Department of Pediatrics, Division of Pediatric Nephrology, University of Mississippi Medical Center, Jackson, MS, USA.
Cancer Lett. 2010 Nov 28;297(2):165-70. doi: 10.1016/j.canlet.2010.05.007. Epub 2010 Jun 12.
The extracellular signal-regulated kinase (ERK) has been shown to mediate cisplatin (CP)-induced toxicity to renal proximal tubule cells. Here, we demonstrate that ERK serves as the kinase that phosphorylates the pro-apoptotic p66shc protein at its Serine36 residue in CP-treated renal proximal tubule cells. Pharmacologic or dominant-negative inhibition of ERK mitigates cisplatin-induced Ser36 phosphorylation of p66shc. Overexpression of p66shc exacerbates while its knockdown or mutation of the Serine36 site to alanine ameliorates CP-induced nephrotoxicity in vitro. Since p66shc is Serine36 phosphorylated in the kidneys of mice after treatment with CP, a similar mechanism might exist in vivo.
细胞外信号调节激酶（ERK）已被证明可介导顺铂（CP）诱导的肾近端小管细胞毒性。在这里，我们证明 ERK 作为激酶，在 CP 处理的肾近端小管细胞中使促凋亡的 p66shc 蛋白在丝氨酸 36 残基处磷酸化。ERK 的药理学或显性抑制减轻了 CP 诱导的 p66shc 的丝氨酸 36 磷酸化。p66shc 的过表达加剧了 CP 诱导的体外肾毒性，而其敲低或丝氨酸 36 位点突变为丙氨酸则减轻了 CP 诱导的肾毒性。由于 CP 处理后的小鼠肾脏中 p66shc 被丝氨酸 36 磷酸化，因此在体内可能存在类似的机制。
