Oncogene c‐fos and mutant R175H p53 regulate expression of Nucleophosmin implicating cancer manifestation. (24th August 2018)

• Record Type: Journal Article
• Authors: Senapati, Parijat; Dey, Suchismita; Sudarshan, Deepthi; Das, Sadhan; Kumar, Manoj; Kaypee, Stephanie; Mohiyuddin, Azeem; Kodaganur, Gopinath S.; Kundu, Tapas K.
• Is Part Of: FEBS journal. Volume 285:Number 18(2018)
• Page Start: 3503
• Page End: 3524
• Publication Date: 2018-08-24
• Subjects: AP‐1 transcription factor -- cancer -- gene regulation -- mutant p53 -- promoter; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.14625
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : Nucleophosmin (NPM1) is a nucleolar protein that is frequently overexpressed in various types of solid tumors. NPM1 is involved in several cellular processes that might contribute significantly to the increased proliferation potential of cancers. Previous reports suggest that NPM1 expression is highly increased in response to mitogenic and oncogenic signals, the mechanisms of which have not been elucidated extensively. Using constructs incorporating different fragments of the NPM1 promoter upstream to a Luciferase reporter gene, we have identified the minimal promoter of NPM1 and candidate transcription factors regulating NPM1 promoter activity by luciferase reporter assays. We have validated the roles of a few candidate factors at the transcriptional and protein level by quantitative reverse transcriptase PCR, immunoblotting and immunohistochemistry, and explored the mechanism of regulation of NPM1 expression using immunoprecipitation and chromatin immunoprecipitation assays. We show here that the expression of NPM1 is regulated by transcription factor c‐fos, a protein that is strongly activated by growth factor signals. In addition, mutant p53 (R175H) overexpression also enhances NPM1 expression possibly through c‐myc and c‐fos. Moreover, both c‐fos and mutant p53 are overexpressed in oral tumor tissues that showed NPM1 overexpression. Collectively, our results suggest that c‐fos and mutant p53 R175H positively regulate NPM1 expression, possibly in synergism, that might lead to oncogenic manifestation. Abstract : The nucleolar protein Nucleophosmin (NPM1) is overexpressed in several types of solid tumors through unclear mechanisms. This study shows that the oncogenic transcription factor AP‐1 enhances NPM1 expression levels by binding to its promoter. The gain‐of‐function mutant of tumor suppressor p53, R175H, also upregulates NPM1 expression. AP‐1 recruits R175H to the NPM1 promoter and synergistically enhances NPM1 expression.