Chand Hitendra S, Montano Gilbert, Huang Xuesong, Randell Scott H, Mebratu Yohannes, Petersen Hans, Tesfaigzi Yohannes
COPD Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA.
Department of Cell and Molecular Physiology, The University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Nat Commun. 2014 Nov 27;5:5567. 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 5' 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 p53(Arg) compared with p53(Pro) 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.
尽管p53及其变体在抑制Bcl-2水平方面对致癌作用和其他慢性疾病有影响，但其基本机制仍知之甚少。Bcl-2维持黏液细胞化生，而p53基因敲除小鼠表现出黏液细胞长期增加。在这里，我们表明p53通过与5'非翻译区（UTR）相互作用来降低bcl-2 mRNA的半衰期。p53富含脯氨酸结构域（PRD）内的脯氨酸被精氨酸取代会改变p53与bcl-2 mRNA的相互作用。因此，与p53（Pro）相比，p53（Arg）的原代人气道培养物中存在更多的黏液细胞。此外，与p53（Pro）相比，p53（Arg）对含SAM结构域的Ets样因子（SPDEF）的启动子区域具有更高的亲和力并激活该区域，SPDEF是黏液分化的驱动因子。在两种遗传背景下，p53 PRD中脯氨酸被靶向替换的小鼠显示出SPDEF和Bcl-2的表达增强以及黏液细胞化生。总之，这些研究将p53的PRD定义为慢性黏液分泌过多的决定因素。
