T‐cell factors: turn‐ons and turn‐offs

The family of T‐cell factor (Tcf) and lymphoid enhancer factor (Lef) proteins, which in mammals comprises Tcf1, Lef1, Tcf3 and Tcf4, form a subgroup of the high mobility group (HMG) box‐containing superfamily of transcription factors. Alternative splicing and promoter usage give rise to multiple Tcf isoforms, possessing diverse functional domains (Figure 1) (van de Wetering et al ., 1996; Korinek et al ., 1998; Duval et al ., 2000; Hovanes et al ., 2000, 2001). Tcfs bind DNA as monomers. The 80 amino acid HMG box mediates sequence‐specific binding to a core consensus sequence AGATCAAAGGG through contacts made predominantly within the minor groove of the DNA helix (Giese et al ., 1991; van de Wetering et al ., 1991; van Beest et al ., 2000). Tcfs, like other HMG box‐containing transcription factors, have been described as architectural proteins due to their ability to induce substantial bends in DNA, potentially facilitating the formation of large nucleoprotein complexes and thereby promoting transcription (Giese et al ., 1992). However, Tcf molecules by themselves are incapable of modulating transcription. Instead they bind a number of auxilliary proteins, thereby recruiting essential functional domains to the regulatory regions of target genes. This review will focus mainly on the identity of these Tcf co‐factors. Figure 1. Schematic representation of Tcf splice variants and their most conserved domains. Short forms of Tcf1 and Lef1 lack the N‐terminal domain, which interacts with β‐catenin. The CAD domain in Lef1 is required for context‐dependent activation of the TCRα enhancer. The HMG box mediates sequence‐specific DNA binding. The most divergent region of the Tcf family members is the C‐terminus, which in certain longer isoforms contains a conserved motif, CRARF, whose function is presently unknown, and two CtBP binding sites. Tcfs are highly conserved through evolution (Figure 2). Experiments …