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J. Biol. Chem., Vol. 276, Issue 27, 24645-24653, July 6, 2001

This Article Full Text Full Text (PDF) All Versions of this Article: 276/27/24645    most recent M101975200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yoo, M.-H. Articles by Kim, J.-H. Search for Related Content PubMed PubMed Citation Articles by Yoo, M.-H. Articles by Kim, J.-H. Social Bookmarking                      What's this?

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^¶, and Jae-Hong Kim

From the  Department of Life Science, Kwangju Institute of Science and Technology, Kwang-Ju 500-712, ^§ College of Pharmacy, Pusan National University, Pusan 609-735, and ^¶ College of Pharmacy, Chonnam National University, Kwang-Ju 500-757, Korea

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-Ras^V12 is mainly via a Rac-linked cascade, although the Raf-mitogen-activated protein kinase cascade is required for full activation. In addition, Ha-Ras^V12-induced DNA synthesis was significantly attenuated by microinjection of recombinant Rac^N17, a dominant negative mutant of Rac1. To identify the mediators downstream of Rac in the Ha-Ras^V12 signaling, we investigated the involvement of cytosolic phospholipase A₂. Oncogenic Ha-Ras^V12-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-Ras^V12 transactivates c-fos SRE and transformation. Our findings point to cytosolic phospholipase A₂ as a novel potential target for suppressing oncogenic Ha-Ras^V12 signaling in the cell.

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