Resistance of Differentiating Spermatogonia to Radiation-Induced Apoptosis and Loss in p53-Deficient Mice

Hasegawa, Masatoshi; Zhang, Yun; Niibe, Hideo; Terry, Nicholas H. A.; Meistrich, Marvin L.

doi:10.2307/3579959

Cited by 110 publications

(80 citation statements)

References 21 publications

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“…In the cytoplasm it might function directly via mitochondria, a route that also has been described for p53 (Marchenko et al, 2000). Radiation induced spermatogonial apoptosis still occurs in p53 de®cient mice (Beumer et al, 1998;Hasegawa et al, 1998), and recently various p53 independent apoptotic pathways involving p73 have been described (Soengas and Lowe, 2000). Importantly, also induction of p73 by c-Abl was found to be independent of p53 (Gong et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…However, in p53 knock-out mice ionizing radiation still can induce apoptosis in spermatogonia, although most of these cells are more radioresistant than in wild type mice (Beumer et al, 1998;Hasegawa et al, 1998). Apparently, there is at least one alternative route leading to spermatogonial apoptosis.…”

Section: Introductionmentioning

confidence: 99%

“…After exposure to ionizing radiation, the tumour suppressor p53 is induced in spermatogonia and has been shown to play a central role in DNA damage induced spermatogonial apoptosis (Beumer et al, 1998;Gobe et al, 1999;Hasegawa et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Role for c-Abl and p73 in the radiation response of male germ cells

et al. 2001

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p53 plays a central role in the induction of apoptosis of spermatogonia in response to ionizing radiation. In p53 7/ 7 testes, however, spermatogonial apoptosis still can be induced by ionizing radiation, so p53 independent apoptotic pathways must exist in spermatogonia. Here we show that the p53 homologues p63 and p73 are present in the testis and that p73, but not p63, is localized in the cytoplasm of spermatogonia. Unlike p53, neither p63 nor p73 protein levels were found to increase after a dose of 4 Gy of X-rays. Although p73 protein levels did not increase, its interaction with the nonreceptor tyrosine kinase c-Abl and its phosphorylation on tyrosine residues did. c-Abl and p73 co-localize in the cytoplasm of spermatogonia and spermatocytes and in the residual bodies. Furthermore, c-Abl protein levels increase after irradiation. p63 was not found to colocalize or interact with c-Abl neither before nor after irradiation. In conclusion, in the testis ionizing radiation elevates cytoplasmic c-Abl that in turn interacts with p73. This may represent an additional, cytoplasmic, apoptotic pathway. Although less e cient than the p53 route, this pathway may cause spermatogonial apoptosis as observed in p53 de®cient mice. Oncogene (2001) 20, 4298 ± 4304.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role for c-Abl and p73 in the radiation response of male germ cells

et al. 2001

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“…In adult testis, tumor suppressor p53 is involved in apoptosis of spermatogonia after a genotoxic stress. 2,3 Classically, p53 induces apoptosis mainly via the intrinsic, mitochondrial pathway, which involves the initiator caspase-2 and caspase-9, and the downstream executioner caspases (3/7 and 6). Caspases are cysteine proteases present as precursors, activated by dimerization or by proteolytic cleavage after cell death signal triggering.…”

Section: Introductionmentioning

confidence: 99%

Caspase-independent death of meiotic and postmeiotic cells overexpressing p53: calpain involvement

et al. 2006

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In a model of male sterility (MTp53) owing to enforced p53 expression in spermatocytes II and spermatids of transgenic mice, we focused on the role of caspases. Most of them are expressed in all differentiation stages, but only the transcriptional levels of caspase-2 and caspase-3 are modified in MTp53 germ cells. In normal testis, cleaved caspase-3 and caspase-9 are detected during the elongation of spermatids. Despite this constitutive presence of caspases during terminal differentiation, calpains are the main effectors of germ cell loss in MTp53 testes: calpain 1 RNA levels are increased, caspase-3-like activity is markedly decreased while calpain activity is higher and the calpain inhibitor E64d ((2S, 3S)-trans-epoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester) reduces TUNEL labeling in MTp53 testis, whereas pancaspase inhibitor zVADfmk (N-benzyloxycarbonyl-ValAla-Asp(OMe)-fluoromethylketone) has no effect. Our work suggests that despite the presence, and potent involvement, of caspases in male haploid cell maturation, calpains are the executioners of the death of terminally differentiating germ cells.

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“…p53 null mice or mice with reduced levels of p53 show some germ-cell degeneration during the meiotic prophase, with a high frequency of multinucleated giant cells within the testicular seminiferous tubules (Rotter et al 1993). p53 also mediates stress-induced spermatogonial apoptosis after DNA damage (Hasegawa et al 1998). In mouse embryos, p53 is expressed at high levels until the mid-gestation stage (Schmid et al 1991).…”

Section: The Role Of the P53 Family Genes In Reproduction In Vertebratesmentioning

confidence: 99%

The Role of p53 Gene Family in Reproduction

2009

Cold Spring Harbor Perspectives in Biology

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The p53 family of genes ( p53, p63, and p73) is conserved over evolutionary time scales. Although the functions of p53 gene and its protein as a tumor suppressor have been firmly established, the earliest functions for the p53 ancestral genes in worms and flies are to ensure germ-line genomic integrity and the fidelity of the developmental process. In vertebrates, the p53 family of genes retains those functions in germ-line genomic integrity but have added important functions in regulation of reproduction. Loss of the p53, p63, or p73 genes in female mice leads to a significant decrease of fertility. The p53 gene product regulates maternal reproduction at the implantation stage of the embryo. p63 and p73 play important roles in monitoring the genomic quality of oocytes. The p53 pathway appears to play a similar role in human fertility. In humans, certain alleles containing a functional single-nucleotide polymorphism (SNP) in the p53 pathway are under positive evolutionary selection. Selected alleles of these SNPs in the p53 pathway are associated with decreased fertility. This important function of the p53 pathway in reproduction provides a plausible explanation for the evolution of p53 as a tumor suppressor gene and the positive selection of some alleles in the p53 gene and its pathway. These observations provide a good possible example of antagonistic pleiotrophy for fertility, tumor suppression, and longevity.

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Resistance of Differentiating Spermatogonia to Radiation-Induced Apoptosis and Loss in p53-Deficient Mice

Cited by 110 publications

References 21 publications

Role for c-Abl and p73 in the radiation response of male germ cells

Role for c-Abl and p73 in the radiation response of male germ cells

Caspase-independent death of meiotic and postmeiotic cells overexpressing p53: calpain involvement

The Role of p53 Gene Family in Reproduction

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