Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis

Abstract

THE D-type cyclins (D1, D2 and D3) are critical governors of the cell-cycle clock apparatus during the G1 phase of the mammalian cell cycle. These three D-type cyclins are expressed in overlapping, apparently redundant fashion in the proliferating tissues. To investigate why mammalian cells need three distinct D-type cyclins, we have generated mice bearing a disrupted cyclin D2 gene by using gene targeting in embryonic stem cells. Cyclin D2-deficient females are sterile owing to the inability of ovarian granulosa cells to proliferate normally in response to follicle-stimulating hormone (FSH), whereas mutant males display hypoplastic testes. In ovarian granulosa cells, cyclin D2 is specifically induced by FSH via a cyclic-AMP-dependent pathway, indicating that expression of the various D-type cyclins is under control of distinct intracellular signalling pathways. The hypoplasia seen in cyclin D2(-/-) ovaries and testes prompted us to examine human cancers deriving from corresponding tissues. We find that some human ovarian and testicular tumours contain high levels of cyclin D2 messenger RNA.

Identification of the critical region of 12p over-representation in testicular germ cell tumors of adolescents and adults

“…Obviously, cyclin D2 is not likely to be the gene explaining the gain of 12p-sequences in TGCTs. The published ®ndings support this view, because this gene is preferentially expressed in yolk sac tumors and not for example in embryonal carcinoma cell lines (Sicinski et al, 1996), being representative for the stem cells of NS (Andrews et al, 1990). The fact that the presence of the cyclin D2 in NS depends on the histology (Houldsworth et al, 1997) is neutral with respect to the hypothesis that cyclin D2 is the gene of interest.…”

“…For example, cyclin D2 (CCND2), mapped to 12p13 (Inaba et al, 1992) gene of interest (Sicinski et al, 1996;Houldsworth et al, 1997). We demonstrated by Southern blot analysis using a cDNA probe on all YACs within that region that cyclin D2 maps outside the SROA (not shown).…”

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

“…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.…”

“…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).…”

“…The fact that a marked testicular atrophy was the only obvious phenotype of mice de®cient in p19 INK4d (Zindy et al, 2000), in contrast to apparently normal testes in mice genetically deprived of the INK4a locus (Serrano et al, 1996), suggested a speci®c role of p19 INK4d in mouse spermatogenesis. Marked testicular defects in mice devoid of Cdk4 (Rane et al, 1999) or cyclin D2 (Sicinski et al, 1996) further suggested a critical role of cyclin D-dependent kinases and their regulators in testis biology. While searching for potential aberrations of p19 INK4d in testicular tumours, we were also hoping to address the puzzling discrepancy between the apparently indistinguishable biochemical properties of all INK4 family members including the p16 INK4a tumour suppressor and the fact that p19 INK4d appears to be neither deleted nor mutated in tumours (Ruas and Peters, 1998).…”