Luo X, He Q, Huang Y, Sheikh M S
Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, NY 13210, USA.
Cell Death Differ. 2005 Oct;12(10):1310-8. doi: 10.1038/sj.cdd.4401659.
PUMA, a key mediator of p53-induced apoptosis, is a BH3-only domain proapoptotic protein that localizes to mitochondria and interacts with antiapoptotic Bcl-2 and Bcl-X(L). Recent evidence implicates Bax to be an important mediator of PUMA-activated apoptotic signals. We have previously demonstrated that Bax deficiency significantly affects thapsigargin (TG)-mediated endoplasmic reticulum calcium pool depletion-induced apoptosis. We now present evidence that TG upregulates PUMA expression and that although Bax-deficient cells exhibit resistance to TG, Bax deficiency does not attenuate TG upregulation of PUMA expression. Furthermore, TG transcriptionally upregulates PUMA expression in a p53-independent manner and that PUMA-deficient cells are more resistant to undergo TG-induced apoptosis than the PUMA-proficient counterparts. Thus, our results demonstrate that TG engages PUMA and Bax for full transduction of apoptotic signals and both PUMA and Bax appear to exist in the same TG-activated apoptotic pathway in which PUMA may reside upstream of Bax.
PUMA是p53诱导凋亡的关键介质，是一种仅含BH3结构域的促凋亡蛋白，定位于线粒体并与抗凋亡蛋白Bcl-2和Bcl-X(L)相互作用。最近的证据表明，Bax是PUMA激活的凋亡信号的重要介质。我们之前已经证明，Bax缺陷会显著影响毒胡萝卜素（TG）介导的内质网钙库耗竭诱导的凋亡。我们现在提供证据表明，TG上调PUMA表达，并且尽管Bax缺陷细胞对TG具有抗性，但Bax缺陷并不会减弱TG对PUMA表达的上调作用。此外，TG以不依赖p53的方式转录上调PUMA表达，并且PUMA缺陷细胞比PUMA正常的细胞更能抵抗TG诱导的凋亡。因此，我们的结果表明，TG利用PUMA和Bax来完全转导凋亡信号，并且PUMA和Bax似乎存在于相同的TG激活的凋亡途径中，其中PUMA可能位于Bax的上游。
