Protein Modification

The activities of transcription factors are often modulated by post-translational modifications including ubiquitination, sumoylation, acetylation, methylation, and phosphorylation (Baek and Rosenfeld, 2004; Gill, 2004). Such modifications are known to regulate the DNA binding activity, repression activity, protein-protein interactions (such as the interaction between repressors and corepressors), and the subcellular localization of factors. Activators are often inactivated by protein modifications, resulting in loss of activation and hence repression. For example, phosphorylation inhibits the DNA-binding activity of several activators, such as c-Jun, Octl, HNF-4, and others (Hunter and Karin, 1992; Viollet et al., 1997). Phosphorylation of Drosophila Groucho by MAPK attenuates its repression activity (Hasson et al., 2005). Acetylation of Sp3 by p300 converts it from a repressor to an activator (Ammanamanchi et al., 2003). When sumoylation of BKLF, a zinc finger repressor, is blocked, its repression activity is reduced, but its DNA-binding activity is not affected (Perdomo et al., 2005). The tumor-suppressor Retinoblastoma protein (Rb) interacts with both the DNA binding factor E2F and HDACs in GO and in early G1 phases of the cell cycle (Cress and Seto, 2000; Ferreira et al., 2001). The association with these factors represses E2F-regulated promoters through the deacetylation of nearby histones. Rb is then phosphorylated by cyclin-CDK kinase complexes during the transition from G1 to S phase. The phosphorylated Rb can dissociate from E2F and HDAC (Takaki et al., 2004), and as a consequence, E2F can recruit CBP to activate transcription. As mentioned above, the acetylation of TCF facilitates separation from its coactivator beta-Catenin (Waltzer and Bienz, 1998). Similarly, the acetylation of El A by p300 and P/CAF disrupts the interaction with CtBP (Zhang et al., 2000). Finally, when sumoylation of hCtBPl is blocked, this factor is translocated from the nucleus into the cytoplasm (Lin et al., 2003).

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