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MCAT  -  malonyl CoA:ACP acyltransferase...

Homo sapiens

Synonyms: FASN2C, MCT, MT, Malonyl-CoA-acyl carrier protein transacylase, mitochondrial, Mitochondrial malonyl CoA:ACP acyltransferase, ...
 
 
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Disease relevance of MCAT

  • Findings of increased brain metallothionein-I and -II (MT-I/-II) mRNA expression in cDNA microarray experiments led us to investigate MT isoforms and their relationship to brain zinc metabolism, cellular toxicity, and neurodevelopmental abnormalities in this model [1].
  • Multiple copies of either hMRE-a or mMRE-d conferred hypoxia responsiveness to a minimal MT promoter [2].
  • Interestingly, the occurrence of spontaneous tumor nodules in MT/ret mice with melanoma-associated vitiligo is significantly delayed when compared in melanoma mice without vitiligo [3].
  • Strikingly, while all of the inactive mutants were severely impaired in their interaction with B subunit, most of these mutants formed complexes with polyomavirus MT [4].
  • The finding that MT 2A appears to be the main isoform associated with cell proliferation in invasive ductal breast cancer tissues, may have therapeutic implications [5].
 

Psychiatry related information on MCAT

 

High impact information on MCAT

  • DNAase I protection analysis indicates that genetically defined enhancer elements in hMT IIA, SV40, and the human collagenase gene contain high-affinity AP-1-binding sites, each with a conserved recognition motif, TGACTCA [7].
  • Using in situ hybridization, we have now localized the MT genes to band q22 of chromosome 16 [8].
  • These results suggest that the MT genes or their regulatory regions may function as an 'activating' sequence for an as yet unidentified cellular gene located at 16p13 [8].
  • Hybridization of a MT probe to malignant cells from two patients with an inv(16) showed labelled sites on both arms of the inverted chromosome, indicating that the breakpoint at 16q22 splits the MT gene cluster [8].
  • Because glucocorticoid hormones lead to an intracellular accumulation of zinc, the question arises of whether the induction of MT gene expression by steroids is a 'primary induction response' (ref. 18), or due to elevated intracellular Zn2+ [9].
 

Chemical compound and disease context of MCAT

  • MT-expressing clones displayed greater resistance to cadmium toxicity than control cell lines [10].
  • The role of prostaglandins in endocrine diarrheagenic syndromes was evaluated by measuring peripheral concentration of immunoreactive PGE and PGF in patients with non-endocrine diarrhea as well as those with the Zollinger-Ellison (Z-E) syndrome, MCT, carcinoid tumors and the WDHA syndrome [11].
  • Medium-chain (MCT) and long-chain (LCT) triglyceride diets were compared during and after 4 or 12 wk of hypocaloric feeding in obese women to determine the effects on weight loss, ketones, nitrogen balance, and insulin action [12].
  • However, the subjects in group 2 (MCT) demonstrated an increase in glucose requirement to maintain euglycemia during the clamp after weight loss (delta 0.18 +/- 0.13 mmol.m-2.min-1) whereas subjects in group 1 (LCT) had a diminished requirement (delta -0.12 +/- 0.10, p = 0.036) [12].
  • Iodine-131 metaiodobenzylguanidine (MIBG) scintigraphy showed the bilateral pheochromocytomas but did not demonstrate uptake in the MCT [13].
 

Biological context of MCAT

  • However, when cells were incubated with N,N,N',N'-tetrakis(2-pyridylmethyl)ethyl-enediamine (TPEN), a membrane-permeant Zn(2+) chelator, the stimulation of MT transcription by SNP was blocked, suggesting that SNP-induced upregulation of these genes is zinc-dependent [14].
  • Metal induction is mediated by several copies of a 15 bp consensus sequence (metal-responsive element, MRE) present in the promoter region of MT genes [15].
  • Hyperexpressibility of the MT gene, a gene for which expression is clearly controlled by DNA methylation, was also detected in transformed cells [16].
  • These data underline an important role for dMTF-1 in MT gene regulation and thus heavy metal homeostasis [17].
  • A third cDNA clone, DDIU4, was found also to code for a similar-size UV-inducible transcript which was unrelated to MT by both sequence analysis and kinetics of induction [18].
 

Anatomical context of MCAT

  • Additionally, the induction of MT by SNP after zinc pretreatment appears to be mediated by metal-activated transcription factor-1 (MTF-1), which is induced by labile zinc in the cytosol [14].
  • More recently MT induction by the steroid hormone dexamethasone (Dex) has been demonstrated in HeLa cells and adrenalectomized rats [9].
  • This rapid induction of MT RNA by UV irradiation was not observed in human fibroblasts [18].
  • A newly identified brain-specific MT gene, MT-III, is predominantly expressed in zinc-containing neurons of the hippocampus and absent from glial elements [19].
  • The pattern of expression of each specific MT gene in response to various heavy metals was different among the four cell lines studied indicating differential regulation of MT gene expression [20].
 

Associations of MCAT with chemical compounds

  • The results showed that MT expression led to a significant increase (5-210%) in overall biosorption efficiency (eta(ads)), especially for biosorption of Cd [21].
  • Finally, a global evaluation of our results suggests that the higher the Cu-thionein character of a MT peptide, the higher is its tendency to harbor nonproteic ligands (i.e., sulfide anions) when building divalent metal clusters, especially Cd-MT complexes [22].
  • Pretreatment of HepG2 cells with zinc sulfate (ZnSO(4)) followed by SNP exposure caused MT and glucose-6-phosphate dehydrogenase (G6PD) mRNA levels to increase more than in cells only exposed to SNP [14].
  • Furthermore, mammalian MT genes are activated best by zinc and cadmium, whereas in Drosophila cells, cadmium and copper are more potent inducers than zinc [17].
  • Both MT induction and cytoprotection against CdCl2 and cisplatin were blocked by concomitant incubation with a recombinant human IL-1 receptor antagonist protein [23].
 

Physical interactions of MCAT

  • These data suggest that transition metals, other than zinc, that activate MT gene expression may do so by mechanisms independent of an increase in the DNA binding activity of MTF-1 [24].
 

Regulatory relationships of MCAT

  • These results demonstrate that the methylated and unmethylated MT-I promoter are differentially regulated by DNA methyltransferase and methyl-CpG binding proteins, and DNMT1 could suppress MT promoter by a transcriptional mechanism independent of its enzymatic function [25].
  • Neither control-transfected nor MT-expressing cell lines were sensitive to the cytotoxic effect of TNF alone, even at concentrations as high as 200 ng/ml [10].
 

Other interactions of MCAT

  • Stable cell lines overexpressing variable levels of MTF1, the key transactivator of the MT genes, demonstrated differential resistance toward the inhibitory effect of Cr6+, indicating MTF1 as a target of chromium toxicity [26].
  • A human MT gene from the functional locus on chromosome 16, MT1L, is characterised and shown to produce mRNA in at least four human tissues [27].
  • Tissues selected included liver, motor cortex and cervical cord at C6; MT mRNAs analyzed included MT1A, 1B, 1E, 1F, 1G, 2A, and 3 [28].
  • Except of MT3, already known as brain-specific, and MT1B which was not expressed in any tissue, mRNA levels of the other MT genes tended to be higher in ALS than in control liver samples, but the differences did not attain statistical significance [28].
  • DU-145 cells constitutively expressed only MT-IIa and MT-Ie mRNA and the IL-1 beta-mediated increase in MT protein was preceded by a marked elevation solely in MT-IIa mRNA [23].
 

Analytical, diagnostic and therapeutic context of MCAT

  • Western blotting confirmed that total MT protein levels were also increased in response to these stresses [29].
  • Despite the considerable value of cell culture, we need to use more discrete regions of the developing brain in situ in order to analyze the MT and their modifications into cells developing their "natural" environment [30].
  • By the criteria of comigration on two-dimensional gels, tryptic peptide mapping, and immunoblotting, we showed that the 72- and 74-kDa proteins that associate with wild-type MT in human cells are the major human 70-kDa heat shock proteins [31].
  • MT transcripts were monitored in whole lenses, epithelia, and fibers by RT-PCR and confirmed to be authentic by sequencing [32].
  • The expression profiles of the MT protein and MT-2A mRNA were further evaluated in 79 cases of human invasive ductal breast carcinoma by immunohistochemistry and in situ hybridization, and correlated with cancer cell proliferation (determined by Ki-67 nuclear antigen immunolabeling) [5].

References

  1. Metallothioneins and zinc dysregulation contribute to neurodevelopmental damage in a model of perinatal viral infection. Williams, B.L., Yaddanapudi, K., Kirk, C.M., Soman, A., Hornig, M., Lipkin, W.I. Brain Pathol. (2006) [Pubmed]
  2. Activation of metallothionein gene expression by hypoxia involves metal response elements and metal transcription factor-1. Murphy, B.J., Andrews, G.K., Bittel, D., Discher, D.J., McCue, J., Green, C.J., Yanovsky, M., Giaccia, A., Sutherland, R.M., Laderoute, K.R., Webster, K.A. Cancer Res. (1999) [Pubmed]
  3. Spontaneous vitiligo in an animal model for human melanoma: role of tumor-specific CD8+ T cells. Lengagne, R., Le Gal, F.A., Garcette, M., Fiette, L., Ave, P., Kato, M., Briand, J.P., Massot, C., Nakashima, I., Rénia, L., Guillet, J.G., Prévost-Blondel, A. Cancer Res. (2004) [Pubmed]
  4. Catalytically inactive protein phosphatase 2A can bind to polyomavirus middle tumor antigen and support complex formation with pp60(c-src). Ogris, E., Mudrak, I., Mak, E., Gibson, D., Pallas, D.C. J. Virol. (1999) [Pubmed]
  5. Metallothionein 2A expression is associated with cell proliferation in breast cancer. Jin, R., Chow, V.T., Tan, P.H., Dheen, S.T., Duan, W., Bay, B.H. Carcinogenesis (2002) [Pubmed]
  6. Metallothioneins in brain--the role in physiology and pathology. Aschner, M., Cherian, M.G., Klaassen, C.D., Palmiter, R.D., Erickson, J.C., Bush, A.I. Toxicol. Appl. Pharmacol. (1997) [Pubmed]
  7. Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements. Lee, W., Mitchell, P., Tjian, R. Cell (1987) [Pubmed]
  8. Metallothionein gene cluster is split by chromosome 16 rearrangements in myelomonocytic leukaemia. Le Beau, M.M., Diaz, M.O., Karin, M., Rowley, J.D. Nature (1985) [Pubmed]
  9. Metallothionein mRNA induction in HeLa cells in response to zinc or dexamethasone is a primary induction response. Karin, M., Andersen, R.D., Slater, E., Smith, K., Herschman, H.R. Nature (1980) [Pubmed]
  10. Overexpression of metallothionein confers resistance to the cytotoxic effect of TNF with cadmium in MCF-7 breast carcinoma cells. Sciavolino, P.J., Lee, T.H., Vilcek, J. Lymphokine Cytokine Res. (1992) [Pubmed]
  11. Prostaglandins E and F in endocrine diarrheagenic syndromes. Jaffe, B.M., Condon, S. Ann. Surg. (1976) [Pubmed]
  12. Hypocaloric feeding in obese women: metabolic effects of medium-chain triglyceride substitution. Yost, T.J., Eckel, R.H. Am. J. Clin. Nutr. (1989) [Pubmed]
  13. Pentavalent technetium-99m (V)-DMSA uptake in a pheochromocytoma in a patient with Sipple's syndrome. Adams, B.K., Fataar, A., Byrne, M.J., Levitt, N.S., Matley, P.J. J. Nucl. Med. (1990) [Pubmed]
  14. Cytotoxicity of nitric oxide is alleviated by zinc-mediated expression of antioxidant genes. Chung, M.J., Hogstrand, C., Lee, S.J. Exp. Biol. Med. (Maywood) (2006) [Pubmed]
  15. Cloned transcription factor MTF-1 activates the mouse metallothionein I promoter. Radtke, F., Heuchel, R., Georgiev, O., Hergersberg, M., Gariglio, M., Dembic, Z., Schaffner, W. EMBO J. (1993) [Pubmed]
  16. Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression. Zhao, C.Q., Young, M.R., Diwan, B.A., Coogan, T.P., Waalkes, M.P. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  17. The Drosophila homolog of mammalian zinc finger factor MTF-1 activates transcription in response to heavy metals. Zhang, B., Egli, D., Georgiev, O., Schaffner, W. Mol. Cell. Biol. (2001) [Pubmed]
  18. Coordinate induction of metallothioneins I and II in rodent cells by UV irradiation. Fornace, A.J., Schalch, H., Alamo, I. Mol. Cell. Biol. (1988) [Pubmed]
  19. The functional significance of brain metallothioneins. Aschner, M. FASEB J. (1996) [Pubmed]
  20. Cell-type specific and differential regulation of the human metallothionein genes. Correlation with DNA methylation and chromatin structure. Jahroudi, N., Foster, R., Price-Haughey, J., Beitel, G., Gedamu, L. J. Biol. Chem. (1990) [Pubmed]
  21. Localization Effect on the Metal Biosorption Capability of Recombinant Mammalian and Fish Metallothioneins in Escherichia coli. Kao, W.C., Chiu, Y.P., Chang, C.C., Chang, J.S. Biotechnol. Prog. (2006) [Pubmed]
  22. The Zn- and Cd-Clusters of Recombinant Mammalian MT1 and MT4 Metallothionein Domains Include Sulfide Ligands. T??o, L., Villarreal, L., Atrian, S., Capdevila, M. Exp. Biol. Med. (Maywood) (2006) [Pubmed]
  23. Interleukin-1 beta-mediated metallothionein induction and cytoprotection against cadmium and cis-diamminedichloroplatinum. Kondo, Y., Kuo, S.M., Lazo, J.S. J. Pharmacol. Exp. Ther. (1994) [Pubmed]
  24. The DNA binding activity of metal response element-binding transcription factor-1 is activated in vivo and in vitro by zinc, but not by other transition metals. Bittel, D., Dalton, T., Samson, S.L., Gedamu, L., Andrews, G.K. J. Biol. Chem. (1998) [Pubmed]
  25. Epigenetic regulation of metallothionein-i gene expression: differential regulation of methylated and unmethylated promoters by DNA methyltransferases and methyl CpG binding proteins. Majumder, S., Kutay, H., Datta, J., Summers, D., Jacob, S.T., Ghoshal, K. J. Cell. Biochem. (2006) [Pubmed]
  26. Chromium(VI) down-regulates heavy metal-induced metallothionein gene transcription by modifying transactivation potential of the key transcription factor, metal-responsive transcription factor 1. Majumder, S., Ghoshal, K., Summers, D., Bai, S., Datta, J., Jacob, S.T. J. Biol. Chem. (2003) [Pubmed]
  27. Human metallothionein gene MT1L mRNA is present in several human tissues but is unlikely to produce a metallothionein protein. Holloway, A.F., Stennard, F.A., West, A.K. FEBS Lett. (1997) [Pubmed]
  28. Expression of different metallothionein messenger ribonucleic acids in motor cortex, spinal cord and liver from patients with amyotrophic lateral sclerosis. Blaauwgeers, H.G., Anwar Chand, M., van den Berg, F.M., Vianney de Jong, J.M., Troost, D. J. Neurol. Sci. (1996) [Pubmed]
  29. Metallothionein IIA is up-regulated by hypoxia in human A431 squamous carcinoma cells. Murphy, B.J., Laderoute, K.R., Chin, R.J., Sutherland, R.M. Cancer Res. (1994) [Pubmed]
  30. Characteristics of microtubules at the different stages of neuronal differentiation and maturation. Meininger, V., Binet, S. Int. Rev. Cytol. (1989) [Pubmed]
  31. The cellular proteins which can associate specifically with polyomavirus middle T antigen in human 293 cells include the major human 70-kilodalton heat shock proteins. Pallas, D.C., Morgan, W., Roberts, T.M. J. Virol. (1989) [Pubmed]
  32. Identification and spatial analysis of metallothioneins expressed by the adult human lens. Oppermann, B., Zhang, W., Magabo, K., Kantorow, M. Invest. Ophthalmol. Vis. Sci. (2001) [Pubmed]
 
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