title: A genetic variant of p53 restricts the mucous secretory phenotype by regulating SPDEF and Bcl-2 expression.
abstract: 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.
authors.affiliation: COPD Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA.
authors.forename: Hitendra S
authors.initials: HS
authors.lastname: Chand
authors.affiliation: COPD Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Montano
authors.affiliation: COPD Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Cell and Molecular Physiology, The University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Randell
authors.affiliation: COPD Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA.
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Mebratu
authors.affiliation: COPD Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA.
authors.forename: Hans
authors.initials: H
authors.lastname: Petersen
authors.affiliation: COPD Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA.
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Tesfaigzi
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D020397:Goblet Cells / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009077:Mucins / Q000378:metabolism*; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D012907:Smoking / Q000235:genetics* / Q000378:metabolism
chemical_list: D009077:Mucins; D019253:Proto-Oncogene Proteins c-bcl-2; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; C403974:SPDEF protein, human; C519908:Spdef protein, mouse