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Genetic disruption of Abl nuclear import reduces renal apoptosis in a mouse model of cisplatin-induced nephrotoxicity
Authors:P Sridevi  M K Nhiayi  J Y J Wang
Institution:1.Division of Hematology-Oncology, Department of Medicine, Moores UCSD Cancer Center, UCSD School of Medicine, University of California, San Diego, La Jolla, CA, USA
Abstract:DNA damage activates nuclear Abl tyrosine kinase to stimulate intrinsic apoptosis in cancer cell lines and mouse embryonic stem cells. To examine the in vivo function of nuclear Abl in apoptosis, we generated Abl-μNLS (μ, mutated in nuclear localization signals) mice. We show here that cisplatin-induced apoptosis is defective in the renal proximal tubule cells (RPTC) from the Ablμ/μ mice. When injected with cisplatin, we found similar levels of platinum in the Abl+/+ and the Ablμ/μ kidneys, as well as similar initial inductions of p53 and PUMAα expression. However, the accumulation of p53 and PUMAα could not be sustained in the Ablμ/μ kidneys, leading to reductions in renal apoptosis and tubule damage. Co-treatment of cisplatin with the Abl kinase inhibitor, imatinib, reduced the accumulation of p53 and PUMAα in the Abl+/+ but not in the Ablμ/μ kidneys. The residual apoptosis in the Ablμ/μ mice was not further reduced in the Ablμ/μ; p53−/− double-mutant mice, suggesting that nuclear Abl and p53 are epistatic to each other in this apoptosis response. Although apoptosis and tubule damage were reduced, cisplatin-induced increases in phospho-Stat-1 and blood urea nitrogen were similar between the Abl+/+ and the Ablμ/μ kidneys, indicating that RPTC apoptosis is not the only factor in cisplatin-induced nephrotoxicity. These results provide in vivo evidence for the pro-apoptotic function of Abl, and show that its nuclear localization and tyrosine kinase activity are both required for the sustained expression of p53 and PUMAα in cisplatin-induced renal apoptosis.
Keywords:nephrotoxicity  p53  proximal renal tubule cells  PUMA-α    tyrosine kinase
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