Abstract
p53 is a major tumor suppressor whose function is pivotal for protection against cancer. In over half of human cancers, p53 is inactivated due to either point mutation or loss of p53 gene. It has been well established that in addition to abrogating the tumor-suppressive function of wild-type p53, mutant p53 gains new functions and actively contributes to various stages of tumor progression. However, little is known about whether microRNA (miRNA) is involved in the gain-of-function of mutant p53. Here we report miR-27a as a novel downstream transcriptional target of mutant p53-273H. Mutant p53 binds to the miR-27a promoter region and suppresses its expression. We also identify epidermal growth factor receptor (EGFR) as a direct target of miR-27a. Via the miR-27a/EGFR axis, mutant p53-273H promotes a sustained EGF-induced extracellular signal–regulated kinase 1/2 activation, thereby facilitating cell proliferation and tumorigenesis. Collectively, this work reveals a direct link between the gain-of-function of mutant p53 and miRNA and uncovers a novel mutant p53-273H/miR-27a/EGFR pathway that has an important role in promoting tumor development.
Highlights
P53, the function of p53 is often inactivated due to alterations in its regulators and/or mediators.[2]
Previous studies have suggested that the gain-of-function of mutant p53 is largely attributed by the transcriptional regulation of some cancer-related genes, such as MDR1, c-MYC and NFKB2.48–50 In this study, we provide evidence demonstrating that miRNA has an important role in the gain-offunction of mutant p53
We show that miR-27a is transcriptionally repressed by mutant p53, contributing to the gain-of-function of mutant p53 in promoting cell proliferation and tumorigenesis
Summary
P53, the function of p53 is often inactivated due to alterations in its regulators and/or mediators.[2]. MicroRNAs (miRNAs), which regulate the stability and translational efficiency of partially complementary target mRNAs, are small RNA molecules, typically 19–23 nucleotides in length.[23,24] It has been shown that more than half of miRNA genes are located in cancer-associated genomic regions or in fragile sites.[25] Increasing evidence has documented nearly ubiquitous dysregulation of miRNA expression in cancer cells.[26,27,28] Altered expression of specific miRNAs has been shown to promote tumorigenesis.[27,28] It has been recently reported that miRNA has an important. Received 12.1.13; revised 19.2.13; accepted 26.2.13; Edited by G Raschellarole in mutant p53 gain-of-function.[29,30,31] the details of how mutant p53 promotes tumorigenesis through miRNA are still largely unknown
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