ReviewThe Sp-family of transcription factors
Introduction
Transcriptional regulation is exerted by the combinatorial action of proteins binding to distinct promoter and enhancer elements. Usually a limited number of cis-acting DNA elements is recognized not only by a single transcription factor but by a set of different proteins which are often structurally related (Latchman, 1995). Important and widely distributed promoter elements are G-rich elements such as the GC-box (GGGGCGGGG) and the related GT/CACCC-box (GGTGTGGGG). These elements are required for the appropriate expression of many ubiquitous, tissue-specific and viral genes. In addition, they occur frequently in the regulatory region of genes which are under a specific mode of control such as cell cycle regulation, hormonal activation and developmental patterning.
For some time it has been known that the general transcription factor Sp1 (Specificity protein 1) can bind to and act through the GC-boxes and it was generally accepted that this protein is an extremely versatile protein involved in the expression of many different genes documented by more than 2600 citations. More recently, however, it became clear that Sp1 is not the only protein acting through ‘Sp1-binding sites’ but simply represents the first identified and cloned protein of a small protein family. Currently this family consists of four proteins designated Sp1, Sp2, Sp3 and Sp4. Accordingly our view on Sp1 and its function has changed significantly. Here, I will summarize and discuss advances which have been directed towards understanding the properties and function of the individual Sp-proteins.
Section snippets
Molecular cloning of Sp transcription factors
Sp1 was originally identified as the transcription factor which binds to and activates transcription from multiple GC-boxes in the simian virus 40 (SV40) early promoter (Dynan and Tjian, 1983, Gidoni et al., 1984) and the thymidine kinase (TK) promoter (Jones et al., 1985). Molecular cloning of a partial human Sp1 cDNA from HeLa cells was described in 1987 (Kadonaga et al., 1987). Since that time, the cDNA sequence published and deposited in databases is still incomplete. It encodes for the 696
Structural features of Sp-family members
All four human Sp-family members have similar domain structures (Fig. 1A). They contain three zinc fingers close to the C-terminus and glutamine-rich domains adjacent to serine/threonine stretches in their N-terminal region. The 81 amino acids C2H2-type zinc finger region which represents the DNA-binding domain is the most highly conserved part of the proteins. Alignment of that region shows that Sp1, Sp3 and Sp4 are more closely related to each other than to Sp2 (Fig. 1B). According to
Evolutionary relationship of the four Sp genes
The structural similarity of the four Sp-proteins suggests that they are evolutionally closely related. This is indeed the case and documented by their chromosomal localization in the human genome. All four Sp genes are found on paralogous chromosomal regions on human chromosomes 12q13 (Sp1), 17q21.3-q22 (Sp2), 2q31 (Sp3) and 7q21.3-q22 (Sp4) (Kalff-Suske et al., 1995, Kalff-Suske et al., 1996, Matera and Ward, 1993, Scohy et al., 1998). The human Sp genes are linked to the homeobox gene
Sp1: The prototype of the family
Molecular cloning of Sp1 and its subsequent dissection revealed the functional domains of the protein. Both glutamine-rich regions (designated A and B) (Fig. 1A) can act as strong activation domains (Courey and Tjian, 1988). Mapping of the activation domain revealed that interspersed bulky hydrophobic amino acids are essential for transcriptional activation and not, per se, the glutamine residues (Gill et al., 1994). More recently, an inhibitory domain has been mapped to the N-terminus (Murata
Regulation by the ratio of Sp1 and Sp3
It is clear that in a given cell type, co-expression of Sp1 and Sp3 occurs and we have to assume that these two proteins compete for the same binding sites in vivo. The initial characterization of Sp1 and Sp3 shows that they differ in their capacity to activate or repress transcription. Independently of whether Sp3 acts as an activator or as a repressor of Sp1-mediated activation, the relative abundance of Sp1 and Sp3 should allow regulation of gene activities. The abundance of Sp1 and Sp3
Physiological function of Sp-proteins
In the past, a large variety of biological functions have been assigned to Sp1-binding sites and to Sp1. However, the identification of the three paralogous proteins Sp2, Sp3 and Sp4 raises the question as to which tasks are performed by which protein. This question is particularly interesting for Sp1 and Sp3 because both proteins are present in the same cell and are indistinguishable in their DNA-binding specificity. Gene disruption in mice is a powerful tool for obtaining information on
Yet more and more GC/GT-box binding proteins
In the past, essential GC-boxes in promoters were often equated with “Sp1-binding sites’ thereby overlooking the fact that Sp1 is not the only protein which recognizes this important element. In addition to Sp3 and Sp4 there exist at least three other proteins, BTEB1 (basic transcription element binding protein 1) (Imataka et al., 1992), TIEG1 and TIEG2 (TGFβ-inducible early protein genes 1 and 2) (Cook et al., 1998, Fautsch et al., 1998, Subramaniam et al., 1995) which have a binding
Conclusions
The cloning and initial characterization of a family of Sp-proteins as well as other GC/GT-box binding proteins provides much information about the potential functions and activities of these proteins. The most obvious question, however, concerns the specificity of the individual family members especially of Sp1 and Sp3. Neither binding site preferences nor differential expression patterns seem to confer specificity of these two proteins. However, activation of a given promoter requires the
Acknowledgments
I thank H. Braun and H. Göllner for discussions and M. Kalff-Suske for critically reading the manuscript. The Deutsche Forschungsgemeinschaft and the Stiftung P.E. Kempkes financially support research in my group.
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