p53的核功能是DNA损伤诱导的PUMA介导的细胞凋亡所必需的。
The nuclear function of p53 is required for PUMA-mediated apoptosis induced by DNA damage.
作者信息
Wang Peng, Yu Jian, Zhang Lin
机构信息
Departments of Pharmacology and Pathology, Cancer Institute, University of Pittsburgh School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.
出版信息
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4054-9. doi: 10.1073/pnas.0700020104. Epub 2007 Feb 28.
The tumor suppressor p53 can induce apoptosis by activating gene expression in the nucleus, or by directly permeabilizing mitochondria in the cytoplasm. It has been shown that PUMA, a downstream target of p53 and a BH3-only Bcl-2 family member, plays an essential role in apoptosis induced by both nuclear and cytoplasmic p53. To understand how PUMA does so, we used homologous recombination to delete the binding sites of p53 in the promoter of PUMA in human colorectal cancer cells. As a result, the induction of PUMA and apoptosis in response to p53 and DNA-damaging agents were abrogated. Transcription coactivator recruitment and histone modifications in the PUMA promoter were suppressed. However, induction of PUMA and apoptosis in response to non-DNA-damaging stimuli were unaffected. These results indicate that the binding of nuclear p53 to the specific sites within the PUMA promoter is essential for its ability to induce apoptosis and is likely to be required for its tumor suppressive capacity.
肿瘤抑制因子p53可通过激活细胞核中的基因表达或直接使细胞质中的线粒体通透化来诱导细胞凋亡。研究表明，p53的下游靶点、仅含BH3结构域的Bcl-2家族成员PUMA在细胞核和细胞质p53诱导的细胞凋亡中起关键作用。为了解PUMA如何发挥作用，我们利用同源重组技术删除了人类结肠癌细胞中PUMA启动子上p53的结合位点。结果，PUMA的诱导以及对p53和DNA损伤剂的细胞凋亡反应均被消除。PUMA启动子中的转录共激活因子募集和组蛋白修饰受到抑制。然而，对非DNA损伤刺激的PUMA诱导和细胞凋亡未受影响。这些结果表明，细胞核p53与PUMA启动子内特定位点的结合对于其诱导细胞凋亡的能力至关重要，并且可能是其肿瘤抑制能力所必需的。
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