Mouse Heat-Shock Factor 1 (HSF1) Is Involved in Testicular Response to Genotoxic Stress Induced by Doxorubicin
Mouse Heat-Shock Factor 1 (HSF1) Is Involved in Testicular Response to Genotoxic Stress Induced by Doxorubicin
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DOI：
10.1095/biolreprod.108.070334
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发表时间：
2008-12-01
影响因子：
3.6
通讯作者：
Christians, Elisabeth S.
中科院分区：
文献类型：
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作者：
Salmand, Pierre A.;Jungas, Thomas;Christians, Elisabeth S.
热休克因子1（HSF 1）保护细胞和生物体免受各种类型的应激，通过触发促进细胞存活的复杂反应或在应激诱导的改变无法挽救时触发细胞死亡。尽管在暴露于热休克或蛋白毒性应激的精子发生中观察到HSF 1的这种双重作用，但据报道HSF 1还有助于细胞抵抗遗传毒性应激，例如由多柔比星（一种临床常用的抗癌药物）引起的遗传毒性应激。为了更好地了解HSF 1的应激/细胞依赖性功能，我们使用野生型和Hsf 1（tm 1 Ijb）/Hsf 1（tm 1 Ijb）雄性来确定HSF 1在生精细胞中引起的遗传毒性应激反应中的作用。在单次腹腔注射阿霉素（DOXO; 5 mg/kg）后2天内，Hsf 1（+/+）而非Hsf 1（-/-）生精细胞的增殖显著减少，而有丝分裂生殖细胞和中期I精母细胞的细胞死亡增加。到21天，减数分裂细胞在所有处理的Hsf 1（+/+）睾丸中耗尽，但在Hsf 1（-/-）的。然而，3个月后，精子发生显示出更好的迹象，恢复在Hsf 1（+/+）比Hsf 1（-/-）男性。综上所述，这些数据表明，睾丸中对遗传毒性应激的急性反应涉及HSF 1依赖性机制，该机制以TRP 53非依赖性方式诱导凋亡细胞死亡，但也可以长期干预以恢复曲细精管。
Heat-shock factor 1 (HSF1) protects cells and organisms against various types of stress, either by triggering a complex response that promotes cell survival or by triggering cell death when stress-induced alterations cannot be rescued. Although this dual role of HSF1 was observed in spermatogenesis exposed to heat shock or proteotoxic stress, HSF1 was also reported to contribute to cell resistance against genotoxic stress, such as that caused by doxorubicin, an anticancer drug in common clinical use. To better understand the stress/cell-dependent functions of HSF1, we used wild-type and Hsf1(tm1Ijb)/Hsf1(tm1Ijb) males to determine the role of HSF1 in the genotoxic stress response elicited in spermatogenic cells. Within 2 days after a single intraperitoneal injection of doxorubicin (DOXO; 5 mg/kg), proliferation of Hsf1(+/+) but not Hsf1(-/-)spermatogenic cells was significantly reduced, whereas cell death was increased in mitotic germ cells and metaphase I spermatocytes. By 21 days, meiotic cells were depleted in all treated Hsf1(+/+) testes but not in Hsf1(-/-)ones. Nevertheless, after 3 mo, spermatogenesis showed better signs of recovery in Hsf1(+/+) than in Hsf1(-/-) males. Taken together, these data indicate that acute response to genotoxic stress in the testis involves HSF1-dependent mechanisms that induce apoptotic cell death in a TRP53-independent manner, but also intervene on a longer term to restore seminiferous tubules.