Synergistic induction of apoptosis by p53-inducible Bcl-2 family proteins Noxa and Puma.
Synergistic induction of apoptosis by p53-inducible Bcl-2 family proteins Noxa and Puma.
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DOI：
10.1272/jnms.74.148
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发表时间：
2007-04
期刊：
影响因子：
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通讯作者：
Wataru Nakajima;N. Tanaka
中科院分区：
文献类型：
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作者：
Wataru Nakajima;N. Tanaka
p53的一个重要抑瘤功能是诱导表达癌基因的细胞凋亡。在这种情况下，鉴定了编码Bcl-2家族bh3蛋白的p53诱导基因Noxa和Puma。基因敲除研究表明，Noxa和Puma都参与了癌基因表达细胞的凋亡诱导。BH3-only蛋白诱导细胞凋亡，并激活下游细胞凋亡效应因子Bax和Bak。在本研究中，我们发现Noxa和Puma协同激活Bax和Bak，诱导细胞凋亡。虽然Noxa通过灭活Mcl-1和Bcl-X(L)来激活Bak，但基因敲低研究表明Mcl-1和Bcl-X(L)都不参与这种协同作用。此外，在Bak缺失的情况下，Puma而不是Noxa直接激活Bax，而Noxa增强了Bak缺失细胞中Puma介导的Bax激活。这些结果表明存在一种新的noxa介导的细胞凋亡调控途径。虽然我们检测到Noxa和Bim（一种肿瘤抑制转录因子foxo3诱导蛋白）协同诱导细胞凋亡，但在其他BH3-only蛋白对，Bim和Bid，或Bim和Puma中没有发现这种协同作用。从这些结果来看，可以认为p53通过允许两个分子共享诱导凋亡的全部能力来谨慎地控制细胞凋亡。
One critical tumor-suppressive function of p53 is the induction of apoptosis in oncogene-expressing cells. In this context, p53-inducible genes encoding the BH3-only proteins of the Bcl-2 family, Noxa and Puma, were identified. Gene knockout studies revealed that both Noxa and Puma are involved in apoptosis induction in oncogene-expressing cells. BH3-only proteins induce apoptosis, and activate the downstream apoptosis effectors Bax and Bak. In this study, we found that Noxa and Puma synergistically activate Bax and Bak, and induce apoptosis. Although Noxa activates Bak by inactivating Mcl-1 and Bcl-X(L), gene knockdown studies revealed that neither Mcl-1 nor Bcl-X(L) is involved in this synergism. Moreover, Puma, but not Noxa, directly activated Bax in the absence of Bak, and Noxa enhanced Puma-mediated Bax activation in Bak-deficient cells. These results suggest the existence of a novel regulatory pathway for Noxa-mediated apoptosis. Although we detected synergistic induction of apoptosis by Noxa and Bim, a tumor suppressive transcriptional factor FoxO3-inducible protein, no such synergism was observed for other pairs of BH3-only proteins, Bim and Bid, or Bim and Puma. From these results, it can be considered that p53 carefully controls apoptosis by allowing two molecules to share full ability to induce apoptosis.