Review
HMGI/Y proteins: flexible regulators of transcription and chromatin structure

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Abstract

The mammalian HMGI/Y (HMGA) non-histone proteins participate in a wide variety of cellular processes including regulation of inducible gene transcription, integration of retroviruses into chromosomes and the induction of neoplastic transformation and promotion of metastatic progression of cancer cells. Recent advances have contributed greatly to our understanding of how the HMGI/Y proteins participate in the molecular mechanisms underlying these biological events. All members of the HMGI/Y family of ‘high mobility group’ proteins are characterized by the presence of multiple copies of a conserved DNA-binding peptide motif called the ‘AT hook’ that preferentially binds to the narrow minor groove of stretches of AT-rich sequence. The mammalian HMGI/Y proteins have little, if any, secondary structure in solution but assume distinct conformations when bound to substrates such as DNA or other proteins. Their intrinsic flexibility allows the HMGI/Y proteins to participate in specific protein-DNA and protein-protein interactions that induce both structural changes in chromatin substrates and the formation of stereospecific complexes called ‘enhanceosomes’ on the promoter/enhancer regions of genes whose transcription they regulate. The formation of such regulatory complexes is characterized by reciprocal inductions of conformational changes in both the HMGI/Y proteins themselves and in their interacting substrates. It may well be that the inherent flexibility of the HMGI/Y proteins, combined with their ability to undergo reversible disordered-to-ordered structural transitions, has been a significant factor in the evolutionary selection of these proteins for their functional role(s) in cells.

Introduction

In summing up a recent meeting on the high mobility group (HMG) of non-histone chromatin proteins [1], Alan P. Wolffe observed: ‘There must be money in proteins that control your fat, your teeth, your sex and your health (besides minor things such as transcription, cell division and DNA recombination and repair).’ Although somewhat facetious, this statement aptly illustrates the extent of renewed interest being lavished on these small, non-histone chromosomal proteins that for many years remained an enigma but are now recognized as founding members of a new class of gene regulatory proteins called ‘architectural transcription factors’ [2]. The structure and function of the three currently recognized families of HMG proteins, i.e., HMG1/2, HMG-14/17 and HMGI/Y, have been extensively reviewed [1], [3], [4], [5]. However, given the rapid advances recently made in our understanding of the multiple biological roles played by members of the HMGI/Y family it is timely that we should, in this review, focus exclusively on these proteins. The most extensively studied function of the HMGI/Y proteins is their role in the promotion of gene activation where, by acting as a sort of molecular ‘glue’, they facilitate formation of stereospecific complexes called ‘enhanceosomes’ [6] on the promoter/enhancer regions of inducible genes as a consequence of both specific protein-DNA and protein-protein interactions. Nevertheless, because of their unique combination of structural and biological characteristics, the HMGI/Y proteins are also involved in a diverse range of other cellular processes including the regulation of chromatin structure and active participation in pathologic processes such as neoplastic transformation and metastatic progression. The HMGI/Y proteins also perform important functions as host-supplied factors involved in viral gene regulation and retroviral integration events. Owing to the burgeoning growth of studies on the HMGI/Y proteins, this review is, of necessity, selective in its coverage and we therefore apologize to any of our colleagues whose work we have inadequately discussed. Wherever possible, we have tried to refer readers to other reviews or papers that will enable them to access most of the original publications in the various areas covered.

At the outset it is important to mention that the names of the HMG gene and protein families have recently been changed in order to simplify the old nomenclatures and avoid possible ambiguities among the different proteins [1]. A Web page containing details of the new HMG nomenclatures can be accessed at: http://www.informatics.jax.org/mgihome/nomen/genefamilies/hmgfamily.shtml.

In the new terminology, the HMGI/Y family, which includes the previously designated HMGI/Y and HMGI-C proteins, is now referred to as the ‘HMGA’ family. All of the members of the HMGA family are characterized by the presence of highly conserved DNA-binding domains called ‘AT hooks’ that preferentially bind to stretches of DNA with a narrow minor groove. Table 1 lists both the old and new names for the HMGA genes and proteins. In addition to their DNA-binding properties, all members of the HMGA family share similar structural and biochemical characteristics and, where examined, also seem to have many common biological functions. For these reasons, in this review we will collectively refer to them simply as either HMGI/Y or HMGA proteins, unless the discussion of individual proteins is indicated.

Section snippets

The HMGA (a.k.a., HMGI/Y) genes and proteins

All of the members of the canonical mammalian HMGA protein families share important characteristics that, together, distinguish them from all other classes of eukaryotic nuclear proteins (reviewed in [3]). Circular dichroism (CD) and nuclear magnetic resonance (NMR) studies suggest that the HMGA proteins possess little, if any, secondary structure while free in solution but assume induced structural features when bound to other molecules (e.g. to DNA or other proteins). Each HMGA protein

HMGA proteins regulate gene transcription in vivo

Table 2 presents a partial list of specific genes whose transcription has been reported to be regulated, in either a positive or negative fashion, by the HMGA proteins in vivo. Previous reviews [3], [5] have discussed in detail the most widely accepted model for how the HMGA proteins function in such regulation namely, through either the facilitation, or inhibition, of the formation of ‘enhanceosomes’ [6] on the promoter regions of the genes they regulate. Enhanceosome formation, most

HMGA proteins and viral function

HMGA proteins have been implicated as host cell-supplied factors involved in controlling transcriptional expression of a number of viral genes (Table 2). Examples include: regulation of expression of the early and late genes of the human papovavirus JC virus [110]; regulation of the EBNA1 gene of Epstein-Bar virus (EBV) involved in controlling viral latency [111]; regulation of the IE-3 gene of herpes simplex virus-1 (HSV-1) that codes for the immediate-early protein ICP4 [112]; regulation of

HMGA genes and cell proliferation

The level of expression of HMGA genes is maximal during embryonic development and in rapidly proliferating cells but is low, or undetectable, in fully differentiated or non-dividing adult cells and tissues (reviewed in [3]). Nevertheless, HMGA gene products are rapidly induced in quiescent normal cells exposed to factors that stimulate metabolic activation and growth and are thought to be involved in the control of cell proliferation [7], [120], [121], [122]. Lanahan et al. [123] detected

Conclusion: the importance of being flexible

The collection of characteristics that distinguishes the HMGA proteins from other chromatin proteins and transcription factors includes their possession of multiple AT hook DNA-binding domains, their preferential recognition of structural features of DNA rather than nucleotide sequence, their intrinsic lack of structure and inherent flexibility, their ability to undergo reversible disordered-to-ordered structural transitions when binding substrates and their induction of conformational changes

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