Zhang Y, Xiong Y
Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, and Program in Molecular Biology and Biotechnology, University of North Carolina at Chapel Hill, NC 27599-7295, USA.
Science. 2001 Jun 8;292(5523):1910-5. doi: 10.1126/science.1058637.
The p53 protein is present in low amounts in normally growing cells and is activated in response to physiological insults. MDM2 regulates p53 either through inhibiting p53's transactivating function in the nucleus or by targeting p53 degradation in the cytoplasm. We identified a previously unknown nuclear export signal (NES) in the amino terminus of p53, spanning residues 11 to 27 and containing two serine residues phosphorylated after DNA damage, which was required for p53 nuclear export in colloboration with the carboxyl-terminal NES. Serine-15-phosphorylated p53 induced by ultraviolet irradiation was not exported. Thus, DNA damage-induced phosphorylation may achieve optimal p53 activation by inhibiting both MDM2 binding to, and the nuclear export of, p53.
p53蛋白在正常生长的细胞中含量较低，并在受到生理损伤时被激活。MDM2通过抑制p53在细胞核中的反式激活功能或靶向p53在细胞质中的降解来调节p53。我们在p53的氨基末端鉴定出一个先前未知的核输出信号（NES），其跨越第11至27位残基，并包含两个在DNA损伤后被磷酸化的丝氨酸残基，该信号与羧基末端NES协同作用是p53核输出所必需的。紫外线照射诱导的丝氨酸15磷酸化的p53未被输出。因此，DNA损伤诱导的磷酸化可能通过抑制MDM2与p53的结合以及p53的核输出，实现p53的最佳激活。
