Caspase-independent death of meiotic and postmeiotic cells overexpressing p53: calpain involvement.
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-Val-Ala-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.
Coureuil
M
M
Département de Radiobiologie et Radiopathologie (DRR), CEA/Institut Nationale de la Santé et de la Recherche Médicale Unité 566/Université Paris VII, 60 avenue du général Leclerc, BP6, Fontenay aux Roses Cedex 92265, France.
Fouchet
P
P
Prat
M
M
Letallec
B
B
Barroca
V
V
Dos Santos
C
C
Racine
C
C
Allemand
I
I
D000595:Amino Acid Sequence; D000818:Animals; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D053143:Caspase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death; D004789:Enzyme Activation; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic; D007248:Infertility, Male / Q000378:metabolism; D008297:Male; D008540:Meiosis / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D013087:Spermatids / Q000166:cytology* / Q000378:metabolism; D013090:Spermatocytes / Q000166:cytology* / Q000378:metabolism; D013091:Spermatogenesis / Q000502:physiology; D013737:Testis / Q000166:cytology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D002154:Calpain; D053143:Caspase 2; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; C112682:Capn1 protein, mouse