Male germ cell development: turning on the apoptotic pathways

Tripathi, Rakshamani; Shaha, Chandrima

doi:10.1016/j.jri.2009.05.009

Cited by 74 publications

(57 citation statements)

References 34 publications

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“…1A), revealing a severe defect in spermatogenesis. Because normal spermatogenesis requires a delicate balance between cell death and survival, insufficient as well as excessive apoptosis in the testis can cause male infertility (25). Specifically, sperm cell development is blocked by loss of the cell death mediator Bax (26), or combined deficiency of the cell death initiating BH3-only proteins Bim and Blk (the mouse ortholog of BIK) (27).…”

Section: Significancementioning

confidence: 99%

Enhanced stability of Mcl1, a prosurvival Bcl2 relative, blunts stress-induced apoptosis, causes male sterility, and promotes tumorigenesis

Okamoto

Coultas

Metcalf

et al. 2013

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

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The B-cell CLL/lymphoma 2 (Bcl2) relative Myeloid cell leukemia sequence 1 (Mcl1) is essential for cell survival during development and for tissue homeostasis throughout life. Unlike Bcl2, Mcl1 turns over rapidly, but the physiological significance of its turnover has been unclear. We have gained insight into the roles of Mcl1 turnover in vivo by analyzing mice harboring a modified allele of Mcl1 that serendipitously proved to encode an abnormally stabilized form of Mcl1 due to a 13-aa N-terminal extension. Although the mice developed normally and appeared unremarkable, the homozygous males unexpectedly proved infertile due to defective spermatogenesis, which was evoked by enhanced Mcl1 prosurvival activity. Under unstressed conditions, the modified Mcl1 is present at levels comparable to the native protein, but it is markedly stabilized in cells subjected to stresses, such as protein synthesis inhibition or UV irradiation. Strikingly, the modified Mcl1 allele could genetically complement the loss of Bcl2, because introduction of even a single allele significantly ameliorated the severe polycystic kidney disease and consequent runting caused by Bcl2 loss. Significantly, the development of c-MYC-induced acute myeloid leukemia was also accelerated in mice harboring that Mcl1 allele. Our collective findings reveal that, under certain circumstances, the N terminus of Mcl1 regulates its degradation; that some cell types require degradation of Mcl1 to induce apoptosis; and, most importantly, that rapid turnover of Mcl1 can serve as a tumor-suppressive mechanism.protein turnover | programmed cell death

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Section: Significancementioning

confidence: 99%

Enhanced stability of Mcl1, a prosurvival Bcl2 relative, blunts stress-induced apoptosis, causes male sterility, and promotes tumorigenesis

Okamoto

Coultas

Metcalf

et al. 2013

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

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“…Spermatogenesis is a process whereby germ cells generate proliferation, differentiation and deformation in the epithelium lining the seminiferous tubules and is vulnerable to the interference of external factors such as drugs, radiation and reproductive and somatic pathologies. Other external factors, including seasonal breeding, temperature and environmental pollutants, are also likely to increase the constitutive levels of apoptosis in germ cells (20). Sertoli cells of the blood-testis barrier are injured early following exposure to environmental toxic substances (including BPA) (21).…”

mentioning

confidence: 99%

Effects of exposure to bisphenol A during pregnancy and lactation on the testicular morphology and caspase-3 protein expression of ICR pups

et al. 2013

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Abstract. Bisphenol A (BPA), a xenoestrogen and endocrine-disrupting chemical, is a cause for concern due to its being a potential human carcinogen. The aim of this study was to investigate the effects of continued maternal exposure to BPA on the testicular structures and expression of caspase-3 protein in male ICR offspring during pregnancy and lactation and explore its possible mechanism. Pregnant ICR mice were divided into two control groups, which were either given or not given the solvent dimethyl sulfoxide (DMSO) and three treatment groups, which were gavaged with water-soluble BPA dissolved in DMSO at three different concentrations from gestational day 0 to weaning on postnatal day (PND) 21.

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“…32 In the present study, protein ( Figure 3D) and transcriptional upregulation (Figure 4) of apoptotic markers for extrinsic (Fas, FasL, and caspase 8) and intrinsic (Bax, Bcl2, and caspase 9) pathways was observed identical to findings reported earlier. 33,34 B-cell lymphoma 2 (Bcl2) has been localized exclusively in spermatids 35 in humans and the same may also be true for rats. However, the spermatid number declines significantly after DNG þ TU treatment.…”

Section: Discussionmentioning

confidence: 91%

Complete Sperm Suppression in Rats With Dienogest Plus Testosterone Undecanoate Is Facilitated Through Apoptosis in Testicular Cells

Meena

Misro

Ghosh³

2013

Reprod. Sci.

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Complete suppression of the production of sperm in rats with dienogest (DNG, 40 mg/kg body weight [bw]) plus testosterone undecanoate (TU, 25 mg/kg bw), every 45 days, was found to be associated with a significant increase in germ cell apoptosis. Caspase 3 activity and expression in testis were simultaneously upregulated. Rise in the activities of caspase 8 and 9 was associated with overexpression of upstream marker proteins from extrinsic (Fas [Fatty acid synthase], FasL [Fatty acid synthase ligand], and caspase 8) and intrinsic (Bax [Bcl2-associated-x protein], Bcl2 [B-cell lymphoma 2], and caspase 9) pathways of apoptosis. Apart from the germ cells, interstitial cell apoptosis was also observed along with a decline in the number of functional Leydig cells. It is therefore concluded that complete suppression of the production of sperm with DNG þ TU is facilitated mainly through the removal of precursor germ cells through apoptosis. The process is largely modulated by upregulation of upstream and downstream marker proteins from intrinsic as well as extrinsic pathway of metazoan apoptosis.

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Male germ cell development: turning on the apoptotic pathways

Cited by 74 publications

References 34 publications

Enhanced stability of Mcl1, a prosurvival Bcl2 relative, blunts stress-induced apoptosis, causes male sterility, and promotes tumorigenesis

Enhanced stability of Mcl1, a prosurvival Bcl2 relative, blunts stress-induced apoptosis, causes male sterility, and promotes tumorigenesis

Effects of exposure to bisphenol A during pregnancy and lactation on the testicular morphology and caspase-3 protein expression of ICR pups

Complete Sperm Suppression in Rats With Dienogest Plus Testosterone Undecanoate Is Facilitated Through Apoptosis in Testicular Cells

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