title: Gain-of-function mutant p53 upregulates CXC chemokines and enhances cell migration.
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.
authors: VCU Philips Institute of Oral and Craniofacial Molecular Biology, Richmond, VA 23298, USA. wayeudall@vcu.edu
authors: W Andrew
authors: WA
authors: Yeudall
authors: Catherine A
authors: CA
authors: Vaughan
authors: Hiroshi
authors: H
authors: Miyazaki
authors: Mahesh
authors: M
authors: Ramamoorthy
authors: Mi-Yon
authors: MY
authors: Choi
authors: Christopher G
authors: CG
authors: Chapman
authors: Huixin
authors: H
authors: Wang
authors: Elena
authors: E
authors: Black
authors: Anna A
authors: AA
authors: Bulysheva
authors: Swati Palit
authors: SP
authors: Deb
authors: Brad
authors: B
authors: Windle
authors: Sumitra
authors: S
authors: Deb
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D019743:Chemokines, CXC / Q000235:genetics* / Q000378:metabolism; D047369:Chromatin Immunoprecipitation / Q000379:methods; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques / Q000379:methods; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D019743:Chemokines, CXC; D006657:Histones; D052003:NF-kappa B p52 Subunit; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53