| First Author | Sridevi P | Year | 2013 |
| Journal | Cell Death Differ | Volume | 20 |
| Issue | 7 | Pages | 953-62 |
| PubMed ID | 23660976 | Mgi Jnum | J:221235 |
| Mgi Id | MGI:5638521 | Doi | 10.1038/cdd.2013.42 |
| Citation | Sridevi P, et al. (2013) Genetic disruption of Abl nuclear import reduces renal apoptosis in a mouse model of cisplatin-induced nephrotoxicity. Cell Death Differ 20(7):953-62 |
| abstractText | 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-muNLS (mu, mutated in nuclear localization signals) mice. We show here that cisplatin-induced apoptosis is defective in the renal proximal tubule cells (RPTC) from the Abl(mu/mu) mice. When injected with cisplatin, we found similar levels of platinum in the Abl(+/+) and the Abl(mu/mu) kidneys, as well as similar initial inductions of p53 and PUMAalpha expression. However, the accumulation of p53 and PUMAalpha could not be sustained in the Abl(mu/mu) 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 PUMAalpha in the Abl(+/+) but not in the Abl(mu/mu) kidneys. The residual apoptosis in the Abl(mu/mu) mice was not further reduced in the Abl(mu/mu); 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 Abl(mu/mu) 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 PUMAalpha in cisplatin-induced renal apoptosis. |
