Ruaro E M, Collavin L, Del Sal G, Haffner R, Oren M, Levine A J, Schneider C
Laboratorio Nazionale Consorzio Interuniversitario per le Biotecnologie, Area Science Park Padriciano 99, 34012 Trieste, Italy.
Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4675-80. doi: 10.1073/pnas.94.9.4675.
The involvement of p53 in regulating diverse cellular processes dictates that it must respond to multiple signaling mechanisms, thus coordinating the response to various "stress conditions." Genotoxic stress has served as a paradigm to dissect the transactivation-dependent branch of the pathway by which p53 can induce growth arrest. Alternate mechanisms have been invoked to explain transactivation-independent effects of p53, especially in the context of apoptosis. We have identified a p53-dependent pathway initiated by the gas1 product, a plasma membrane protein highly expressed during G0, which activates a transactivation-independent p53 growth arrest function. Through a detailed deletional analysis and site-specific mutagenesis of p53 we show that the Gas1-dependent signal transduction relies on a proline-rich region (amino acids 63-85) of murine p53. In vivo competition experiments using combinations of such mutants implicate this functional domain of p53 as a docking site in the transmission of antiproliferative signals.
p53参与调控多种细胞过程，这表明它必须对多种信号机制作出反应，从而协调对各种“应激条件”的反应。基因毒性应激已成为剖析p53诱导生长停滞的转录激活依赖性途径分支的范例。人们提出了其他机制来解释p53的非转录激活依赖性效应，尤其是在细胞凋亡的背景下。我们发现了一条由Gas1产物启动的p53依赖性途径，Gas1是一种在G0期高度表达的质膜蛋白，它激活了一种非转录激活依赖性的p53生长停滞功能。通过对p53进行详细的缺失分析和位点特异性诱变，我们发现Gas1依赖性信号转导依赖于小鼠p53富含脯氨酸的区域（氨基酸63-85）。使用这些突变体组合进行的体内竞争实验表明，p53的这一功能域是抗增殖信号传递中的一个对接位点。
