The Regulation of AP-1 Activity by Mitogen-activated Protein Kinases

Abstract

AP-1 is a sequence-specific transcriptional activator composed of members of the Jun and Fos families (for review see Ref. 1Angel P. Karin M. Biochim. Biophys. Acta. 1991; 1072: 129-157Crossref PubMed Scopus (3256) Google Scholar). These proteins, which belong to the bZIP group of DNA binding proteins (for review see Ref. 2Johnson P.F. McKnight S.L. Annu. Rev. Biochem. 1989; 58: 799-839Crossref PubMed Scopus (829) Google Scholar), associate to form a variety of homo- and heterodimers that bind to a common site(1Angel P. Karin M. Biochim. Biophys. Acta. 1991; 1072: 129-157Crossref PubMed Scopus (3256) Google Scholar). First identified by its role in human metallothionein IIA gene regulation(3Lee W. Haslinger A. Karin M. Tjian R. Nature. 1987; 325: 368-372Crossref PubMed Scopus (484) Google Scholar), AP-1 was also found as a transcription factor that mediates gene induction by the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and hence the name TRE1 1The abbreviations used are: TRETPA (12-O-tetradecanoylphorbol-13-acetate) response elementMAPKmitogen-activated protein kinaseSREserum response elementTCFternary complex factorCBPCREB binding proteinJAKJanus kinaseERKextracellular stimulus responsive kinaseATFactivating transcription factorJNKJun N-terminal kinaseCREBcAMP response element binding proteinFRKFos regulating kinaseMEKMAPK or ERK kinase. 1The abbreviations used are: TRETPA (12-O-tetradecanoylphorbol-13-acetate) response elementMAPKmitogen-activated protein kinaseSREserum response elementTCFternary complex factorCBPCREB binding proteinJAKJanus kinaseERKextracellular stimulus responsive kinaseATFactivating transcription factorJNKJun N-terminal kinaseCREBcAMP response element binding proteinFRKFos regulating kinaseMEKMAPK or ERK kinase.(TPA response element) for its recognition site(4Angel P. Imagawa M. Chiu R. Stein B. Imbra R.J. Rahmsdorf H.J. Jonat C. Herrlich P. Karin M. Cell. 1987; 49: 729-739Abstract Full Text PDF PubMed Scopus (2152) Google Scholar). Following its discovery, AP-1 activity was found to be induced by many other stimuli, including growth factors, cytokines, T cell activators, neurotransmitters, and UV irradiation (1Angel P. Karin M. Biochim. Biophys. Acta. 1991; 1072: 129-157Crossref PubMed Scopus (3256) Google Scholar). Several mechanisms are involved in induction of AP-1 activity and may be classified as those that increase the abundance of AP-1 components and those that stimulate their activity. A complete discussion of all the mechanisms that regulate AP-1 activity, either positively or negatively, is beyond the scope of this minireview, and the reader is referred to an earlier, more comprehensive review(1Angel P. Karin M. Biochim. Biophys. Acta. 1991; 1072: 129-157Crossref PubMed Scopus (3256) Google Scholar). The present review focuses on the role of mitogen-activated protein kinases (MAPKs) in regulation of AP-1 activity. The regulation and functions of these important signal-transducing enzymes were recently reviewed(5Marshall C.J. Cell. 1995; 80: 179-185Abstract Full Text PDF PubMed Scopus (4225) Google Scholar, 6Cobb M. Goldsmith E.J. J. Biol. Chem. 1995; 270: 14843-14846Abstract Full Text Full Text PDF PubMed Scopus (1659) Google Scholar). TPA (12-O-tetradecanoylphorbol-13-acetate) response element mitogen-activated protein kinase serum response element ternary complex factor CREB binding protein Janus kinase extracellular stimulus responsive kinase activating transcription factor Jun N-terminal kinase cAMP response element binding protein Fos regulating kinase MAPK or ERK kinase. TPA (12-O-tetradecanoylphorbol-13-acetate) response element mitogen-activated protein kinase serum response element ternary complex factor CREB binding protein Janus kinase extracellular stimulus responsive kinase activating transcription factor Jun N-terminal kinase cAMP response element binding protein Fos regulating kinase MAPK or ERK kinase. The reader should be aware that although AP-1 DNA binding activity can be conveniently measured by electrophoretic mobility shift or footprinting assays, changes in AP-1 DNA binding activity do not mirror the transcriptional activity of this complex factor. Therefore, when dealing with AP-1, it is critical to measure its ability to activate transcription of an AP-1-dependent reporter gene. A useful promoter for such experiments is that of the human collagenase gene (4Angel P. Imagawa M. Chiu R. Stein B. Imbra R.J. Rahmsdorf H.J. Jonat C. Herrlich P. Karin M. Cell. 1987; 49: 729-739Abstract Full Text PDF PubMed Scopus (2152) Google Scholar). The reasons for this discrepancy are several. First and foremost, several proteins can form complexes that bind to AP-1 sites. These proteins, however, differ considerably in their ability to activate transcription of target genes. For instance, both c-Fos and Fra-1 form stable heterodimers with any of the Jun proteins, and these heterodimers have similar DNA binding activities and specificities, yet c-Fos has a potent transactivation domain that is absent from the smaller Fra-1 protein(7Suzuki T. Okuno H. Yoshida T. Endo T. Nishina H. Iba H. Nucleic Acids Res. 1992; 19: 5537-5542Crossref Scopus (194) Google Scholar). Second, phosphorylation at specific sites enhances the transactivating potential of several AP-1 proteins, including c-Jun and c-Fos, without having any effect on their DNA binding activities(8Smeal T. Binetruy B. Mercola D. Grover-Bardwick A. Heidecker G. Rapp U.R. Karin M. Mol. Cell. Biol. 1992; 12: 3507-3513Crossref PubMed Scopus (305) Google Scholar, 9Deng T. Karin M. Nature. 1994; 371: 171-175Crossref PubMed Scopus (318) Google Scholar). Most of the genes that encode AP-1 components behave as “immediate-early” genes, i.e. genes whose transcription is rapidly induced, independently of de novo protein synthesis, following cell stimulation. Among these, the regulation of c-fos and c-jun transcription is best understood. Several cis elements mediate c-fos induction in response to a diverse spectrum of extracellular stimuli (reviewed in Ref. 10Treisman R. Trends Biochem. Sci. 1992; 17: 423-426Abstract Full Text PDF PubMed Scopus (349) Google Scholar). A cAMP response element mediates c-fos induction in response to neurotransmitters and polypeptide hormones which, by using either cAMP or Ca2+ as second messengers, activated either protein kinase A or calmodulin-dependent protein kinases, respectively(11Sheng M.E. Thompson M.A. Greenberg M.E. Science. 1994; 252: 1427-1430Crossref Scopus (1279) Google Scholar). A serum response element (SRE) mediates c-fos induction by growth factors, cytokines, and other stimuli that activate MAPKs(10Treisman R. Trends Biochem. Sci. 1992; 17: 423-426Abstract Full Text PDF PubMed Scopus (349) Google Scholar), and a Sis-inducible enhancer mediates induction by stimuli that activate the JAK group of protein kinases (12Darnell Jr., J.E. Kerr I.M. Stark G.R. Science. 1994; 264: 1415-1421Crossref PubMed Scopus (4974) Google Scholar). Given this complexity, it is not surprising that c-fos transcription is rapidly induced in response to almost any imaginable extracellular stimulus (Fig. 1A). The SRE is recognized by the serum response factor, whose binding results in recruitment of the ternary complex factor (TCF), which cannot bind to the SRE by itself(10Treisman R. Trends Biochem. Sci. 1992; 17: 423-426Abstract Full Text PDF PubMed Scopus (349) Google Scholar). Following mitogenic stimulation, Elk-1, one of several candidate TCFs(13Treisman R. Curr. Opin. Genet. & Dev. 1994; 4: 96-101Crossref PubMed Scopus (619) Google Scholar), is rapidly phosphorylated, most likely by members of the ERK group of MAPKs(14Gille H. Sharrocks A. Shaw P. Nature. 1992; 358: 414-417Crossref PubMed Scopus (814) Google Scholar, 15Marais R. Wynne J. Treisman R. Cell. 1993; 73: 381-393Abstract Full Text PDF PubMed Scopus (1104) Google Scholar). Phosphorylation of Elk-1 was reported to facilitate formation of the ternary