title: Pla2g16 phospholipase mediates gain-of-function activities of mutant p53.
abstract: p53(R172H/+) mice inherit a p53 mutation found in Li-Fraumeni syndrome and develop metastatic tumors at much higher frequency than p53(+/-) mice. To explore the mutant p53 metastatic phenotype, we used expression arrays to compare primary osteosarcomas from p53(R172H/+) mice with metastasis to osteosarcomas from p53(+/-) mice lacking metastasis. For this study, 213 genes were differentially expressed with a P value <0.05. Of particular interest, Pla2g16, which encodes a phospholipase that catalyzes phosphatidic acid into lysophosphatidic acid and free fatty acid (both implicated in metastasis), was increased in p53(R172H/+) osteosarcomas. Functional analyses showed that Pla2g16 knockdown decreased migration and invasion in mutant p53-expressing cells, and vice versa: overexpression of Pla2g16 increased the invasion of p53-null cells. Furthermore, Pla2g16 levels were increased upon expression of mutant p53 in both mouse and human osteosarcoma cell lines, indicating that Pla2g16 is a downstream target of the mutant p53 protein. ChIP analysis revealed that several mutant p53 proteins bind the Pla2g16 promoter at E26 transformation-specific (ETS) binding motifs and knockdown of ETS2 suppressed mutant p53 induction of Pla2g16. Thus, our study identifies a phospholipase as a transcriptional target of mutant p53 that is required for metastasis.
authors.affiliation: Department of Genetics.
authors.forename: Shunbin
authors.initials: S
authors.lastname: Xiong
authors.affiliation: Department of Genetics.
authors.forename: Huolin
authors.initials: H
authors.lastname: Tu
authors.affiliation: Department of Biochemistry and Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39216;
authors.forename: Madhusudhan
authors.initials: M
authors.lastname: Kollareddy
authors.affiliation: Department of Genetics.
authors.forename: Vinod
authors.initials: V
authors.lastname: Pant
authors.affiliation: Department of Genetics.
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Genetics.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Genetics.
authors.forename: James G
authors.initials: JG
authors.lastname: Jackson
authors.affiliation: Department of Genetics.
authors.forename: Young-Ah
authors.initials: YA
authors.lastname: Suh
authors.affiliation: Department of Genetics.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Elizondo-Fraire
authors.affiliation: Department of Genetics.
authors.forename: Peirong
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Genetics.
authors.forename: Gilda
authors.initials: G
authors.lastname: Chau
authors.affiliation: Department of Genetics.
authors.forename: Mehrnoosh
authors.initials: M
authors.lastname: Tashakori
authors.affiliation: Department of Genetics.
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Wasylishen
authors.affiliation: Department of Bioinformatics and Computational Biology, and.
authors.forename: Zhenlin
authors.initials: Z
authors.lastname: Ju
authors.affiliation: Department of Molecular Biology, The Weizmann Institute, Rehovot 76100, Israel; and.
authors.forename: Hilla
authors.initials: H
authors.lastname: Solomon
authors.affiliation: Department of Molecular Biology, The Weizmann Institute, Rehovot 76100, Israel; and.
authors.forename: Varda
authors.initials: V
authors.lastname: Rotter
authors.affiliation: Department of Genetics.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Adel K
authors.initials: AK
authors.lastname: El-Naggar
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Donehower
authors.affiliation: Department of Biochemistry and Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39216;
authors.forename: Luis Alfonso
authors.initials: LA
authors.lastname: Martinez
authors.affiliation: Department of Genetics, gglozano@mdanderson.org.
authors.forename: Guillermina
authors.initials: G
authors.lastname: Lozano
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009361:Neoplasm Invasiveness; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054512:Phospholipases A2, Calcium-Independent / Q000096:biosynthesis* / Q000235:genetics; D020218:Response Elements; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D025521:Tumor Suppressor Proteins; C490065:PLAAT3 protein, human; D054512:Phospholipases A2, Calcium-Independent; C490066:Plaat3 protein, mouse
keywords: fatty acid metabolism; mammary tumor