The impact of R213 mutation on p53-mediated p21 activity
2014
Zhang, Yan | Zhang, Yan-jun | Zhao, Hai-yong | Zhai, Qiao-li | Zhang, Ye | Shen, Yu-fei
p53 is a transcriptional regulator in the nucleus that functions as a tumor suppressor and its mutations are frequently found in human tumors. It has been reported that p53 with R213Q mutation is exist in certain tumor cell lines and its methylation on R213 as well. However, the mechanisms and consequences of these modifications on p53 function are not fully understood. Mutations of p53 at R213Q (R/Q) and R213K (R/K) were respectively constructed and transfected into the p53 null H1299 cells. As shown in luciferase reporter assays, either R/Q or R/K disrupted the efficiency of p53 transactivation. EMSA and ChIP assays revealed that these mutants were less efficient in targeting the consensus binding sequences of p53 in the regulatory region of p21 gene. In addition, R/Q and R/K mutants attenuated the expression of p21 gene and counteracted the p53 mediated G1/S arrest to deliver a normal cell cycle progression as in the mock H1299 cells. Through this study, we have provided the first evidence on the pivotal role of arginine 213 that determines the p53 mediated functions of p21 in human cancer cells.
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