ReviewRoles of the NFI/CTF gene family in transcription and development
Introduction
The Nuclear Factor I (NFI) family of site-specific DNA-binding proteins plays wide reaching roles in animal physiology, biochemistry and pathology. While first described as being required for the replication of Adenovirus DNA, this family of transcription/replication proteins has been implicated in the replication of several other viruses and has been shown to regulate the transcription of a large variety of cellular and viral genes. In addition, NFI proteins have been associated with changes in the growth state of cells and with a number of oncogenic processes and disease states. Since the role of NFI in adenovirus DNA replication has been recently reviewed (de Jong and van der Vliet, 1999), we will focus here on the evolution of the NFI gene family and on the role of NFI proteins in gene expression and development.
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Discovery of viral and cellular NFI-binding sites
After the initial observation that NFI protein isolated from nuclear extracts of human HeLa cells greatly stimulated the initiation of adenovirus DNA replication (Nagata et al., 1982), it was shown that NFI was a site-specific DNA-binding protein that bound to the adenovirus origin of replication (Nagata et al., 1983). Direct isolation of NFI-binding sites from cellular DNA (Gronostajski et al., 1985) and comparison with viral and cellular sites identified by DNA-binding assays (Hennighausen et
Evolution of the NFI multigene family
NFI cDNAs isolated from rat (Paonessa et al., 1988), human (Santoro et al., 1988), hamster (Gil et al., 1988b), mouse (Inoue et al., 1990) and porcine (Meisterernst et al., 1988b, Meisterernst et al., 1989) sources indicated that multiple NFI genes are present in vertebrate genomes. Several different nomenclatures arose for the NFI genes, leading to confusion regarding the number of NFI genes in mammals. The Sippel laboratory identified four NFI genes in the chicken [designated NFI-A, NFI-B,
Unusual features of NFI transcripts
While the general features discussed below (N-terminal DNA-binding and C-terminal transcriptional modulation domains) accurately describe the vertebrate NFI proteins, additional complexity is generated by alternative processing of NFI transcripts (Fig. 1). Alternative processing takes three forms: (1) alternative polyadenylation between exons 2 and 3 of NFI-B, yielding the short NFI-B3 described below (Liu et al., 1997); (2) alternative splicing of exons in the 3′ regions of all four NFI genes,
Structural and functional domains of NFI proteins
As mentioned above, transcripts of each of the four vertebrate NFI genes are alternatively spliced generating multiple proteins from each gene. This complexity of protein and mRNA isoforms can be simplified if we consider domains that are conserved in all of the isoforms and between the four vertebrate genes. However, since recent studies have demonstrated significant differences between the functional activities of products of the four NFI genes, it should be remembered that generalizations
N-terminal DNA-binding/dimerization domain
The typical NFI protein is composed of an N-terminal DNA-binding/dimerization domain and C-terminal transcriptional activation and/or repression domains (Fig. 1). The N-terminal DNA-binding/dimerization domain is preceded by alternative exons encoding 8–47 aa domains of unknown function [although there is strong conservation of this region between the four genes (Kruse et al., 1991, Kruse and Sippel, 1994a, Meisterernst et al., 1989, Rupp et al., 1990)] (Fig. 1, E1a–c). Deletion analysis has
C-terminal transactivation and repression domains
While the DNA-binding and replication activities of NFI proteins reside in the N-terminal domain, C-terminal domains have been implicated in most, though not all, regulation of gene expression by NFI. As described above, alternative splicing generates many variants of the C-terminal domains of NFI proteins, only a fraction of which have been tested for functional activity (Fig. 1). The initial cloning and characterization of NFI-C/CTF transcripts demonstrated that the C-terminal 100 residues of
Mechanisms of transcriptional modulation by NFI proteins: transactivation
As discussed above, binding sites of NFI proteins have been implicated in both activation and repression of promoters. This suggests that NFI proteins likely affect transcription through multiple mechanisms. The best studied mechanism used by NFI proteins to activate transcription is through direct interaction with basal transcription factors (Fig. 3, top). The largest NFI-C isoform (NFI-C/CTF1) has an ∼100 aa proline rich domain (Mermod et al., 1989) that contains a single copy of the
Mechanisms of transcriptional modulation by NFI proteins: repression
As is seen with transactivation, it seems likely that multiple mechanisms exist by which NFI proteins can repress transcription. One mechanism postulated for repression by NFI proteins is through direct competition with more potent transactivators for binding at adjacent sites (Fig. 3, middle). Competition between NFI proteins and Sp1 for binding to adjacent sites has been proposed as a means for NFI to repress Sp1 activation of the mouse α1(I) collagen promoter (Nehls et al., 1991, Nehls et
Hormonal and signal transduction pathways in which NFI has been implicated
NFI proteins or binding sites have been shown to affect the expression of genes regulated by a number of signal transduction pathways, including those controlled by insulin (Cooke and Lane, 1999b), TGF-β (Alevizopoulos et al., 1995, Alevizopoulos et al., 1997, Riccio et al., 1992, Rossi et al., 1988, Sun et al., 1998), cAMP (Chu et al., 1991, Cooke and Lane, 1999a, Lu et al., 1992), steroid hormones (Chaudhry et al., 1999, Garlatti et al., 1996), vitamin D (Candeliere et al., 1996), vitamin B6 (
NFI proteins in development and cancer
Binding sites for NFI proteins have been characterized from genes expressed specifically in almost every organ system and tissue, including brain (Bedford et al., 1998, Elder et al., 1992), lung (Bachurski et al., 1997), liver (Cardinaux et al., 1994, Cereghini et al., 1987, Corthesy et al., 1990, Gil et al., 1988a, Jackson et al., 1993, Quinn et al., 1988), kidney (Leahy et al., 1999), muscle (Funk and Wright, 1992, Spitz et al., 1997), blood (Fischer et al., 1993, Knezetic and Felsenfeld, 1993
Summary
While much information has been gathered regarding the role of NFI-binding sites and proteins in gene expression, it is difficult to put it all into a global perspective. This is because the control of tissue-specific gene expression during development is perhaps the most complex biological regulatory system known and is the basis for all metazoan development. Clearly, NFI-binding sites play essential roles in the expression of genes in multiple organs and tissues, and changes in the expression
Acknowledgements
The author would like to thank Dr Christine Campbell for helpful discussions. This work was supported in part by National Institutes of Health grant HD34908 and National Science Foundation grant MCB-9612367 to R.M.G.
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