A genetic variant of p53 restricts the mucous secretory phenotype by regulating SPDEF and Bcl-2 expression

作者：Chand Hitendra S; Montano Gilbert; Huang Xuesong; Randell Scott H; Mebratu Yohannes; Petersen Hans; Tesfaigzi Yohannes^*

来源：Nature Communications, 2014, 5(1): 6567.

DOI：10.1038/ncomms6567

Despite implications for carcinogenesis and other chronic diseases, basic mechanisms of p53 and its variants in suppressing Bcl-2 levels are poorly understood. Bcl-2 sustains mucous cell metaplasia, whereas p53(-) / (-) mice display chronically increased mucous cells. Here we show that p53 decreases bcl-2 mRNA half-life by interacting with the 50 untranslated region (UTR). The p53- bcl-2 mRNA interaction is modified by the substitution of proline by arginine within the p53 proline-rich domain (PRD). Accordingly, more mucous cells are present in primary human airway cultures with p53(Arg) compared with p53(Pro). Also, the p53Arg compared with p53Pro displays higher affinity to and activates the promoter region of SAM-pointed domain-containing Ets-like factor (SPDEF), a driver of mucous differentiation. On two genetic backgrounds, mice with targeted replacement of prolines in p53 PRD show enhanced expression of SPDEF and Bcl-2 and mucous cell metaplasia. Together, these studies define the PRD of p53 as a determinant for chronic mucous hypersecretion.

• 出版日期2014-11