Bahl R, Arora S, Nath N, Mathur M, Shukla N K, Ralhan R
Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi.
Oncogene. 2000 Jan 20;19(3):323-8. doi: 10.1038/sj.onc.1203325.
p21(waf1/cip1), an important regulator of the cell cycle, binds to PCNA and acts as a mediator of the growth suppressing and apoptosis promoting functions of p53. We report a hitherto unobserved polymorphism in the carboxy terminal domain (codon 149) of p21(waf1/cip1) gene, the domain encoding the PCNA binding motif. The codon 149 polymorphism (GAT-->GGT) was observed in 42 of 50 (84%) esophageal squamous cell carcinomas (ESCCs) and eight of 50 (16%) normal individuals. The resultant amino acid substitution from aspartate to glycine may have vital implication in PCNA mediated cell cycle regulation by p21(waf1/cip1). The second polymorphism at codon 31, involving a C-->A transversion at nucleotide 168 (AGC-->AGA) changing the amino acid from serine to arginine, was observed in 2/50 (4%) ESCCs at a relatively lower frequency in the Indian population than that reported in the West. No significant association was observed between p21(wap1/cip1) polymorphism at codon 149 and p21(wap1/cip1) protein expression in ESCC in this cohort of patients. Interestingly, the frequency of p21(wap1/cip1) variants (codon 149) in ESCCs (18 of 19 cases) with wild-type p53 was significantly higher than in tumors with p53 mutations, suggesting that this polymorphism affects the p53 pathway and may play an important role in esophageal tumorigenesis. Analysis of p21(waf1/cip1) expression in relation to p53 gene and protein status revealed its induction by p53-dependent as well as independent pathways in esophageal tumorigenesis.
p21（waf1/cip1）是细胞周期的重要调节因子，它与增殖细胞核抗原（PCNA）结合，并作为p53生长抑制和促凋亡功能的介质。我们报告了p21（waf1/cip1）基因羧基末端结构域（密码子149）中一种迄今未观察到的多态性，该结构域编码PCNA结合基序。在50例食管鳞状细胞癌（ESCC）中有42例（84%）以及50例正常个体中有8例（16%）观察到密码子149多态性（GAT→GGT）。由此导致的从天冬氨酸到甘氨酸的氨基酸替换可能对p21（waf1/cip1）介导的PCNA细胞周期调控具有重要意义。在密码子31处的第二种多态性，涉及核苷酸168处的C→A颠换（AGC→AGA），使氨基酸从丝氨酸变为精氨酸，在2/50（4%）的ESCC中被观察到，在印度人群中的频率相对低于西方报道的频率。在该队列患者中未观察到ESCC中密码子149处的p21（wap1/cip1）多态性与p21（wap1/cip1）蛋白表达之间存在显著关联。有趣的是，具有野生型p53的ESCC（19例中的18例）中p21（wap1/cip1）变体（密码子149）的频率显著高于具有p53突变的肿瘤，这表明这种多态性影响p53途径，可能在食管肿瘤发生中起重要作用。对与p53基因和蛋白状态相关的p21（waf1/cip1）表达分析显示，其在食管肿瘤发生中通过p53依赖性和非依赖性途径被诱导。
