Cisplatin induces apoptosis through the ERK-p66shc pathway in renal proximal tubule cells.
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.
Clark
Jeb S
JS
Department of Pediatrics, Division of Pediatric Nephrology, University of Mississippi Medical Center, Jackson, MS, USA.
Faisal
Amir
A
Baliga
Radhakrishna
R
Nagamine
Yoshikuni
Y
Arany
Istvan
I
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology* / Q000633:toxicity; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D010766:Phosphorylation; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D048049:Extracellular Signal-Regulated MAP Kinases; D002945:Cisplatin