Gain-of-function mutant p53 upregulates CXC chemokines and enhances cell migration

William Andrew Yeudall, Catherine A. Vaughan, Hiroshi Miyazaki, Mahesh Ramamoorthy, Mi Yon Choi, Christopher G. Chapman, Huixin Wang, Elena Black, Anna A. Bulysheva, Swati Palit Deb, Brad Windle, Sumitra Deb

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

The role of dominant transforming p53 in carcinogenesis is poorly understood. Our previous data suggested that aberrant p53 proteins can enhance tumorigenesis and metastasis. Here, we examined potential mechanisms through which gain-of-function (GOF) p53 proteins can induce motility. Cells expressing GOF p53 -R175H, -R273H and -D281G showed enhanced migration, which was reversed by RNA interference (RNAi) or transactivation-deficient mutants. In cells with engineered or endogenous p53 mutants, enhanced migration was reduced by downregulation of nuclear factor-kappaB2, a GOF p53 target. We found that GOF p53 proteins upregulate CXC-chemokine expression, the inflammatory mediators that contribute to multiple aspects of tumorigenesis. Elevated expression of CXCL5, CXCL8 and CXCL12 was found in cells expressing oncogenic p53. Transcription was elevated as CXCL5 and CXCL8 promoter activity was higher in cells expressing GOF p53, whereas wild-type p53 repressed promoter activity. Chromatin immunoprecipitation assays revealed enhanced presence of acetylated histone H3 on the CXCL5 promoter in H1299/R273H cells, in agreement with increased transcriptional activity of the promoter, whereas RNAi-mediated repression of CXCL5 inhibited cell migration. Consistent with this, knockdown of the endogenous mutant p53 in lung cancer or melanoma cells reduced CXCL5 expression and cell migration. Furthermore, short hairpin RNA knockdown of mutant p53 in MDA-MB-231 cells reduced expression of a number of key targets, including several chemokines and other inflammatory mediators. Finally, CXCL5 expression was also elevated in lung tumor samples containing GOF p53, indicating relevance to human cancer. The data suggest a mechanistic link between GOF p53 proteins and chemokines in enhanced cell motility.

Original languageEnglish (US)
Pages (from-to)442-451
Number of pages10
JournalCarcinogenesis
Volume33
Issue number2
DOIs
StatePublished - 2012
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research

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    Yeudall, W. A., Vaughan, C. A., Miyazaki, H., Ramamoorthy, M., Choi, M. Y., Chapman, C. G., Wang, H., Black, E., Bulysheva, A. A., Deb, S. P., Windle, B., & Deb, S. (2012). Gain-of-function mutant p53 upregulates CXC chemokines and enhances cell migration. Carcinogenesis, 33(2), 442-451. https://doi.org/10.1093/carcin/bgr270