Diabetes-Induced Oxidative DNA Damage Alters p53-p21CIP1/Waf1 Signaling in the Rat Testis
Diabetes-Induced Oxidative DNA Damage Alters p53-p21CIP1/Waf1 Signaling in the Rat Testis
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DOI：
10.1177/1933719114533729
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发表时间：
2015-01-01
影响因子：
2.9
通讯作者：
Al-Bader, Maie M.
中科院分区：
文献类型：
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作者：
Kilarkaje, Narayana;Al-Bader, Maie M.
糖尿病正日益成为大规模发病和死亡的主要原因。糖尿病引起的氧化应激改变了许多细胞内信号通路。虽然睾丸功能障碍是糖尿病男性的主要担忧，但导致性腺功能减退的睾丸机制改变尚不清楚。7，8-二氢-8-氧-2-脱氧鸟苷(7，8-二氢-8-氧-2-脱氧鸟苷)所示的线粒体DNA氧化损伤和p53在Ser315残基上的磷酸化(p-p53ser315)在糖尿病1个月大鼠的睾丸中以阶段和细胞特异性的方式增加。糖尿病延长3个月(DM3)导致核氧化DNA损伤增加，同时p-p53ser315表达减少。粗线型和细线型精母细胞、第1、11、12级精母细胞、次级精母细胞和支持细胞的细胞核及减数分裂图显示p-p53ser315表达增强。在两组糖尿病患者中，下游靶标P53和蛋白21(细胞周期蛋白依赖激酶相互作用蛋白1/野生型P53激活因子1)(p21(CIP1/Waf1))的表达增加没有表现出任何时间依赖的效应，但同时发生在DM1中p-p53ser315的上调和DM3中该蛋白的下调。糖尿病组粗线期精母细胞和圆形精细胞中p21(CIP1/Waf1)的表达以胞浆为主，但也有核周表达。P21(CIP1/Waf1)的胞浆定位可能提示该蛋白具有抗细胞凋亡的作用。核周定位可能与DNA损伤修复的细胞周期停滞有关。糖尿病上调睾丸生殖细胞中的p21(CIP1/Waf1)信号，与p-p53ser315表达的改变有关，可能是为了对抗DNA损伤诱导的细胞死亡。
Diabetes is increasingly becoming a major cause of large-scale morbidity and mortality. Diabetes-induced oxidative stress alters numerous intracellular signaling pathways. Although testicular dysfunction is a major concern in diabetic men, the mechanistic alterations in the testes that lead to hypogonadism are not yet clear. Oxidative mitochondrial DNA damage, as indicated by 7,8-dihydro-8-oxo-2-deoxyguanosine, and phosphorylation of p53 at ser315 residue (p-p53ser315) increased in a stage- and cell-specific manner in the testes of rats that were diabetic for 1 month (DM1). Prolongation of diabetes for 3 months (DM3) led to an increase in nuclear oxidative DNA damage in conjunction with a decrease in the expression of p-p53ser315. The nuclei of pachytene and preleptotene spermatocytes, steps 1, 11, and 12 spermatids, secondary spermatocytes and the Sertoli cells, and the meiotic figures showed an increase in the expression of p-p53ser315. An increase in the expression of a downstream target of p53 and protein 21(cyclin-dependent kinase interacting protein 1/wild-type p53-activated factor 1) (p21(CIP1/Waf1)) in both diabetic groups did not show any time-dependent effects but occurred concurrent with an upregulation of p-p53ser315 in DM1 and a downregulation of the protein in DM3. In diabetic groups, the expression of p21(CIP1/Waf1) was mainly cytoplasmic but also perinuclear in pachytene spermatocytes and round spermatids. The cytoplasmic localization of p21(CIP1/Waf1) may be suggestive of an antiapoptotic role for the protein. The perinuclear localization is probably related to the cell cycle arrest meant for DNA damage repair. Diabetes upregulates p21(CIP1/Waf1) signaling in testicular germ cells in association with alteration in p-p53ser315 expression, probably to counteract DNA damage-induced cell death.