Division of Hematology-Oncology, Department of Medicine, Moores UCSD Cancer Center, UCSD School of Medicine, University of California, San Diego, La Jolla, CA 92093-0820, USA.
Cell Death Differ. 2013 Jul;20(7):953-62. doi: 10.1038/cdd.2013.42. Epub 2013 May 10.
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 Abl(μ/μ) mice. When injected with cisplatin, we found similar levels of platinum in the Abl(+/+) and the Abl(μ/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 Abl(μ/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 Abl(μ/μ) kidneys. The residual apoptosis in the Abl(μ/μ) mice was not further reduced in the Abl(μ/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 Abl(μ/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.
DNA 损伤激活核 Abl 酪氨酸激酶，刺激癌细胞系和小鼠胚胎干细胞的内在凋亡。为了研究核 Abl 在凋亡中的体内功能，我们生成了 Abl-μNLS（μ，核定位信号突变）小鼠。我们在此表明，顺铂诱导的凋亡在 Abl(μ/μ)小鼠的肾近端小管细胞 (RPTC) 中存在缺陷。当注射顺铂时，我们发现 Abl(+/+)和 Abl(μ/μ)肾脏中的铂含量相似，以及 p53 和 PUMAα 表达的初始诱导相似。然而，p53 和 PUMAα 的积累在 Abl(μ/μ)肾脏中无法维持，导致肾细胞凋亡和小管损伤减少。顺铂与 Abl 激酶抑制剂伊马替尼联合治疗可减少 Abl(+/+)肾脏中 p53 和 PUMAα 的积累，但不能减少 Abl(μ/μ)肾脏中的积累。Abl(μ/μ); p53(-/-)双突变小鼠中残留的凋亡没有进一步减少，表明在这种凋亡反应中，核 Abl 和 p53 是上位关系。尽管凋亡和小管损伤减少，但 Abl(+/+)和 Abl(μ/μ)肾脏中顺铂诱导的磷酸化 Stat-1 和血尿素氮增加相似，表明 RPTC 凋亡不是顺铂诱导肾毒性的唯一因素。这些结果为 Abl 的促凋亡功能提供了体内证据，并表明其核定位和酪氨酸激酶活性都是顺铂诱导肾细胞凋亡中 p53 和 PUMAα 持续表达所必需的。
