Kung Che-Pei, Khaku Sakina, Jennis Matthew, Zhou Yan, Murphy Maureen E
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania. Drexel University College of Medicine, Program in Molecular Cell Biology and Genetics, Philadelphia, Pennsylvania.
Mol Cancer Res. 2015 Feb;13(2):250-62. doi: 10.1158/1541-7786.MCR-14-0385. Epub 2014 Sep 25.
The tumor-suppressor protein p53, encoded by TP53, inhibits tumorigenesis by inducing cell-cycle arrest, senescence, and apoptosis. Several genetic polymorphisms exist in TP53, including a proline to arginine variant at amino acid 72 (P72 and R72, respectively); this polymorphism alters p53 function. In general, the P72 variant shows increased ability to induce cell-cycle arrest, whereas the R72 variant possesses increased ability to induce apoptosis, relative to P72. At present, the underlying mechanisms for these functional differences are not fully understood. Toward elucidating the molecular basis for these differences, a gene-expression microarray analysis was conducted on normal human fibroblast cells that are homozygous for P72 and R72 variants, along with subclones of these lines that express a p53 short hairpin (shp53). Approximately three dozen genes were identified whose transactivation is affected by the codon 72 polymorphism. One of these is the tripartite-motif family-like 2 (TRIML2) gene, which is preferentially induced by the R72 variant. Importantly, the accumulated data indicate that TRIML2 interacts with p53, and facilitates the modification of p53 with SUMO2. TRIML2 also enhances the ability of p53 to transactivate a subset of proapoptotic target genes associated with prolonged oxidative stress, including PIDD, PIG3 (TP53I3), and PIG6 (PRODH). These data indicate that TRIML2 is part of a feed-forward loop that activates p53 in cells expressing the R72 variant, particularly after prolonged stress.
The defined actions of TRIML2, in part, explain the underlying molecular basis for increased apoptotic potential of the R72 variant of p53.
由TP53编码的肿瘤抑制蛋白p53通过诱导细胞周期停滞、衰老和凋亡来抑制肿瘤发生。TP53存在几种基因多态性，包括第72位氨基酸处脯氨酸到精氨酸的变体（分别为P72和R72）；这种多态性改变了p53的功能。一般来说，相对于P72，P72变体显示出更强的诱导细胞周期停滞的能力，而R72变体具有更强的诱导凋亡的能力。目前，这些功能差异的潜在机制尚未完全了解。为了阐明这些差异的分子基础，对纯合P72和R72变体的正常人成纤维细胞以及表达p53短发夹（shp53）的这些细胞系的亚克隆进行了基因表达微阵列分析。大约有三打基因被鉴定出其反式激活受密码子72多态性的影响。其中之一是三联基序家族样2（TRIML2）基因，它优先由R72变体诱导。重要的是，积累的数据表明TRIML2与p53相互作用，并促进p53与SUMO2的修饰。TRIML2还增强了p53反式激活与延长氧化应激相关的一组促凋亡靶基因的能力，包括PIDD、PIG3（TP53I3）和PIG6（PRODH）。这些数据表明TRIML2是一个前馈环的一部分，该前馈环在表达R72变体的细胞中激活p53，特别是在长期应激后。
TRIML2的明确作用部分解释了p53的R72变体凋亡潜力增加的潜在分子基础。
