Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Signaling pathways involved in regulation of gene expression by arachidonic acid

MT Rizzo MD

Signal Transduction Laboratory, Methodist Research Institute, Indianapolis, IN

Arachidonic acid, a biologically active fatty acid, is released mainly upon agonist-stimulation of phospholipase A2. Once released, arachidonic acid can undergo to rapid conversion into eicosanoids. Although these metabolites influence several cellular processes, arachidonic acid itself is involved in the regulation of a wide array of cellular functions. Thus, studies by other investigators and us have implicated arachidonic acid as a mediator of growth factor-dependent activation of signaling pathways involved in the regulation of gene expression. Among key signaling enzymes activated by arachidonic acid are members of the mitogen-activated protein kinase (MAPK) family, including the p44 and p42 extracellular signal-regulated kinases, p38 MAPK and the c-jun amino-terminal kinases (JNKs). Activation of this family of enzymes leads to phosphorylation of specific transcription factors, which in turn affect the pattern of gene expression in response to external stimuli. We have found that stimulation of bone marrow stromal cells by arachidonic acid increases JNK activity leading to phosphorylation and activation of c-jun. Activation of JNK by arachidonic acid was blocked by tyrosine kinase inhibitors, suggesting the involvement of a tyrosine kinase-dependent signaling pathway. In the present study, we have investigated the tyrosine phosphorylation events involved in activation of JNK by arachidonic acid. Following stimulation of stromal cells with arachidonic acid, a dose- and time-dependent increase of Src family kinase activity was detected. The mechanisms of arachidonic acid-dependent activation of the Src family tyrosine kinases and the role of these kinases in activation of JNK will be discussed.

KEY WORDS: arachidonic acid, fatty acid, mitogen-activated protein kinase, c-jun amino-terminal kinases, JNKs, Src.

For more information, contact

Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on satellite symposium.