Regulation and composition of activator protein 1 (AP-1) transcription factors controlling collagenase and c-Jun promoter activities

• Published in: Biochemical journal 2001-12, Vol.360 (Pt 3), p.599-607
• Main Authors: Steinmüller, L, Cibelli, G, Moll, J R, Vinson, C, Thiel, G
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; ATF2 protein; ATF4 protein; c-Fos protein; C/EBP protein; Carcinoma, Hepatocellular; Cells, Cultured; collagenase; Collagenases - genetics; Gene Expression Regulation, Neoplastic; Genes, jun; Genes, Reporter; Humans; Leucine Zippers; Liver Neoplasms; MAP Kinase Kinase Kinase 1; MEKK1 protein; Molecular Sequence Data; Mutagenesis, Site-Directed; Promoter Regions, Genetic; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-jun - genetics; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Sequence Alignment; Sequence Homology, Amino Acid; Transcription Factor AP-1 - chemistry; Transcription Factor AP-1 - metabolism; Transcription Factors - metabolism
• ISSN: 0264-6021; 1470-8728
• DOI: 10.1042/0264-6021:3600599

The activator protein 1 (AP-1) transcription factor is composed of heterodimers of the Fos/activating transcription factor (ATF) and Jun subfamilies of basic-region leucine-zipper (B-ZIP) proteins. In order to determine the identities of individual B-ZIP proteins in various AP-1 complexes we tested the effect of dominant-negative mutants to the B-ZIP proteins c-Fos, ATF2, ATF4 and CCAAT-enhancer-binding protein (C/EBP) on the activities of the collagenase and c-Jun promoters. These dominant-negative mutants inhibit DNA binding of wild-type B-ZIP proteins in a leucine-zipper-dependent fashion. Transcription of a collagenase promoter/reporter gene was induced in HepG2 hepatoma cells by expression of c-Fos and c-Jun, administration of PMA ("TPA") or by expression of a truncated form of MEK (mitogen-activated/extracellular-signal-regulated kinase kinase) kinase-1, MEKK1Delta. In all cases, the dominant-negative mutants A-Fos and A-ATF2 decreased collagenase promoter activity. However, A-ATF4 and A-C/EBP had no effect. A-Fos and A-ATF2 also reduced MEKK1Delta-induced stimulation of the c-Jun promoter. In contrast, constitutive c-Jun promoter activity was blocked solely by A-ATF2, strongly suggesting that ATF2 and/or an ATF2-dimerizing protein are of major importance for c-Jun transcription in unstimulated cells. These results demonstrate that AP-1 transcription factors of different compositions control c-jun gene transcription in resting or stimulated cells.