Journal of Heredity Advance Access originally published online on June 15, 2005
Journal of Heredity 2005 96(7):777-781; doi:10.1093/jhered/esi083
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"Best Friends" Sharing the HMGA1 Gene: Comparison of the Human and Canine HMGA1 to Orthologous Other Species
From the Small Animal Clinic, School of Veterinary Medicine, Bischofsholer Damm 15, 30137 Hanover, Germany (Murua Escobar, Soller, and Nolte), and Center for Human Genetics, University of Bremen, Leobener Str ZHG, 28359 Bremen, Germany (Meyer, Winkler, Richter, and Bullerdiek)
Address correspondence to Ingo Nolte at the address above, or e-mail: inolte{at}klt.tiho-hannover.de.
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Abstract |
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HMGA1 nonhistone proteins are reported to participate in various 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. Overexpression of HMGA1 was shown to be characteristic for various malignant tumors, suggesting a relation between the neoplastic phenotype and a high titer of the protein. Also chromosomal aberrations affecting the human HMGA1 gene at 6p21 were described in several tumors, e.g., uterine leiomyomas, pulmonary chondroid hamartomas, and follicular thyroid adenomas. We characterize the molecular structure of the canine HMGA1 cDNA, its splice variants, and predicted proteins HMGA1a and HMGA1b. Furthermore, we compared the CDS of both splice variants for 12 different breeds, screened them for SNPs, characterised a basic expression pattern, and mapped the gene via FISH. Additionally, we compared the known human, canine, murine, rat, hamster, bovine, pig, Xenopus, and chicken HMGA1 transcripts.
High mobility group proteins named according to their characteristic mobility in gel electrophoresis are small chromatin-associated nonhistone proteins, which can be subdivided into three families because of their functional sequence motives: the HMGA (functional motive "AT-hook"), HMGB (functional motive "HMG-box"), and HMGN (functional motive "nucleosomal binding domain") protein families (for review see Bustin 2001). By binding DNA with their functional motives, the HMG proteins induce DNA conformation changes influencing the binding of various transcription factors and thus taking indirect influence on transcription regulation as so-called architectural transcription factors (for detail see Bustin and Reeves 1996).
The proteins HMGA1a, HMGA1b, and HMGA2 of the human HMGA genes are associated with various human diseases, including cancer. Members of the human HMGA1 protein family presently known are HMGA1a and HMGA1b, which by modifying chromatin structure take influence on transcription and up- and down-regulation of a number of target genes, for example, ATF2, IFN-ß, NF-
B, Interleukin-2 receptor, E-Selektin, Interleukin-4, Interfeone-A, ERCC1, and Cyclin A (Chuvpilo et al. 1993; Du and Maniatis 1994; Thanos and Maniatis 1992; Lewis et al. 1994; John et al. 1995, 1996; Klein-Hessling et al. 1996; Yie et al. 1997; Borrmann et al. 2003).
The expression pattern of the HMGA genes in human adult tissues shows only very low levels or even absent expression, whereas it is abundantly expressed in embryonic cells (Rogalla et al. 1996; Chiappetta et al. 1996). In humans the HMGA1 gene is located on HSA 6p21, a region often affected by aberrations leading to an up-regulation of this gene in various benign mesenchymal tumors, for example, endometrial polyps, lipomas, pulmonary chondroid hamartomas, and uterine leiomyomas (Williams et al. 1997; Kazmierczak et al. 1998; Tallini et al. 2000). This suggests that transcriptional activation due to these chromosomal alterations is probably an early and often even primary event of cancer development. Recently, the canine HMGA1 gene has been mapped to CFA 23. This cytogenetic assignment indicates that the canine HMGA1 gene does not map to a hotspot of chromosomal breakpoints seen in canine tumours (Becker et al. 2003).
HMGA1 expression in human malignant epithelial tumors is reported to be associated with an aggressive behavior of the tumors. Overexpression of HMGA1 was detected in a number of malignancies, including thyroid, prostatic, pancreatic, uterine cervical, and colorectal cancer (Tamimi et al. 1993; Chiappetta et al. 1995; Fedele et al. 1996; Bandiera et al. 1998; Abe et al. 1999, 2000; Czyz et al. 2004; Takaha et al. 2004). The correlation between HMGA expression and tumor aggressiveness in some of these malignancies has led to the conclusion that HMGA expression may present a powerful diagnostic and prognostic molecular marker.
Due to the similarities of various human and canine cancer entities, the characterization of the canine HMGA genes could open new fields for experimental and therapeutic approaches. We recently characterized the canine HMGA1a and HMGA1b transcripts, deduced their proteins, evaluated them as targets for therapeutic approaches, and characterized a basic expression pattern in healthy tissues (Murua Escobar et al. 2004). Sequence comparison showed a 100% identity between the human and canine protein molecules. Although both species showed the identical two proteins, the number of found cDNA transcripts varies. For the human HMGA1 seven different cDNA transcripts (Figure 1: SPV1–SPV7) were described (Johnson et al. 1988) of which SPV1 and SPV2 are the commonly found variants. The characterized dog variants showed the same composition structure as the mentioned human variants SPV1 and SPV2. Canine counterparts of the human transcript variants SPV3–SPV7 could not be detected using polymerase chain reaction (PCR) amplification approaches. Comparison of the human cDNAs to the known transcripts of other species shows that the dog is the only species showing similar transcripts to those commonly found in humans referring to exon structure and distribution. In detail, human and dog are the only known species showing the presence of exon one and two in both HMGA1a or HMGA1b transcripts, respectively (Figure 1). Both isoforms (HMGA1a and HMGA1b) were found in mouse (BC013455 [GenBank] , NM_016660 [GenBank] ), hamster (AF1893762, AF193763 [GenBank] ), and rat (NM_139327 [GenBank] , AF511040 [GenBank] ), of which for the last two species the described transcripts are limited to the protein coding sequences and the mouse transcripts show either exon one (HMGA1a) or exon two (HMGA1b) in the respective transcripts (Figure 1).
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For the HMGA1 transcripts of horse (CD535395 [GenBank] ), pig (AU296646 [GenBank] ), chicken (AY303673 [GenBank] ), bovine (CK951567 [GenBank] ), and Xenopus (BC084025), either the HMGA1a or the HMGA1b isoform are currently (2004) present at the NCBI database. For CDS (coding sequence) and protein identity analysis, we used the described sequences and deduced, if necessary, the corresponding parts for analyses. The in silico analyses were done using Lasergene software programs (DNASTAR, Madison). The coding sequence identities of the canine HMGA1 transcripts to the sequences from other species vary between 72.0% (chicken AY303673 [GenBank] ) and 95.7% (pig AU296646 [GenBank] , horse CD535395 [GenBank] ) (Table 1). Identity comparison of the deduced proteins revealed similarities between 69.7% (chicken AY303673 [GenBank] ) and 100.0% (human: P17096 [GenBank] , X14957 [GenBank] , horse CD535395 [GenBank] ) (Table 1). The proteins of all species showed strong conservation in the functional AT-Hook DNA binding domains. Common for all species analysed is that the protein coding sequences are composed of four exons (Figure 1). The described proteins of the different species are composed of 107 amino acids and 96 amino acids, respectively, for HMGA1a and HMGA1b. Also common for those species where both protein isoforms were described is that the difference between the splicing variants is the "typical" 33-bp deletion in the HMGA1b transcripts resulting in the lack of 11 amino acids.
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Previous results describing the comparison of the protein coding sequences in 12 canine breeds revealed that the mentioned deletion is also conserved in the analyzed breeds. SNP screening in these breeds resulted in detection of one-amino-acid change in a single breed. A Teckel showed a nucleotide transition from A to G at the first base of codon 64 in its HMGA1b transcript leading to an amino acid replacement from threonine to alanine (Murua Escobar et al. 2004). As far as we know, no other canine HMGA1 polymorphisms have been described. Summarizing the HMGA1 transcript and protein comparison data emphasizes the relevance of the canine species as a model organism for the research and development of therapeutic approaches for human disorders.
Due to the mentioned properties of the HMGA1 gene, its proteins HMGA1a/HMGA1b, and its reported role in development of cancer, future studies targeting HMGA1 proteins could be of significant value.
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Acknowledgments |
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This paper was delivered at the 2nd International Conference on the "Advances in Canine and Feline Genomics: Comparative Genome Anatomy and Genetic Disease," Universiteit Utrecht, Utrecht, The Netherlands, October 14–16, 2004.
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Footnotes |
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Corresponding Editor: Francis Galibert
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