Multiple Signaling Pathways Control the Activation of the CEF-4/9E3 Cytokine Gene by pp60v-src

doi:10.1074/jbc.271.37.22528

Volume 271, Number 37, Issue of September 13, 1996 pp. 22528-22537
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

Multiple Signaling Pathways Control the Activation of the CEF-4/9E3 Cytokine Gene by pp60^v-^src

(Received for publication, March 15, 1996, and in revised form, June 18, 1996)

Bojana Bojovi $c$ , Natalie Rodrigues , Mohammed Dehbi ^¶ and Pierre-André Bédard

From the Department of Biology, York University, North York, Ontario M3J 1P3 and the ^¶ Departement de Biochimie, Universite de Montreal CP 6128, Succursale Centre-Ville, Montreal, Quebec H3C 3J7, Canada

The CEF-4/9E3 cytokine gene is expressed aberrantly in chicken embryo fibroblasts (CEF) transformed by the Rous sarcoma virus. The expression of CEF-4 is dependent on both transcriptional and post-transcriptional mechanisms of regulation. The characterization of the promoter region indicated that three distinct regulatory elements corresponding to an AP-1 binding site (or TRE), a PRDII/ $kappa$ B domain, and a CAAT box are involved in the activation by pp60^v-^src. In this report we investigate the signaling pathways controlling the expression of the TRE and PRDII domain. The expression of a dominant negative mutant of p21^ras reduced the activity of both elements. In contrast a similar mutant of c-Raf-1 affected modestly the activation dependent on the TRE but not PRDII. The stress-activated protein kinase (SAPK)/Jun N-terminal kinase (JNK) pathway was important for the activity of PRDII and the TRE but was not markedly stimulated by pp60^v-^src. The addition of calphostin C and the inhibition of protein kinase C (PKC) diminished the accumulation of the CEF-4 mRNA and reduced the activity of a TRE-controlled promoter. Likewise, the depletion of PKC by chronic treatment with phorbol esters inhibited the activation of the TRE. Rous sarcoma virus-transformed CEF treated with calphostin C were also flatter, did not display a high degree of criss-crossing, and appeared morphologically normal. Hence PKC was important for the activation of AP-1 and the morphological transformation of CEF. The constitutive expression of CEF-4 was correlated with transformation only when dependent on the TRE. This was not true for PRDII, which was the only element required for the constitutive activation to the CEF-4 promoter in nontransformed cells treated chronically with phorbol esters.

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