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02Main.Pdf (3.115Mb) Hox Transcription Factors: Their Involvement in Human Cancer Cells and In Vitro Functional Specificity Author Svingen, Terje Published 2005 Thesis Type Thesis (PhD Doctorate) School School of Biomolecular and Physical Sciences DOI https://doi.org/10.25904/1912/1181 Copyright Statement The author owns the copyright in this thesis, unless stated otherwise. Downloaded from http://hdl.handle.net/10072/365774 Griffith Research Online https://research-repository.griffith.edu.au CHAPTER 1 General Introduction CHAPTER 1 General Introduction 1 CHAPTER 1 General Introduction 1.1 GENERAL INTRODUCTION Homeobox genes are regulatory genes encoding small proteins that act as transcription factors during normal development (Gehring and Hiromi 1986) and were first identified in the fruit fly Drosophila melanogaster (Lewis 1978). A common feature of these proteins is the presence of a highly conserved 61-amino acid motif, the homeodomain that enables homeodomain proteins to bind to DNA at specifically recognised binding sites and transcriptionally activate their target genes, as extensively reviewed (Levine and Hoey 1988; Scott et al. 1989; McGinnis and Krumlauf 1992). At present, a large number of homeobox genes have been characterised, now comprising an extensive super-family of regulatory genes with members found in all animal species. There is a large catalogue of divergent homeobox sub-families, of which the best characterised and most extensively studied is the HOX/Hox-family. In mammalian species, there are 39 Hox genes organised in four clusters located on four different chromosomes in the genome (Scott 1992). They are structural and functional homologs of the Drosophila homeotic complexes (Hom-C), and are thought to have arisen through the combination of cis-amplification and trans-duplication of the Drosophila bithorax and antennapedia complexes during separate evolutionary events (Krumlauf 1994; Meyer 1996). As the Hox proteins were identified quite early as regulatory transcription factors with DNA-specific recognition facilitated via the conserved homeodomain, much effort has gone into trying to elucidate the exact mechanisms by which the Hox proteins gain their functional specificity and where in the regulatory hierarchy they exert their effect. Even so, although much has been learned, there are still large gaps in the puzzle that eventually will draw out a picture enabling us to fully appreciate the intricate control mechanisms governed by the Hox proteins. As the homeodomain-containing transcription factors were found to be key regulators of embryogenesis and normal development, researchers considered that potentially these regulatory proteins could also be involved in various aspects of cancer development. Although the underlying cellular mechanisms that destine a normal cell to become neoplastic are highly variable, collective principles governing malignant growth are distinguishable. Amongst these are self-sufficiency in growth 2 CHAPTER 1 General Introduction signals, sustained angiogenesis, tissue invasion and evasion of apoptosis (Hanahan and Weinberg 2000). Since the physiological processes governing oncogenesis across a large number of cancer cell genotypes are similar, it has been postulated that the large and diverse collection of cancer-associated genes might be tied to the operation of a small group of regulatory circuits. Furthermore, as the molecular mechanisms involved in carcinogenesis deal with the acquisition, regulation and maintenance of cell identity, many researchers have proposed regulatory proteins involved in embryogenesis and the maintenance of normal cells to be potential candidates as oncogenic regulators (Castronovo et al. 1994; Ford 1998; Cillo et al. 1999; Hanahan and Weinberg 2000; Cillo et al. 2001). Hence, the homeobox genes became a focal point for several research groups trying to elucidate the genetic control of carcinogenesis. Not only were the homeodomain transcription factors quickly being characterised as major players throughout embryogenesis, but research also strongly suggested that the homeobox gene families were key regulators of many biological processes in adult eukaryotic cells. Among these processes are cell-cell and cell-extracellular matrix interactions (Srebow et al. 1998), capillary morphogenesis and angiogenesis (Boudreau et al. 1997; Myers et al. 2000), cell cycle control (Ford et al. 1998), and cell growth and differentiation (Magli et al. 1991). The present study seeks to further investigate the potential involvement of homeodomain-containing transcription factors in human carcinogenesis. Due to the vast number of homeobox genes present in the human genome – estimated to 0.1- 0.2% of the whole vertebrate genome (Stein et al. 1996) – the class I homeobox, or Hox genes, will be the main focus, with subtle references to related homeobox gene families. As will become evident, other aspects of Hox transcriptional and functional specificity in the non-malignant cellular environment will form an equally important part of this thesis. There is still much to be elucidated regarding these normal regulatory principles however, if the potential involvement of Hox genes in carcinogenesis is to be unravelled. 3 CHAPTER 1 General Introduction 1.2 THE HOX TRANSCRIPTION FACTORS 1.2.1 Homeotic Genes and the Homeodomain Although the early work of Lewis (1978) allowed for the characterization of key genetic loci controlling Drosophila development, including homeotic genes, the actual homeobox was to be discovered some years later (McGinnis et al. 1984; Scott and Weiner 1984). The homeobox is a highly conserved 183-bp DNA sequence that encodes a 61-amino acid domain, termed the homeodomain, and was originally characterised by nuclear magnetic resonance (NMR) spectroscopy (Qian et al. 1989; Billeter et al. 1990) on a 68 amino acid residue Antp homeodomain expressed in E. coli (Muller et al. 1988). The tertiary structure of the homeodomain is a so-called helix-turn-helix motif (Figure 1.1) that enables homeodomain proteins to bind to DNA at specifically recognised binding sites (Figure 1.2) and transcriptionally activate their target genes (Wuthrich et al. 1992; Latchman 1995). FIGURE 1.1: The Homeodomain Tertiary Structure. Homeodomain from the Drosophila Antennapedia protein. The three helices making up the Drosophila Antennapedia homeodomain are prototypic for all homeobox proteins, serving as the core structure even for divergent homeobox families. Source: PDF file from (RCSB 2000), with image produced with Swiss PDB viewer: (Guex et al. 2004). 4 CHAPTER 1 General Introduction FIGURE 1.2: Homeodomain Protein Segment Bound to DNA. The third helix with its acidic tail resides in the major groove of the DNA duplex, making most of the recognition contacts with the DNA. The N-terminal flexible arm and the loop between helix 1 and helix 2 also make important contacts with the DNA duplex. Source: (ExPASy 2000). In addition to the homeodomain, the homeobox genes also encode other highly conserved structures (Figure 1.3). The homeodomain itself ends with an acidic tail, with an as yet undetermined structure. Furthermore, many homeodomain proteins, albeit not all, contain a highly conserved pentapeptide (IYPWM), the homeopeptide, just upstream from the homeodomain. Finally, homeobox proteins contain a conserved amino-terminal region followed by a variable region, usually rich in alanine, serine, glycine, proline or glutamine (Castronovo et al. 1994). 5 CHAPTER 1 General Introduction FIGURE 1.3: Schematic Representation of a Prototypic Homeodomain Protein. The main conserved regions of a prototypic homeodomain protein (Antp/Hox). The homeodomain is further highlighted with the three alpha helices. The prototypic Hox gene encoding this structure generally contains one intron between the homeopeptide and the homeodomain. Source: (Castronovo et al. 1994) The homeodomain proteins have been shown to be key regulators of embryonic development and differentiation (Marx 1992) and they are found in all animals tested to date, and even in many plants (Ulijaszek et al. 1998). There are numerous classes of homeobox genes and novel isolates are still being identified, adding to the list of more than 340 known homeodomain sequences (Gehring et al. 1994). It has been estimated that as much as 0.1% of the vertebrate genome is accounted for by homeobox genes, and by 1996, 170 different homeobox genes had already been cloned from vertebrate genomes (Stein et al. 1996). Also after the release of the human genome, extensive analyses has revealed that the homeobox indeed seems to be represented at this 0.1% level (Tupler et al. 2001), and there are still puzzling new discoveries being made, as for instance the discovery of a Hox14 paralog gene in horn sharks and coelacanths (Ferrier 2004; Powers and Amemiya 2004). As the homeobox genes were first discovered in the fruit fly Drosophila melanogaster and much of our understanding of these important transcription factors originates from these early studies, a brief discussion on the Drosophila homeotic genes will follow, before focusing more directly on the vertebrate homologs. 6 CHAPTER 1 General Introduction 1.2.2 The Homeotic Genes of Drosophila melanogaster As already mentioned, the homeobox genes were first discovered in Drosophila, with the observations that mutations in such genes often resulted in homeotic transformations of the body plan. An extensive collection of mutations were quickly assembled (Lewis 1978; Kaufman et al. 1980), and as these mutations resulted
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