Wu Yinyuan, Xing Da, Liu Lei, Gao Bo
MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, South China Normal University, GuangZhou 510631, China.
Cancer Lett. 2008 Nov 28;271(2):231-9. doi: 10.1016/j.canlet.2008.06.006. Epub 2008 Jul 25.
The Trp53 tumor suppressor gene product (p53) functions in the nucleus to regulate proapoptotic genes, whereas cytoplasmic p53 directly activates proapoptotic Bcl-2 proteins to permeabilize mitochondria and initiate apoptosis. Here, we demonstrate that both p53 transcription-dependent and -independent pathways contribute to UV-induced apoptosis. First we show that Pifithrin-alpha, a small molecule inhibitor of p53 transcriptional activity, delays Bax translocation and cell death by UV irradiation. Then using CHX (cycloheximide) to prevent new protein expression in response to p53, we also find that Bax translocation and cell death by UV irradiation are delayed. Furthermore we find that overexpression of Bcl-x(L), an inhibitor of cytoplasmic p53 after UV irradiation, prevents cell death. Finally, we observe that Pifithrin-alpha and CHX effectively inhibit PUMA expression by UV irradiation. Taken together, these data indicate that the nuclear p53 promotes PUMA expression, which then displaces cytoplasmic p53 from Bcl-x(L), allowing p53 to induce mitochondrial permeabilization, thereby triggering apoptosis.
肿瘤抑制基因Trp53的产物（p53）在细胞核中发挥作用，调控促凋亡基因，而细胞质中的p53则直接激活促凋亡的Bcl-2蛋白，使线粒体通透化并引发凋亡。在此，我们证明p53的转录依赖性和非依赖性途径均有助于紫外线诱导的凋亡。首先，我们发现p53转录活性的小分子抑制剂Pifithrin-α可延迟紫外线照射引起的Bax易位和细胞死亡。然后，使用环己酰亚胺（CHX）来阻止因p53而产生的新蛋白表达，我们还发现紫外线照射引起的Bax易位和细胞死亡会延迟。此外，我们发现紫外线照射后作为细胞质p53抑制剂的Bcl-x（L）的过表达可防止细胞死亡。最后，我们观察到Pifithrin-α和CHX可有效抑制紫外线照射引起的PUMA表达。综上所述，这些数据表明细胞核中的p53促进PUMA表达，进而使细胞质中的p53从Bcl-x（L）上解离，使p53能够诱导线粒体通透化，从而触发凋亡。
