Biochemistry and biology of the inducible multifunctional transcription factor TFII-I

Abstract

An animal cell has the capability to respond to a variety of external signals through cell surface receptors. The response is usually manifested in terms of altered gene expression in the nucleus. Thus, in modern molecular and cell biology, it has become important to understand how the communication between extracellular signals and nuclear gene transcription is achieved. Originally discovered as a basal factor required for initiator-dependent transcription in vitro, recent evidence suggests that TFII-I is also an inducible multifunctional transcription factor that is activated in response to a variety of extracellular signals and translocates to the nucleus to turn on signal-induced genes. Here I review the biochemical and biological properties of TFII-I and related proteins in nuclear gene transcription, signal transduction and genetic disorders.

Introduction

The signals generated outside a cell are transduced to the nucleus through a series of complicated biochemical steps, ultimately resulting in spatial and/or temporal activation of specific sets of genes (Pawson and Nash, 2000). Thus, there must exist specific protein(s) that serves to direct signal transduction pathways to cell type-specific genes and thereby provide a molecular link between signal transduction and growth, proliferation or developmental programs in a given cell. Transcription factors play a critical role in these processes in general and often serve as links between signal transduction and cell type-specific gene activation. TFII-I is such a ubiquitously expressed multifunctional transcription factor that is activated in response to various extracellular signals and links signal transduction events to transcription.

TFII-I was originally discovered as a basal transcription factor that binds and functions through a core promoter element, initiator (Inr), in vitro (Roy et al., 1991). But at the same time it was also realized that TFII-I has additional capability of binding an unrelated upstream element (E-box) that is usually recognized by a family of helix-loop-helix (HLH) proteins viz., USF, and that TFII-I cooperates in binding to both E-box and Inr elements with USF (Roy et al., 1991). These initial observations raised the exciting possibility that TFII-I is a unique transcription factor that can simultaneously function both as a basal factor and as an activator and thus facilitates communication between the basal machinery assembled at the core promoter and the activator complexes assembled at upstream regulatory site(s) (Roy et al., 1991).

In addition to these unique transcription properties, it has been shown that TFII-I is phosphorylated at both serine and tyrosine residues and that tyrosine phosphorylation of TFII-I is required for its transcriptional functions (Novina et al., 1998). Equally interesting is the observation that a variety of extracellular signals mediating through cell surface receptors, including growth factor receptors, lead to enhanced tyrosine phosphorylation and increased transcriptional activity of TFII-I raising the possibility that apart from its transcriptional roles, TFII-I may mediate receptor-mediated signal transduction events (Kim et al., 1998, Novina et al., 1998, Novina et al., 1999, Yang and Desiderio, 1997). In B cells a significant fraction of TFII-I is associated constitutively with Bruton's tyrosine kinase (Btk) (Novina et al., 1999, Yang and Desiderio, 1997), mutations which lead to X-linked immune deficiency in humans and mice (Rawlings et al., 1993, Thomas et al., 1993, Tsukada et al., 1993, Vetrie et al., 1993). TFII-I is tyrosine phosphorylated by Btk in vitro and upon immunoglobulin receptor cross-linking in B cells (Novina et al., 1999, Yang and Desiderio, 1997). These observations suggest that TFII-I mediates signaling events and links the resulting signal responsive activator complexes to the general transcription machinery.

Recent genetic and biochemical data suggest that TFII-I belongs to a family of protein each having the I-repeat, first identified in the founding member TFII-I (Bayarsaihan and Ruddle, 2000, Franke et al., 1999, O'Mahoney et al., 1998, Osborne et al., 1999, Perez Juardo et al., 1998, Tassabehji et al., 1999, Roy et al., 1997, Yan et al., 2000). Interestingly, both TFII-I and the related protein have been mapped to the breakpoint regions of the 7q11.23 Williams–Beuren syndrome (WBS) deletion (reviewed in Francke, 1999). Furthermore, genetic and biochemical analyses show that each of these proteins has multiple isoforms (Cheriyath and Roy, 2000, Perez Juardo et al., 1998, Tussié-Luna et al., 2001). The tissue and species distribution of these isoforms suggests that they may not have redundant functions. Moreover, recent evidence suggests that the function of these isoforms, even when present simultaneously, may be regulated by their mutual interactions (Cheriyath and Roy, 2000).

How can the basal function of TFII-I be reconciled with its signal dependent inducible transcription functions? Although a complete answer to this problem awaits further study, it appears that one of the isoforms of TFII-I is found constitutively in the nucleus that might selectively function in basal transcription. Thus, different isoforms of TFII-I might serve different transcription functions on different promoters. Additionally, because the isoforms of TFII-I also interact with each other, the homomeric and heteromeric interactions amongst them also might regulate basal versus signal-induced transcription functions. In the following sections, the transcription functions, signaling properties and possible genetic implications of TFII-I and its relative are discussed.