The c-Jun delta-domain inhibits neuroendocrine promoter activity in a DNA sequence- and pituitary-specific manner.
The transcription and transformation activity of c-Jun is governed by a 27-amino acid regulatory motif, labeled the delta-domain, which is deleted in v-Jun. We have previously shown that c-Jun is a potent inhibitor of the rat prolactin (rPRL) promoter activity induced by either oncogenic Ras or phorbol esters. Here, we have characterized the structural and cell-specific requirements for this c-Jun inhibitory response, and we show that this c-Jun inhibitory response mapped to the rPRL footprint II repressor site, was pituitary-specific and required the c-Jun delta-domain. Moreover, alteration of any one of these features (e.g., cis-element, trans-factor, or cell-specific background) switched c-Jun to a transcriptional activator of the rPRL promoter. In HeLa nonpituitary cells, c-Jun alone activated the rPRL promoter via the most proximal GHF-1/Pit-1 binding site, footprint I, and synergized with GHF-1. Finally, recombinant GHF-1 interacted directly with c-Jun but not c-Fos proteins. These data provide important fundamental insights into the molecular mechanisms by which the c-Jun delta-domain functions as a modulatory switch and further imply that the functional role of c-Jun is dictated by cell-specific influences and the delta-domain motif.
Farrow
K N
KN
Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Manning
N
N
Schaufele
F
F
Gutierrez-Hartmann
A
A
D000818:Animals; D001665:Binding Sites; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D011905:Genes, ras; D006367:HeLa Cells; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis; D010902:Pituitary Gland / Q000378:metabolism*; D010911:Pituitary Neoplasms; D011388:Prolactin / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis; D012156:Reticulocytes / Q000378:metabolism; D013379:Substrate Specificity; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011994:Recombinant Proteins; D015534:Trans-Activators; D011388:Prolactin; D004247:DNA; D008156:Luciferases