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Structural and Functional Analysis of the Differential Effects of c-Jun and v-Jun on Prolactin Gene Expression

Department of Medicine (K.N.F., J.J.T., A.G.-H.), Division of Endocrinology, Metabolism and Diabetes, Department of Obstetrics and Gynecology (A.P.B.), and Department of Biochemistry and Molecular Genetics (A.P.B., A.G.-H.), University of Colorado Health Sciences Center, Aurora, Colorado 80045

Address all correspondence and requests for reprints to: Dr. Gutierrez-Hartmann, MS 8106, P.O. Box 6511, Aurora, Colorado 80045. E-mail: A.Gutierrez-Hartmann{at}uchsc.edu.

The protooncogene c-Jun and its oncogenic isoform v-Jun are members of the activator protein 1 family of transcription factors that have been shown to have differential transcriptional effects that are both promoter specific and cell type specific. Previously, we have demonstrated that whereas c-Jun inhibits pituitary-specific rat prolactin (rPRL) promoter activity, expression of v-Jun stimulates the rPRL promoter in GH4 pituitary cells. In this report, we have conducted an extensive structure-function analysis of c-Jun vs. v-Jun to determine which regions of these proteins are responsible for their differential transcriptional effects in this pituitary model system. We show that isoform-specific responses are mediated by complex interactions between the -domain, serine 243, and the amino-terminal transcriptional activation domains. Thus, in contrast to previous reports, no single domain is responsible for the differential transcriptional activities of c-Jun and v-Jun. Mutation of c-Jun serine 243 to phenylalanine and replacement of the c-Jun amino terminus with the corresponding region from v-Jun, thereby removing the -domain, are necessary and sufficient to confer a functional switch from the c-Jun-inhibitory to the v-Jun-activating phenotype. Thus, we propose that isoform-specific subdomains in c-Jun and v-Jun dictate discrete interactions with distinct protein partners, which underlie the differential Jun-dependent transcriptional responses of the rPRL promoter.