Puc Janusz, Keniry Megan, Li Hong Shen, Pandita Tej K, Choudhury Atish D, Memeo Lorenzo, Mansukhani Mahesh, Murty Vundavalli V V S, Gaciong Zbigniew, Meek Sarah E M, Piwnica-Worms Helen, Hibshoosh Hanina, Parsons Ramon
Institute for Cancer Genetics, Columbia University, New York, New York 10032, USA.
Cancer Cell. 2005 Feb;7(2):193-204. doi: 10.1016/j.ccr.2005.01.009.
Pten-/- cells display a partially defective checkpoint in response to ionizing radiation (IR). The checkpoint defect was traced to the ability of AKT to phosphorylate CHK1 at serine 280, since a nonphosphorylated mutant of CHK1 (S280A) complemented the checkpoint defect and restored CDC25A degradation. CHK1 phosphorylation at serine 280 led to covalent binding of 1 to 2 molecules of ubiquitin and cytoplasmic CHK1 localization. Primary breast carcinomas lacking PTEN expression and having elevated AKT phosphorylation had increased cytoplasmic CHK1 and displayed aneuploidy (p <0.005). We conclude that loss of PTEN and subsequent activation of AKT impair CHK1 through phosphorylation, ubiquitination, and reduced nuclear localization to promote genomic instability in tumor cells.
Pten基因敲除的细胞在对电离辐射（IR）的反应中表现出部分缺陷的检查点。该检查点缺陷可追溯到AKT在丝氨酸280处磷酸化CHK1的能力，因为CHK1的非磷酸化突变体（S280A）弥补了检查点缺陷并恢复了CDC25A的降解。丝氨酸280处的CHK1磷酸化导致1至2分子泛素的共价结合以及CHK1在细胞质中的定位。缺乏PTEN表达且AKT磷酸化升高的原发性乳腺癌细胞中，细胞质CHK1增加并表现出非整倍体（p <0.005）。我们得出结论，PTEN的缺失以及随后AKT的激活通过磷酸化、泛素化和核定位减少损害CHK1，从而促进肿瘤细胞的基因组不稳定。
