Pla2g16 phospholipase mediates gain-of-function activities of mutant p53

Shunbin Xiong, Huolin Tu, Madhusudhan Kollareddy, Vinod Pant, Qin Li, Yun Zhang, James G. Jackson, Young Ah Suh, Ana C. Elizondo-Fraire, Peirong Yang, Gilda Chau, Mehrnoosh Tashakori, Amanda R. Wasylishen, Zhenlin Ju, Hilla Solomon, Varda Rotter, Bin Liu, Adel K. El-Naggar, Lawrence A. Donehower, Luis Alfonso MartinezGuillermina Lozano

Research output: Contribution to journalArticlepeer-review

Abstract

p53R172H/+ 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 p53R172H/+ 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 p53R172H/+ 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 transformationspecific (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.

Original languageEnglish (US)
Pages (from-to)11145-11150
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number30
DOIs
StatePublished - 2014
Externally publishedYes

Keywords

  • Fatty acid metabolism
  • Mammary tumor

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