Disease relevance of MEGLUTOL

• Blockage of HMGA expression inhibits the transformation of rat thyroid PC Cl 3 cells treated with oncogene-carrying retroviruses, thus implicating HMGA in rat thyroid transformation [1].
• Uterine myometria and spontaneous leiomyomas from the Eker rat, which carries a germ-line mutation in the tuberous sclerosis complex-2 (Tsc2) tumor suppressor gene, were analyzed for genetic defects in and expression of the Tsc2 and HMGA proteins [2].
• Unregulated proliferation of mesenchymal cells in leiomyomas, lipomas, hamartomas,and other diseases has been linked to the high mobility group (HMGA) family of DNA architectural proteins [2].
• Teratocarcinomas induced by HMGA 2/T ES cell lines presented numerous skeletal muscle-differentiated tissues that were not observed in wt HMGA 2 or control tumours [3].
• HMGA proteins are thought to be causally involved in the progression of different diseases, including benign and malignant tumors, obesity, arteriosclerosis, and restenosis [4].

High impact information on MEGLUTOL

• An HMGA/HMGI(Y)-like domain of NURF301 that facilitates nucleosome sliding indicates the importance of DNA conformational changes in the sliding mechanism [5].
• HMGA proteins are moderately sequence-specific, and help build enhanceosomes by interacting with partner proteins and binding stably to the minor groove of DNA; their acetylation/deacetylation signal enhanceosome assembly or disassembly [6].
• We have examined the subcellular localization of Arabidopsis thaliana HMGA, HMGB1, and HMGB5, revealing that they localize to the cell nucleus [7].
• The HMGA proteins are characterized by the presence of four AT-hook DNA binding motifs, and the HMGB proteins contain an HMG box DNA binding domain [7].
• Fluorescence recovery after photobleaching experiments revealed that HMGA and HMGB proteins are extremely dynamic in the nucleus, indicating that they bind chromatin only transiently before moving on to the next site, thereby continuously scanning the genome for targets [7].

Biological context of MEGLUTOL

• HMGA protein expression is low in normal adult tissues, but abundant during embryonic development and in several experimental and human tumors [1].
• To better understand the role of HMGA and to establish whether its up-regulated expression is sufficient to induce the transformed phenotype, we generated PC Cl 3 cells that overexpress the protein [1].
• Because the phosphorylation of the HMGA proteins attenuates binding affinity and reduces the extent of contacts between the DNA and protein, it is likely that this process mirrors the dynamics and diversity of regulatory processes in chromatin [8].
• Chromosomal aberrations affecting the HMGA genes may therefore influence their expression by an altered stability of the truncated transcripts as a result of the cytogenetic aberrations [9].
• Interestingly, in experimental conditions inhibitory for myogenesis, we observed a strong expression of MyoD and myogenin in HMGA 2/T cells [3].

Anatomical context of MEGLUTOL

• We have previously shown that the expression of the HMGA family members is deregulated in neuroblastoma cell lines and primary tumors [10].
• HMGA proteins in malignant peripheral nerve sheath tumor and synovial sarcoma: preferential expression of HMGA2 in malignant peripheral nerve sheath tumor [11].
• The HMGA ectopic expression in HMGA-negative Dunning G cells does not significantly alter their growth ability, suggesting that, although HMGA expression is necessary for the progression of neoplastic transformation in several cellular models, in these cells it is not sufficient [12].
• Very soon after their original identification in HeLa cells in 1983, HMGA proteins appeared as interesting cancer-related molecules [13].

Associations of MEGLUTOL with other chemical compounds

• Effects of 3-hydroxy-3-methylglutaric acid on plasma and low-density lipoprotein cholesterol levels in familial hypercholesterolemia [14].
• The investigation of a plant cell culture of RUTA CHALEPENSIS L. yielded three compounds: isorutarin, rutacridone, and rutarensin, a so far unknown ester of daphnoretin glucoside ("daphnorin"), as well as 3-hydroxy-3-methylglutaric acid [15].
• Age-dependent excretion of 3-hydroxy-3-methylglutaric acid (HMG) and ketone bodies in the urine of full-term and pre-term newborns [16].
• Urinary levels of 3-hydroxy-3-methylglutaric acid (HMG) were measured by gas-liquid chromatography (GLC) after an extraction with tetrahydrofuran in normal rats, streptozotocin-diabetic rats and starved rats [17].
• Effect in vitro of 3-hydroxy-3-methylglutaric acid on the synthesis of mevalonate and its precursors [18].

Gene context of MEGLUTOL

• The HMGA2 protein belongs to the HMGA family of architectural transcription factors, which play an important role in chromatin organization [19].
• To check if HMGA expression is under control of such elements we performed luciferase assays with several HMGA2 and HMGA1 3'UTRs of different length [9].
• This was confirmed by treatment of chromatin with micrococcal nuclease, demonstrating that the HMGA, HMGB2/3, and SSRP1 proteins are enriched in the highly nuclease-sensitive fraction of chromatin, which is likely to be transcriptionally competent [20].
• Electrophoretic mobility shift assay demonstrated that rice HMGB1 can bind synthetic four-way junction (4H) DNA and DNA minicircles efficiently but the binding to 4H can be completed out by HMGA and histone H1 [21].
• What information is available, however, indicates that all three major families of mammalian HMG proteins (i.e., HMGA, HMGB and HMGN) participate in various DNA repair processes, albeit in different ways [22].

Analytical, diagnostic and therapeutic context of MEGLUTOL

• Using spectroscopic and protein footprinting techniques, we analyzed how individual and consecutive steps of phosphorylation change the conformation of an HMGA protein and affect its contacts with poly(dA-dT).poly(dA-dT) and a fragment of the interferon-beta promoter [8].
• To this end, we explored diagnostic applications of HMGA (HMGA1 and HMGA2) protein immunohistochemistry in comparable groups of synovial sarcoma and malignant peripheral nerve sheath tumors [11].
• Northern blot results show that the expression of HMGA gene is much higher in organs undergoing active cell proliferation [23].
• Previous reports of patients with 3-hydroxy-3-methylglutaric aciduria have described the occurrence of di-trimethylsilyl (TMS) and tri-TMS derivatives of 3-hydroxy-3-methylglutaric acid on analysis using gas chromatography and mass spectrometry, leading to difficulty in quantification and ambiguity in diagnosis [24].

References