HMGI-C
Little is known of the genetics of most types of malignancies, especially the role of HMGI-C gene in the development of fatty tumors. In some families, there seem to be many instances of various and apparently unrelated malignancies, while a few cases appear in other families from similar environments.
HMGI-C is a gene which is crucial to human’s cell growth and differentiation during development of an embryo but it is usually no longer seen in the adult tissues. The HMGI genes are abundantly and, almost ubiquitously, expressedduring embryogenesis, and are absent or expressed at lowlevels in adult mouse and human tissues. HMGI gene overexpressionwas first described in rat thyroid transformed cells and inexperimental thyroid tumors. Further studies assessedHMGI overexpression as a common feature of experimental andhuman malignant neoplasias (Scala, et al, 2001).
The HMGI protein family comprises three members: HMGI-C, HMGIand HMGY. The last two proteins are products of alternativesplicing of the same gene, named HMGI(Y), the HMGI-C proteinis coded for by a related gene. The HMGI proteins bind DNAand participate in the assembly of protein complexes on thepromoters of several inducible genes, thus they are definedas architectural transcription factors (Scala, et al, 2001).
The HMGI family of proteins consists of three members, HMGIC, HMGI and HMGI(Y), and are architectural factors which function as an essential component in the enhancesome. HMGI-C is predominantly expressed in proliferating, undifferentiated mesenchymal cells and not detected in adult tissues. Its function in mesenchymal proliferation and differentiation has been further substantiated by the demonstration that HMGI-C is disrupted and misexpressed in a number of mesenchymal tumor cell types. The latter include fat cell tumors (lipomas) and intriguingly, the HMGI-C -/- mouse mutant reveals a deficiency in fat tissue (Anand & Chada, 2000).
The HMGI-C protein has three AT-hook domains and an acidic carboxy-terminal tail. Rearrangements of the HMGI-C gene have been frequently detected in human benign tumors of mesenchymal origin. In these tumors, the HMGI-C modifications consist in the loss of the C-tail and the fusion with ectopic sequences. Recent results show that the loss of the C-terminal region, rather than the acquisition of new sequences, is sufficient to confer to HMGI-C the ability to transform some cells.
HMGI-C is a nuclear phosphoprotein. Members of the HMGI subfamily of proteins preferentially bind DNA in the minor groove of AT-rich sequences and are thought to affect transcription by acting as architectural proteins, which control the conformation of DNA and provide a framework for the assembly of the transcriptional machinery. Researchers have mapped the murine HMGI-C gene to mouse chromosome 10 in a region homologous to proximal human chromosome 12 (Ishwad, et al, 1997).
Using positional cloning strategies, investigators previously identified the HMGIC gene, located at 12q15, its highly homologous HMGI(Y) gene, located at 6p21, and the RAD51L1 gene, located at 14q24, as some of the major genes involved.
They also found that as a result of the translocation, the HMGIC gene on 12q15 is fused to the RAD51L1 gene on 14q24. Furthermore, it was observed by other investigators that the HMGIC gene may also fuse to alternative genes in distinct types of soft tissue tumors, as e.g. the LPP gene in lipomas and the NF1B gene in pleomorphic adenomas of the salivary gland.
The HMGI-C gene is not much studied in humans as it is most commonly found only in embryos. Most of the studies regarding the HMGI-C gene are done only on mice. In one of these studies, the viable pygmy (pg) mutation on chromosome 10 of the mouse gives rise to small stature owing to disruptions of growth and development. An insertional mutation facilitated cloning of the locus. Subsequently, it was shown that expression of the HMGIC gene is abrogated in three pygmy alleles. Among the four viable spontaneous mouse mutants which disrupt growth, ‘pygmy’ is unique because its phenotype cannot be explained by aberrations in the growth hormone-insulin-like growth factor endocrine pathway.
Some investigators showed that the cause is inactivation of the HMGI-C gene, a member of the HMGI family of proteins which function as architectural factors in the nuclear scaffold and are critical in the assembly of stereospecific transcriptional complexes. HMGI-C and another HMGI family member, HMGI(y), are expressed predominantly during embryogenesis. The HMGI proteins are known to be regulated by cell cycle-dependent phosphorylation which alters their DNA binding affinity. Investigators suggested that identification of the ‘pygmy’ gene as HMGI-C may suggest new avenues of research into the biochemical nature of the African pygmy phenotype (265850) and the numerous growth hormone-resistant human dwarf syndromes.
To study the role of HMGI-C in adipogenesis and obesity, Anand and Chada (2000) examined HMGI-C expression in the adipose tissue of adult obese mice. Mice with a partial or complete deficiency of HMGI-C resisted diet-induced obesity. Disruption of HMGI-C caused a reduction in obesity induced by leptin deficiency in a gene dose-dependent manner.
As expected, expression was not detected in adipose tissue isolated from mice fed a standard diet but surprisingly, expression was observed in the fat tissue isolated from mice fed a high-fat diet. The latter results were also obtained with the adipose tissue isolated from two genetically induced obese mice and expression was not detected in any other tissue. Therefore, different obesity stimuli cause the detection of HMGI-C in adipose tissue (Anand & Chada, 2000). They concluded that their studies implicate a role for HMGI-C in fat cell proliferation, indicating that it may be an adipose-specific target for the treatment of obesity.
To evaluate the role of the HMGIC component in the development of lipoma, other investigators expressed the three DNA-binding domains of HMGI-C in transgenic mice. Despite the ubiquitous expression of the truncated HMGI-C protein, the transgenic mice developed a selective abundance of fat tissue early in life, showed marked adipose tissue inflammation, and had an abnormally high incidence of lipomas. These findings demonstrated that the DNA-binding domain of HMGIC, in the absence of a C-terminal fusion partner, are sufficient to perturb adipogenesis and predispose to lipomas.
HMGI-C expression is not detectable in untransformed, proliferating epithelial cells, but is elevated in a variety of experimentally and naturally transformed epithelial cells. HMGI proteins are overexpressed in all of the malignant neoplasiasso far analyzed.
The assembly of the RNS molecule in HMGI-C genes is accomplished under the influence of an enzyme called RNA polymerase. This is a large protein enzyme that has many functional properties necessary for the formation of the RNA molecule.
Fatty tissue tumors start in primitive cells called mesenchymal cells (embryonic cell mass), or in nerve cells that have not fully developed. They are also called soft tissue tumors or mesenchymal tumors. Normally, mesenchymal cells mature to form the body’s soft tissues, including muscle, fat, cartilage, blood vessels and fibrous (connecting) tissues. Rarely, instead of maturing, these immature cells transform into abnormal, aggressive cells that multiply out of control to form a cancerous tumor.
As previously stated, HMGI-C is a gene that is found in mesenchymal tissues. Rearrangements that occur in the HMGI-C gene can contribute to the development of human benign tumors of mesenchymal origin. In these tumors, modifications exist in the HMGI-C gene.
Credit:ivythesis.typepad.com
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