Sp1- and Krüppel-like transcription factors

Abstract

Sp1-like proteins and Krüppel-like factors (KLFs) are highly related zinc-finger proteins that are important components of the eukaryotic cellular transcriptional machinery. By regulating the expression of a large number of genes that have GC-rich promoters, Sp1-like/KLF transcription regulators may take part in virtually all facets of cellular function, including cell proliferation, apoptosis, differentiation, and neoplastic transformation. Individual members of the Sp1-like/KLF family can function as activators or repressors depending on which promoter they bind and the coregulators with which they interact. A long-standing research aim has been to define the mechanisms by which Sp1-like factors and KLFs regulate gene expression and cellular function in a cell- and promoter-specific manner. Most members of this family have been identified in mammals, with at least 21 Sp1-like/KLF proteins encoded in the human genome, and members are also found in frogs, worms and flies. Sp1-like/KLF proteins have highly conserved carboxy-terminal zinc-finger domains that function in DNA binding. The amino terminus, containing the transcription activation domain, can vary significantly between family members.

Figure 1

Mammalian members of the Sp1-like/KLF family. (a) A phylogenetic tree of human Sp1-like/KLF proteins and mouse Sp5 and Sp6 (mSp5 and mSp6) identifies three general subgroups. Subgroup I consists of the proteins most highly related to Sp1 (Sp1-Sp6). The other Sp1-like/KLF proteins are divided into two additional groups (subgroups II and III). The tree was generated using Genetic Computer Group (GCG) sequence analysis software. (b) Sequence alignment of the zinc-finger domains of Sp1-like/KLF protein family members. The sequence of the zinc-finger motifs of human Sp1 was compared with the corresponding regions of previously identified human Sp1-like proteins and with mouse Sp5. The consensus zinc fingers (ZF1, ZF2 and ZF3) are indicated below the sequences and the amino-acid residues predicted to interact with DNA according to the Klevit model [58] are indicated by arrows. Identical residues are in black, similar residues in gray and different residues in lower case. The percentage similarity between the Sp1 and the other Sp1-like/KLF zinc-finger domains is indicated on the right. Note that the amino acids predicted to make contact with DNA within the first (KHA), second (RER) and third (RHK) zinc-finger domains of Sp1 are nearly identical to the corresponding regions of other members of the Sp1-like/KLF family. All sequences are available in the NCBI human genome database [57].

Figure 2

Structural properties of Sp1-like/KLF proteins. Sp1-like/KLF proteins have highly homologous carboxy-terminal DNA-binding domains characterized by three Cys₂His₂ zinc-finger motifs and recognizing GC-rich DNA elements, and variant amino termini. The members of the family can be classified into subgroups on the basis of common structural and functional features of the amino termini; these correlate well with the subgroups predicted by sequence similarities in Figure 1a. Some members of subgroup I (Sp1, Sp2, Sp3, and Sp4) contain glutamine-rich (Q) and serine/threonine-rich (S/T) amino-terminal transcription activation domains. Two members of subgroup III, KLF10 and KLF11, are TGFβ-inducible repressors and have three conserved amnio-terminal repression domains, including the Sin3 interaction domain (SID), which mediates interaction with the corepressor mSin3A. Three other members of subgroup III, KLF9, KLF13 and KLF16, are also characterized by a functional SID domain. KLF1, KLF2 and KLF4, which belong to subgroup II, are characterized by amino-terminal acidic activation domains, inhibitory regions adjacent to the zinc fingers and a conserved nuclear localization signal (NLS) sequence. In addition, KLF13 contains a similar nuclear localization sequence. Other members of subgroup II, KLF3, KLF8 and KLF12, have a conserved repression motif (PVALS/T) that interacts with the corepressor CtBP2.