MADS box proteins are combinatorial transcription factors in
MADS box proteins are combinatorial transcription factors in that they often derive their regulatory specificity from other DNA binding or accessory factors. In many cases, the cofactor with which MADS box proteins interact specifies which genes are regulated, when they are regulated and if these genes are transcriptionally activated or repressed (reviewed by Shore and Sharrocks, 1995). The specific regulation of target genes is thus dependent on homo- or heterodimerization of MADS box proteins and on their association with accessory factors.
Role of MADS box factors in yeasts As shown in Fig. 3, Saccharomyces cerevisiae contains four MADS box proteins, Mcm1 and Arg80 which are related to the human SRF, and Rlm1 and Smp1 which belong to the MEF2-like family (Alvarez-Buylla et al., 2000). Rlm1 controls expression of genes required for cell wall integrity, while Smp1 is involved in osmotic stress response mediated by the Hog1 signal transduction pathway Watanabe et al., 1995, Dodou and Treisman, 1997, Nadal Ed et al., 2003. Arg80 is only required for repression of arginine anabolic genes and induction of arginine catabolic genes (Messenguy and Dubois, 2000), whereas Mcm1, also involved in the control of arginine metabolism (Messenguy and Dubois, 1993), plays a pleiotropic role in the cell. Mcm1 is essential for cell viability and controls M/G1 and G2/M cell-cycle-dependent transcription Althoefer et al., 1995, McInerny et al., 1997, mating (Jarvis et al., 1989), minichromosome maintenance (Passmore et al., 1988), recombination (Elble and Tye, 1992), TY transcription Errede, 1993, Yu and Fassler, 1993 and osmotolerance (Kuo et al., 1997). Other yeast species also contain MADS box proteins. In Schizosaccharomyces pombe, the map1 gene encodes a protein required for cell-type-specific gene expression, in Ustilago maydis, umc1 encodes a protein that regulates the expression of pheromone-inducible genes Yabana and Yamamoto, 1996, Kruger et al., 1997 and in Candida albicans, CaMCM1 is crucial for morphogenesis (Rottmann et al., 2003).
SRF-like MADS box factors in animals The serum response factor (SRF), a 508-amino-acid phosphoprotein, is expressed in a wide range of cell types and was first identified as a major regulatory protein controlling the serum-activated expression of the c-fos gene Norman et al., 1988, Treisman, 1994. Functional serum response elements (SREs), the TWS119 of SRF, are found in the promoter regions of many immediate-early genes involved in the mitogenic response of proliferative cells Gilman et al., 1986, Greenberg et al., 1987. SREs are also found in the promoters of several muscle genes expressed in post-replicative myocytes where they are involved in controlling gene tissue specificity, as well as their response to hypertrophic growth stimuli Boxer et al., 1989, Chen and Schwartz, 1996, Croissant et al., 1996, Belaguli et al., 1997. SREs can be interchanged between muscle and non-muscle gene promoters without the loss of their function, thus suggesting that in addition to SRF binding to SRE in both types of promoters, its activity is very much determined by other cell-type and promoter-specific factors interacting with SRF (Taylor et al., 1989). In addition to central DNA binding and dimerization domains, SRF contains a C-terminal transcription activation domain (Johansen and Prywes, 1993), but activation of transcription by SRF requires the recruitment of accessory proteins to the SRE elements in response to extracellular signals such as growth and differentiation signals Graham and Gilman, 1991, Hill and Treisman, 1995.
MEF2-like factors in animals Like SRF, MEF2 MADS box proteins control the transcription of genes involved in muscle differentiation and cell proliferation. In mammalian cells, there are four mef2 genes, mef2A, mef2B, mef2C and mef2D, which are expressed in distinct but overlapping patterns during embryogenesis and in adult tissues. In contrast, in Drosophila and C. elegans, there is a single mef2 gene. Their essential role in muscle differentiation has been demonstrated in Drosophila and mouse. In Drosophila, mutation of Dmef2 gene results in embryos lacking differentiated skeletal, cardiac and visceral muscle cells (Lilly et al., 1995). In mice, inactivation of the mef2C gene, which is the first MEF2 isoform expressed during embryonic development, leads to cardiac morphogenetic defects, vascular abnormalities and lethality by embryonic day 9.5 Lin et al., 1997, Bi et al., 1999. Whereas the promoters of many immediate-early genes such as c-fos contain a serum response element (SRE), some of the immediate-early genes such as c-jun do not appear to contain SRE sequences, but contain MEF2 binding sites (Fig. 2e). This MEF2 site is required for serum and epidermal growth factor (EGF) induction of c-jun promoter Han et al., 1992, Han and Prywes, 1995. MEF2 proteins can homo- and heterodimerize with other MEF2 proteins, but they cannot interact with non-MEF2 MADS box factors, suggesting that specific amino acid residues within the MADS box that establish dimerization interface are not conserved outside the MEF2 family. A variety of signalling pathways have been shown to impinge on MEF2 function; these include the mitogen-actived protein kinases (MAPKs), p38 and ERK5/BMK1, which have the potential to phosphorylate MEF2 Yang et al., 1999a, Zhao et al., 1999, Zhao et al., 2002, Puri et al., 2000. p38 phosphorylation of MEF2A and MEF2C requires targeting by a docking domain. In addition, calcium-dependent signalling through calcineurin and Ca2+/calmodulin-dependent kinases (CaMKs) is also implicated in MEF2 activity (reviewed in McKinsey et al., 2002).