Role of the Cytosolic Phospholipase A2-linked Cascade in Signaling by an Oncogenic, Constitutively Active Ha-Ras Isoform

Min Hyuk Yoo, Chang Hoon Woo, Hye Jin You, Sung Hoon Cho, Byung Chul Kim, Ji Eun Choi, Jang Soo Chun, Byung H. Jhun, Tae Sung Kim, Jae-Hong Kim

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Activation of Ras signaling by growth factors has been associated with gene regulation and cell proliferation. Here we characterize the contributory role of cytosolic phospholipase A2 in the oncogenic Ha-Ras V12 signaling pathway leading to activation of c-fos serum response element (SRE) and transformation in Rat-2 fibroblasts. Using a c-fos SRE-luciferase reporter gene, we showed that the transactivation of SRE by Ha-RasV12 is mainly via a Rac-linked cascade, although the Raf-mitogen-activated protein kinase cascade is required for full activation. In addition, Ha-RasV12-induced DNA synthesis was significantly attenuated by microinjection of recombinant RacN17, a dominant negative mutant of Rac1. To identify the mediators downstream of Rac in the Ha-RasV12 signaling, we investigated the involvement of cytosolic phospholipase A2. Oncogenic Ha-RasV12-induced SRE activation was significantly inhibited by either pretreatment with mepacrine, a phospholipase A2 inhibitor, or cotransfection with the antisense oligonucleotide of cytosolic phospholipase A2. We also found cytosolic phospholipase A2 to be situated downstream of Ha-Ras V12 in a signal pathway leading to transformation. Together, these results are indicative of mediatory roles of Rac and cytosolic phospholipase A2 in the signaling pathway by which Ha-RasV12 transactivates c-fos SRE and transformation. Our findings point to cytosolic phospholipase A2 as a novel potential target for suppressing oncogenic Ha-RasV12 signaling in the cell.

Original languageEnglish
Pages (from-to)24645-24653
Number of pages9
JournalJournal of Biological Chemistry
Volume276
Issue number27
DOIs
Publication statusPublished - 2001 Jul 6
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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