Role of the cytosolic phospholipase A(2)-linked cascade in signaling by anoncogenic, constitutively active Ha-Ras isoform

Citation
Mh. Yoo et al., Role of the cytosolic phospholipase A(2)-linked cascade in signaling by anoncogenic, constitutively active Ha-Ras isoform, J BIOL CHEM, 276(27), 2001, pp. 24645-24653
Citations number
49
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
00219258 → ACNP
Volume
276
Issue
27
Year of publication
2001
Pages
24645 - 24653
Database
ISI
SICI code
0021-9258(20010706)276:27<24645:ROTCPA>2.0.ZU;2-W
Abstract
Activation of Res signaling by growth factors has been associated with gene regulation and cell proliferation. Here we characterize the contributory r ole of cytosolic phospholipase A(2) in the oncogenic Ha-Ras(V12) signaling pathway leading to activation of c-fos serum response element (SRE) and tra nsformation in Rat-a fibroblasts. Using a c-fos SRE-luciferase reporter gen e, 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 casc ade is required for full activation. In addition, Ha-Ras(V12)-induced DNA s ynthesis was significantly attenuated by microinjection of recombinant Rac( N17), a dominant negative mutant of Rad. To identify the mediators downstre am of Rac in the Ha-Ras(V12) signaling, we investigated the involvement of cytosolic phospholipase A(2). Oncogenic Ha-Ras(V12)-induced SRE activation was significantly inhibited by either pretreatment with mepacrine, a phosph olipase A(2) inhibitor, or cotransfection with the antisense oligonucleotid e of cytosolic phospholipase A(2). We also found cytosolic phospholipase A( 2) to be situated downstream of Ha-Ras(V12) in a signal pathway leading to transformation. Together, these results are indicative of mediatory roles o f Rac and cytosolic phospholipase A(2) in the signaling pathway by which Ha -Ras(V12) transactivates c-fos SRE and transformation. Our findings point t o cytosolic phospholipase A(2) as a novel potential target for suppressing oncogenic Ha-Ras(V12) signaling in the cell.