclins A1, B2, K, M4, CDK2, all CDKLs, CDKN2c, CDKN2d and INCA1 increased during testis maturation. In contrast, cyclins A2, B1, D2, G1, G2, CDK1, CDK4 and CDK2AP1 showed a maturation-associated decrease. Gene expression profiles of isolated germ cells and testicular somatic cells confirmed these results. Second, we determined cyclin expression patterns in human normal and malignant testis samples (n 5 36) modeling the reciprocal difference between meiosis and mitosis. Testicular tumors strictly expressed cell cycle regulators identified in mitotically dividing germ cells. Expression of several transcripts was histology-specific in testicular tumors, providing novel molecular markers and potential therapeutic targets. Taken together, our data provide a comprehensive expression map of cell cycle regulators at the switch between mitosis and meiosis in testis development and in cancerogenesis. ' 2005 Wiley-Liss, Inc.Key words: cyclin; testicular tumorigenesis; meiosis; mitosis Multicellular organisms rely on a strict regulation of cell division and proliferation. Dysregulation of the mitotic cell cycle has been recognized as a hallmark of the development of malignant diseases. 1 Therefore, a deeper insight into the molecular mechanisms regulating mitosis contributes to the understanding of the tumorigenic process.The molecular machinery functioning in meiotic and postmeiotic germ cells is highly divergent from that used by germ cells in the mitotic cell cycle. 2 The germ line is unique compared to other cell lineages since strict regulation of both, the mitotic and the meiotic cell cycle, is indispensable for the generation of gametes. The seminiferous tubules in the testes of newborn mice only contain undifferentiated spermatogonia and immature Sertoli cells, which both exert mitotic proliferation. 3 The postnatal development is divided in three main stages: mitotic proliferation of spermatogonial stem cells; meiotic differentiation from primary spermatids to haploid early round spermatids; and spermiogenesis in which spermatids are reorganized to mature spermatozoa. The meiotic cell cycle starts in mice around postnatal day (P) 11, with the first appearance of haploid spermatids between P17 and P21. 4 With increasing age, the undifferentiated spermatogonia develop into differentiating spermatogonia of A and B types and subsequently undergo meiosis and spermiogenesis until fertility is reached at 35-37 days of age.The molecular mechanisms governing the stages of mitotic and meiotic cell cycles remain incompletely understood. Several groups have analyzed the impact...

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Expression patterns of mitotic and meiotic cell cycle regulators in testicular cancer and development

Diederichs

Bäumer

Schultz

et al. 2005

Intl Journal of Cancer

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“…Thus, although the RB pathway is frequently targeted in testicular cancer, including overexpression of cyclin D2 (Bartkova et al, 1999;Houldsworth et al, 1997;Sicinski et al, 1996) and defects in p16 INK4a (Chaubert et al, 1997;Heidenreich et al, 1998), the p19 INK4d gene is not among the targeted components in this type of cancer, likely due to a tight developmental control of its expression. The present example of p19 INK4d and testicular cancer should be kept in mind when searching for aberrations of candidate tumour suppressor genes encoded by the INK4 or other multigene families whose products harbour partly overlapping functions.…”

Section: Resultsmentioning

confidence: 99%

“…The unique biology of the testis may also underlie the emerging spectrum of`unorthodox' tumour-associated alterations in the RB pathway so far identi®ed in human testicular cancer. Thus, cyclin D2 rather than cyclin D1 is frequently overexpressed in the common precursor lesion of all germ-cell tumours, carcinoma in situ (CIS), and this aberration is preserved in the invasive testicular tumours including seminomas and embryonal carcinomas, and in cell lines derived from such tumours (Bartkova et al, 1999;Houldsworth et al, 1997;Sicinski et al, 1996). In addition, while expression of pRB is aberrantly low in many germ-cell tumours, this appears to be due to a reversible transcriptional modulation, rather than deletions or mutations of the RB gene seen in other types of cancer (Strohmeyer et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Lack of p19INK4d in human testicular germ-cell tumours contrasts with high expression during normal spermatogenesis

et al. 2000

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p19 INK4d , a member of the INK4 family of cyclindependent kinase inhibitors, negatively regulates the proto-oncogenic cyclin D/CDK4(6) complexes whose ability to phosphorylate the retinoblastoma tumour suppressor (RB) promotes G1/S transition. In contrast to the related p16 INK4a tumour suppressor, expression patterns of 19 INK4d in human tissues and tumours remain unknown. As the RB pathway is commonly targeted in cancer, and mouse models suggest a role for p19 INK4d in spermatogenesis, we examined the abundance and localization of p19 INK4d in the human testis, both during normal development and at various stages of germ-cell tumour pathogenesis. Our data show that the p19 INK4d protein is abundant in spermatocytes of normal human adult testes, whereas virtually no p19 INK4d is detectable in testicular cancer, including the preinvasive carcinoma in situ stage. Together with the lack of p19 INK4d in human foetal germ cells, these results support the concept of foetal origin of the testicular germ-cell tumours, and help better understand the emerging role of the RB pathway in spermatogenesis and tumorigenesis in the human testis. Oncogene (2000) 19, 4146 ± 4150.

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Cell cycle regulators in testicular cancer: Loss of p18INK4C marks progression from carcinomain situ to invasive germ cell tumours

et al. 2000

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D-type cyclins in adult human testis and testicular cancer: relation to cell type, proliferation, differentiation, and malignancy

Cited by 70 publications

References 24 publications

Expression patterns of mitotic and meiotic cell cycle regulators in testicular cancer and development

Expression patterns of mitotic and meiotic cell cycle regulators in testicular cancer and development

Lack of p19INK4d in human testicular germ-cell tumours contrasts with high expression during normal spermatogenesis

Cell cycle regulators in testicular cancer: Loss of p18INK4C marks progression from carcinomain situ to invasive germ cell tumours

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