The family feud: turning off Sp1 by Sp1-like KLF proteins

Abstract

Sp1 is one of the best characterized transcriptional activators. The biological importance of Sp1 is underscored by the fact that several hundreds of genes are thought to be regulated by this protein. However, during the last 5 years, a more extended family of Sp1-like transcription factors has been identified and characterized by the presence of a conserved DNA-binding domain comprising three Krüppel-like zinc fingers. Each distinct family member differs in its ability to regulate transcription, and, as a consequence, to influence cellular processes. Specific activation and repression domains located within the N-terminal regions of these proteins are responsible for these differences by facilitating interactions with various co-activators and co-repressors. The present review primarily focuses on discussing the structural, biochemical and biological functions of the repressor members of this family of transcription factors. The existence of these transcriptional repressors provides a tightly regulated mechanism for silencing a large number of genes that are already known to be activated by Sp1.

Figure 1. Sequence alignment of the zinc-finger domains of KLF proteins

(a) The sequence of the zinc-finger domains of Sp1 was compared with the corresponding regions of the three CtBP-mediated and the five Sin3-mediated KLF repressor proteins. The three consensus zinc fingers (ZF1, ZF2 and ZF3) are outlined by boxes, and the amino acid residues predicted to participate in interactions with DNA are indicated by arrows [16]. Identical residues are in red, similar residues in black and different residues in blue. (b) For each KLF zinc-finger domain, the percentage similarities were calculated in comparison with the equivalent domain of Sp1 and the other KLF proteins. All sequences are available in the NCBI human genome database (http://www.ncbi.nlm.nih.gov/).

Figure 2. CtBP and CtBP-mediated KLF

(a) Structural properties of the CtBP-mediated KLF proteins and CtBP family members. The highly homologous DNA-binding domains of the CtBP-mediated KLF, which are characterized by three Cys₂His₂ zinc-finger motifs, are indicated (blue). The region required for CtBP binding, containing the PXDLS recognition motif, is indicated in red. For the CtBP family members, the putative catalytic His³¹⁵ residue is shown in purple. The regions essential for transcriptional repression of CtBP1 and PXDLS motif/KLF binding are shaded in yellow and green respectively [48]. (b) Model of CtBP-mediated repression. The CtBP-mediated KLF binds to its respective recognition sequence in the promoter of a particular target gene. This protein is then able to recruit a CtBP protein via a conserved PXDLS motif. As a result, CtBP influences repression through association with proteins that include the chromatin-condensing HDACs and/or other inhibitory factors (X), such as polycomb and Ikaros.

Figure 3. mSin3 and mSin3-mediated KLF

(a) Structural properties of the mSin3-mediated KLF proteins and mSin3 family members. As in Figure 2, the three conserved Cys₂His₂ zinc-finger motifs are shown in blue. The SID region involved in interactions with mSin3 is shaded yellow. KLF10 and KLF11 have three conserved N-terminal repression domains, including the previously mentioned SID (R1) along with the R2 and R3 domains (orange). For the mSin3 family members, the four PAH protein interaction motifs are represented by adjacent, green ovals. The locations of Sin3 regions required for interaction with KLF (PAH2), N-CoR (nuclear receptor co-repressor) and HDAC are indicated. (b) Model of mSin3-mediated repression. The Sin3-mediated KLF associates with its respective GC box/BTE site in the promoter of a target gene. The SID domain of these proteins facilitates the recruitment of mSin3A through interaction with PAH2. Consequently, mSin3A recruits N-CoR, which inhibits the basal transcriptional machinery, and HDACs, which modify chromatin structure to a more condensed state, thereby mediating transcriptional repression.