Oncogene c‐fos and mutant R175H p53 regulate expression of Nucleophosmin implicating cancer manifestation

Nucleophosmin ( NPM 1) is a nucleolar protein that is frequently overexpressed in various types of solid tumors. NPM 1 is involved in several cellular processes that might contribute significantly to the increased proliferation potential of cancers. Previous reports suggest that NPM 1 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 NPM 1 promoter upstream to a Luciferase reporter gene, we have identified the minimal promoter of NPM 1 and candidate transcription factors regulating NPM 1 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 NPM 1 expression using immunoprecipitation and chromatin immunoprecipitation assays. We show here that the expression of NPM 1 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 NPM 1 expression possibly through c‐myc and c‐fos. Moreover, both c‐fos and mutant p53 are overexpressed in oral tumor tissues that showed NPM 1 overexpression. Collectively, our results suggest that c‐fos and mutant p53 R175H positively regulate NPM 1 expression, possibly in synergism, that might lead to oncogenic manifestation.