The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p

Christina G. Towers, Anna L. Guarnieri, Doug S. Micalizzi, J. Chuck Harrell, Austin E. Gillen, Jihye Kim, Chu An Wang, Michael U.J. Oliphant, David J. Drasin, Michelle A. Guney, Peter Kabos, Carol A. Sartorius, Aik Choon Tan, Charles M. Perou, Joaquin M. Espinosa, Heide L. Ford

研究成果: Article同行評審

34 引文 斯高帕斯(Scopus)

摘要

TP53 is mutated in 50% of all cancers, and its function is often compromised in cancers where it is not mutated. Here we demonstrate that the pro-tumorigenic/metastatic Six1 homeoprotein decreases p53 levels through a mechanism that does not involve the negative regulator of p53, MDM2. Instead, Six1 regulates p53 via a dual mechanism involving upregulation of microRNA-27a and downregulation of ribosomal protein L26 (RPL26). Mutation analysis confirms that RPL26 inhibits miR-27a binding and prevents microRNA-mediated downregulation of p53. The clinical relevance of this interaction is underscored by the finding that Six1 expression strongly correlates with decreased RPL26 across numerous tumour types. Importantly, we find that Six1 expression leads to marked resistance to therapies targeting the p53-MDM2 interaction. Thus, we identify a competitive mechanism of p53 regulation, which may have consequences for drugs aimed at reinstating p53 function in tumours.

原文English
文章編號10077
期刊Nature communications
6
DOIs
出版狀態Published - 2015 12月 21

All Science Journal Classification (ASJC) codes

  • 化學 (全部)
  • 生物化學、遺傳與分子生物學 (全部)
  • 物理與天文學 (全部)

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