Transient protection from heat-stress induced apoptotic stimulation by metastasis-associated protein 1 in pachytene spermatocytes.
Transient protection from heat-stress induced apoptotic stimulation by metastasis-associated protein 1 in pachytene spermatocytes.
复制标题
粗线期精母细胞中转移相关蛋白 1 对热应激诱导的细胞凋亡刺激提供短暂保护。
DOI：
10.1371/journal.pone.0026013
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Zhang YQ
中科院分区：
文献类型：
--
作者：
Li W;Wu ZQ;Zhao J;Guo SJ;Li Z;Feng X;Ma L;Zhang JS;Liu XP;Zhang YQ
失调的热因子经常与男性不育的发病机制有关，但某些反应的分子基础仍然很大程度上未知。我们以前报道过外源性转移相关蛋白1（MTA 1）过表达可保护生精肿瘤细胞GC-2spd（ts）对抗热诱导的凋亡。为了进一步剖析其内在机制，我们在这里讨论了在高温刺激下粗线期精母细胞中MTA 1和p53之间的精细协调。高水平的MTA 1表达持续1.5小时后，在初级精母细胞热应激显着下降之前，检测到相反的乙酰化状态的p53和p21水平的逐渐增加。GC-2spd（ts）中内源性MTA 1的敲低通过减少HDAC 2的募集而提高了p53的乙酰化，此后导致热处理后细胞凋亡的显著增加。与此一致，在体内干扰C57 BL/6小鼠睾丸中的MTA 1表达也促使了精母细胞分化的损害和支持细胞功能的破坏，由于热应激后凋亡率升高。最后，在人类精索静脉曲张患者的睾丸（圆形精子细胞水平）中观察到粗线期精母细胞的MTA 1表达减弱。这些数据强调了这种组蛋白修饰剂在初级精母细胞中对热应激的瞬时保护作用，其可能在高温应激后的早期阶段作为p53在维持凋亡平衡中的负共调节因子。
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. 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. 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.