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

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

doi:10.1038/sj.onc.1203769

Cited by 50 publications

(53 citation statements)

References 33 publications

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“…As in our data, CDKN2d (p19 INK4d ) has also been found to be lost in testicular germ cell tumors contrasting its high expression in normal spermatogenesis. 21 We detected meiotic induction of cyclin A1 and CDK2, which are essential for spermatogenesis but not for mitosis. [9][10][11][12] CDKN2c (p18 INK4c ) and CDKN2d (p19 INK4d ), whose expression also markedly increased, conferred infertility to double-knockout mice.…”

Section: Discussionmentioning

confidence: 86%

“…We created transgenic mice that expressed both b-galactosidase and EGFP under the control of the murine and the human cyclin A1 promoter, respectively. 12,14,26 Expression of the reporter genes was then analyzed in adjacent testis sections prepared from mice at postnatal days 1,4,8,11,14,18,21,26 and 34 by X-gal staining (b-galactosidase) and fluorescence microscopy (EGFP; Fig. 6a).…”

Section: Human and Murine Cyclin A1 Promoter Activity In Testis Develmentioning

confidence: 99%

“…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. 1 In this study, we provide a comprehensive expression map of cell cycle regulators (cyclins, CDKs and CDK inhibitors) in the mitotic and the meiotic cell cycle by transcriptional profiling and comparing two distinct models of predominantly mitotic or meiotic cells.…”

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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: Discussionmentioning

confidence: 86%

Section: Human and Murine Cyclin A1 Promoter Activity In Testis Develmentioning

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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“…An increasing number of tumour suppressor genes have been recognised for which epigenetic silencing is the predominant mechanism of gene inactivation and for which somatic mutations are rare. While several testicular tumour suppressor genes have now been identified (Bartkova et al, 2000;Datta et al, 2001;Luo et al, 2001;Eyzaguirre and Gatalica, 2002;Honorio et al, 2003), only a few, for example RASSF1A (Honorio et al, 2003), MGMT (SmithSorensen et al, 2002), have been reported to be silenced in testicular tumours through DNA hypermethylation.…”

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confidence: 99%

Hypermethylation of the 5′ CpG island of the gene encoding the serine protease Testisin promotes its loss in testicular tumorigenesis

et al. 2005

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The Testisin gene (PRSS21) encodes a glycosylphosphatidylinositol (GPI)-linked serine protease that exhibits testis tissue-specific expression. Loss of Testisin has been implicated in testicular tumorigenesis, but its role in testis biology and tumorigenesis is not known. Here we have investigated the role of CpG methylation in Testisin gene inactivation and tested the hypothesis that Testisin may act as a tumour suppressor for testicular tumorigenesis. Using sequence analysis of bisulphite-treated genomic DNA, we find a strong relationship between hypermethylation of a 385 bp 5 0 CpG rich island of the Testisin gene, and silencing of the Testisin gene in a range of human tumour cell lines and in 100% (eight/eight) of testicular germ cell tumours. We show that treatment of Testisinnegative cell lines with demethylating agents and/or a histone deacetylase inhibitor results in reactivation of Testisin gene expression, implicating hypermethylation in Testisin gene silencing. Stable expression of Testisin in the Testisin-negative Tera-2 testicular cancer line suppressed tumorigenicity as revealed by inhibition of both anchorage-dependent cell growth and tumour formation in an SCID mouse model of testicular tumorigenesis. Together, these data show that loss of Testisin is caused, at least in part, by DNA hypermethylation and histone deacetylation, and suggest a tumour suppressor role for Testisin in testicular tumorigenesis.

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“…Although several reports have examined expression of isolated G1-S-phase regulators in arrested and apparently cycling germ cells [14,15], an important limitation of these studies is the lack of a comprehensive and direct comparison of the G1-S-phase cell cycle regulators in cells shown to be undergoing mitotic arrest. Interestingly, it has been shown that common molecular abnormalities found in testis cancer include mutations in some regulators of the G1-S-phase of the cell cycle [16]. Defining the normal function of these genes in the cell cycle of developing germ cells promises to ultimately increase our understanding of testis cancer.…”

Section: Introductionmentioning

confidence: 99%

Dynamic Regulation of Mitotic Arrest in Fetal Male Germ Cells

et al. 2007

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During fetal mouse development, germ cells enter the developing gonad at embryonic day (E) 10 -11. In response to signaling from the male or female gonad, the germ cells commit either to spermatogenesis at E12.5 and enter mitotic arrest or to oogenesis and enter meiotic arrest at E13.5. It is unclear whether male commitment of the germ line and mitotic arrest are directly associated or whether they are developmentally separate. In addition, the published data describing the timing of mitotic arrest are inconsistent, and the molecular processes underlying the control of the cell cycle during mitotic arrest also remain unknown. Using flow cytometric techniques, 5-bromo-2-deoxyuridine labeling, and immunofluorescent analysis of cell proliferation, we have determined that germ cells in the embryonic mouse testis arrest in G0 during E12.5 and E14.5. This process is gradual and occurs in an unsynchronized manner. We have also purified germ cells and analyzed molecular changes in male germ cells as they exit the cell cycle. This has allowed us to identify a series of molecular events, including activation of p27 Kip1 , p15 INK4b , and p16 INK4a ; the dephosphorylation and degradation of retinoblastoma protein; and the suppression of CyclinE, which lead to mitotic arrest. For the first time, the data presented here accurately define the mitotic arrest of male germ cells by directly combining the analysis of cell cycle changes with the examination of functionally defined cell cycle regulators. STEM CELLS 2008;26:339 -347 Disclosure of potential conflicts of interest is found at the end of this article.

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

Cited by 50 publications

References 33 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

Hypermethylation of the 5′ CpG island of the gene encoding the serine protease Testisin promotes its loss in testicular tumorigenesis

Dynamic Regulation of Mitotic Arrest in Fetal Male Germ Cells

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