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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.

SUBMITTER: Chand HS

PROVIDER: S-EPMC4247165 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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

Chand Hitendra S HS Montano Gilbert G Huang Xuesong X Randell Scott H SH Mebratu Yohannes Y Petersen Hans H Tesfaigzi Yohannes Y

Nature communications 20141127

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). ...[more]

PMID: 25429397

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Project description:BackgroundSecretory myoepithelial carcinomas (SMCA) are rare, mucinous, signet ring predominant tumors with primitive myoepithelial features. While many mucinous salivary gland tumors have now been molecularly characterized, key drivers in SMCA have yet to be elucidated. Recently, NKX3.1, a homeodomain transcription factor implicated in salivary mucous acinar development was also shown in a subset of salivary mucinous neoplasms, salivary intraductal papillary mucinous neoplasms (SG-IPMN). To date, NKX3.1 expression has not been characterized in other mucinous salivary lesions. Here, we report molecular and extended immunophenotypic findings in SMCA and NKX3.1 expression in the context of other head and neck lesions.MethodsWe retrieved 4 previously reported SMCA, performed additional immunohistochemical and targeted next-generation sequencing (NGS). We also investigated the use of NKX3.1 as a marker for SMCA in the context of its prevalence and extent (using H-score) in a mixed cohort of retrospectively and prospectively tested head and neck lesions (n = 223) and non-neoplastic tissues (n = 66).ResultsNKX3.1 positivity was confirmed in normal mucous acini as well as in mucous acinar class of lesions (5/6, mean H-score: 136.7), including mucinous adenocarcinomas (3/4), SG-IPMN (1/1), and microsecretory adenocarcinoma (MSA) (1/1). All SMCA were positive. Fluorescence in situ hybridization for SS18 rearrangements were negative in all successfully tested cases (0/3). NGS was successful in two cases (cases 3 and 4). Case 3 demonstrated a PTEN c.655C>T p.Q219* mutation and a SEC16A::NOTCH1 fusion while case 4 (clinically aggressive) showed a PTEN c.1026+1G>A p.K342 splice site variant, aTP53 c.524G>A p.R175H mutation and a higher tumor mutation burden (29 per Mb). PTEN immunohistochemical loss was confirmed in both cases and a subset of tumor cells showed strong (extreme) staining for P53 in Case 4.ConclusionDespite a partial myoepithelial phenotype, SMCA, along with mucinous adenocarcinomas/SG-IPMN and MSA, provisionally constitute a mucous acinar class of tumors based on morphology and NKX3.1 expression. Like salivary mucinous adenocarcinomas/SG-IPMN, SMCA also show alterations of the PTEN/PI3K/AKT pathway and may show progressive molecular alterations. We document the first extramammary tumor with a SEC16A::NOTCH1 fusion.

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

Publications

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

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