Transient protection from heat-stress induced apoptotic stimulation by metastasis-associated protein 1 in pachytene spermatocytes.
BACKGROUND
Deregulated thermal factors have been frequently implicated in the pathogenesis of male infertility, but the molecular basis through which certain responses are directed remain largely unknown. We previously reported that overexpression of exogenous Metastasis-associated protein 1 (MTA1) protects spermatogenic tumor cells GC-2spd (ts) against heat-induced apoptosis. To further dissect the underlying mechanism, we addressed here the fine coordination between MTA1 and p53 in pachytene spermatocytes upon hyperthermal stimulation.


RESULTS
High level of MTA1 expression sustained for 1.5 h in primary spermatocytes after heat stress before a notable decrease was detected conversely correlated to the gradual increase of acetylation status of p53 and of p21 level. Knockdown of the endogenous MTA1 in GC-2spd (ts) elevated the acetylation of p53 by diminishing the recruitment of HDAC2 and thereafter led to a dramatic increase of apoptosis after heat treatment. Consistent with this, in vivo interference of MTA1 expression in the testes of C57BL/6 mice also urged an impairment of the differentiation of spermatocytes and a disruption of Sertoli cell function due to the elevated apoptotic rate after heat stress. Finally, attenuated expression of MTA1 of pachytene spermatocytes was observed in arrested testes (at the round spermatid level) of human varicocele patients.


CONCLUSIONS
These data underscore a transient protective effect of this histone modifier in primary spermatocytes against heat-stress, which may operate as a negative coregulator of p53 in maintenance of apoptotic balance during early phase after hyperthermal stress.
Department of Human Anatomy, Histology and Embryology, Fourth Military Medical University, Xi'an, People's Republic of China. liweipepeyato@yahoo.com.cn
Wei
W
Li
Zhi-qun
ZQ
Wu
Jie
J
Zhao
Sheng-jie
SJ
Guo
Zhen
Z
Li
Xiao
X
Feng
Li
L
Ma
Jin-shan
JS
Zhang
Xin-ping
XP
Liu
Yuan-qiang
YQ
Zhang
D000107:Acetylation; D000328:Adult; D000818:Animals; D017209:Apoptosis; D019610:Cytoprotection; D018869:Heat-Shock Response; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006979:Hyperthermia, Induced; D007150:Immunohistochemistry; D007248:Infertility, Male / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008954:Models, Biological; D049471:Pachytene Stage; D012097:Repressor Proteins / Q000378:metabolism*; D013090:Spermatocytes / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D013091:Spermatogenesis; D013696:Temperature; D013737:Testis / Q000378:metabolism / Q000473:pathology; D057891:Tetraploidy; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
C089320:MTA1 protein, human; C503336:Mta1 protein, mouse; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases