The p53/p63/p73 family of transcription factors: overlapping and distinct functions.
The p53/p63/p73 family of transcription factors: overlapping and distinct functions.
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发表时间：
2000-05
影响因子：
4
通讯作者：
M. Levrero;V. Laurenzi;A. Costanzo;J. Gong;J. Wang;G. Melino
中科院分区：
文献类型：
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作者：
M. Levrero;V. Laurenzi;A. Costanzo;J. Gong;J. Wang;G. Melino
p53基因是人类癌症中最常见的突变基因。两个同源物 p63 和 p73 的鉴定表明，p53 是相关转录因子家族的成员。鉴于p53、p63和p73在DNA结合域中的氨基酸序列一致性达到63%，因此它们在基因表达调控方面应该具有冗余功能。事实上，p73 可以激活 p53 调节的基因并抑制生长或诱导细胞凋亡。此外，p53 和 p73 都是由 DNA 损伤诱导的——尽管是通过不同的机制。然而，其他证据表明 p63 和 p73 对于正常发育的调节很重要。 p53 中未发现的延伸 C 末端区域在 p63 和 p73 中交替剪接。在这个 C 末端延伸中，有一个先前在其他调节发育的蛋白质中发现的无菌基序 (SAM)。 p63缺陷小鼠表现出发育异常。有趣的是，人类 p63 基因在患有外指症、外胚层发育不良和面裂 (EEC) 综合征的儿童中发生突变，并且该疾病表型与 p63 缺陷小鼠的疾病表型相似。尽管在神经母细胞瘤和 T 细胞淋巴瘤亚型中观察到 p73 缺失，但 p63 和 p73 基因在人类癌症中很少发生突变。 p53、p63 和 p73 似乎具有重叠和不同的功能：p53 调节应激反应以抑制肿瘤；p53 调节应激反应以抑制肿瘤；p53 调节应激反应以抑制肿瘤。 p63 对于外胚层发育至关重要； p73 可能调节应激反应和发育。由于 p53 和 p73 与不同的上游途径相关，该转录因子家族可能会调节一组共同的基因，以响应不同的细胞外信号和发育线索。
The p53 gene is the most frequently mutated gene in human cancer. The identification of two homologues, p63 and p73, revealed that p53 is a member of a family of related transcription factors. Given that they share amino acid sequence identity reaching 63% in the DNA-binding domain, p53, p63 and p73 should have redundant functions in the regulation of gene expression. Indeed, p73 can activate p53-regulated genes and suppress growth or induce apoptosis. Moreover, p53 and p73 are both induced by DNA damage - albeit through distinct mechanisms. Other evidence, however, suggests that p63 and p73 are important for regulation of normal development. An extended C-terminal region, not found in p53, is alternatively spliced in p63 and p73. Within this C-terminal extension is a sterile motif (SAM) previously found in other proteins that regulate development. The p63-deficient mice showed developmental abnormalities. Interestingly, the human p63 gene is mutated in children who have the disease Ectrodactyly, Ectodermal dysplasia and facial Clefts (EEC) syndrome, and the disease phenotype is similar to the one of p63-deficient mice. The p63 and p73 genes are rarely mutated in human cancer, although p73 loss is observed in neuroblastoma and a subtype of T-cell lymphoma. p53, p63 and p73 appear to have overlapping and distinct functions: p53 regulates the stress response to suppress tumors; p63 is essential for ectoderm development; and p73 might regulate both the stress response and development. Because p53 and p73 are linked to different upstream pathways, this family of transcription factors might regulate a common set of genes in response to different extracellular signals and developmental cues.