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Gene Review

CRAC1  -  colorectal adenoma and carcinoma 1

Homo sapiens

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Disease relevance of CRAC1

  • Using genetic linkage analysis, supplemented by allele loss in tumors, we have provided evidence for a new colorectal cancer susceptibility gene, CRAC1 (colorectal adenoma and carcinoma), mapping to chromosome 15q14-q22 [1].
  • Although there are probably multiple causes of the multiple colorectal adenoma and cancer phenotype in Ashkenazim, an important one is the HMPS/CRAC1 locus on 15q13-q14 [2].
  • Since membrane depolarization is unfavourable to the influx of Ca2+ through the CRAC channels (necessary to drive many events in T cell activation such as cytokine production and proliferation), the effect of hypoxia on T cell receptor-mediated increase in cytoplasmic Ca2+ was determined using fura-2 [3].
  • Increasing the concentrations of H2O2 in the preincubation mixtures resulted in a progressive decline in the neutrophils phagocytic and killing capacity for E. coli and was accompanied by inhibition of HMPS activity and the release of granule enzymes but not of O-2 or H2O2 [4].
  • ClMP proved to be a very potent mutagen in Salmonella typhimurium, whereas HMPS, and HMP in the presence of a sulfate-conjugating system, showed strong mutagenicity only when Cl- or Br- ions were present in the exposure buffer [5].

High impact information on CRAC1

  • Following engagement of the T cell receptor, intracellular channels (IP3 and ryanodine receptors) release Ca(2+) from intracellular stores, and by depleting the stores trigger prolonged Ca(2+) influx through store-operated Ca(2+) (CRAC) channels in the plasma membrane [6].
  • The amplitude and dynamics of the Ca(2+) signal are shaped by several mechanisms, including K(+) channels and membrane potential, slow modulation of the plasma membrane Ca(2+)-ATPase, and mitochondria that buffer Ca(2+) and prevent the inactivation of CRAC channels [6].
  • In T lymphocytes, a store-operated calcium ion (Ca2+) entry mechanism termed the calcium release-activated Ca2+ channel (CRAC channel) underlies the sustained or oscillatory intracellular calcium concentration signal required for interleukin-2 gene expression and cell proliferation [7].
  • Since this region encompassed CRAC1, a locus involved in inherited susceptibility to colorectal adenomas and carcinomas in another Ashkenazi family (SM1311), we determined whether HMPS and CRAC1 might be the same [2].
  • An ancestral Ashkenazi haplotype at the HMPS/CRAC1 locus on 15q13-q14 is associated with hereditary mixed polyposis syndrome [2].

Biological context of CRAC1


Anatomical context of CRAC1

  • Furthermore, salicylic acid in high concentrations did not impair the HMPS pathway, the production of O-2 or the production of H2O2 by granulocytes [11].
  • The presence or absence of a CRAC motif, however, is not a sufficient criterion to determine the extent to which a protein will promote the segregation of cholesterol in membranes [12].
  • CaT1 knock-down strategies fail to affect CRAC channels in mucosal-type mast cells [13].
  • There are, however, certain proteins that are known to interact with cholesterol-rich domains of cell membranes that have CRAC motifs, and synthetic peptides corresponding to these segments also promote the formation of cholesterol-rich domains [14].
  • Rat liver cytosol, fortified with 3'-phosphoadenosine-5'-phosphosulfate, converted HMP into its sulfate ester (HMPS), HMPS bound covalently to isolated DNA [5].

Associations of CRAC1 with chemical compounds

  • A segment of this protein has a sequence that corresponds to a cholesterol recognition/interaction amino acid consensus (CRAC) motif; this motif has been suggested to cause the incorporation of proteins into cholesterol-rich domains [12].
  • We discuss two examples of these cholesterol-recognition elements: the cholesterol recognition/interaction amino acid consensus (CRAC) domain and the sterol-sensing domain (SSD) [14].
  • Mezerein stimulated the oxidative metabolism of PMNs in an identical manner to PMA as indicated by a burst in the activity of the HMPS pathway, the production of H2O2, hydroxyl radical and stable oxidants [15].
  • Antisera have been prepared against the purified HMPS, and these were used to select mutants specifically and highly deficient in the polysaccharide [16].
  • When Cl- anions were present at physiological concentrations, an additional reaction product of HMPS, 1-chloromethylpyrene (ClMP), could be identified on the basis of its chromatographic properties and its mass spectrum, using the authentic standard for comparison [5].

Analytical, diagnostic and therapeutic context of CRAC1


  1. Inherited susceptibility to colorectal adenomas and carcinomas: evidence for a new predisposition gene on 15q14-q22. Tomlinson, I., Rahman, N., Frayling, I., Mangion, J., Barfoot, R., Hamoudi, R., Seal, S., Northover, J., Thomas, H.J., Neale, K., Hodgson, S., Talbot, I., Houlston, R., Stratton, M.R. Gastroenterology (1999) [Pubmed]
  2. An ancestral Ashkenazi haplotype at the HMPS/CRAC1 locus on 15q13-q14 is associated with hereditary mixed polyposis syndrome. Jaeger, E.E., Woodford-Richens, K.L., Lockett, M., Rowan, A.J., Sawyer, E.J., Heinimann, K., Rozen, P., Murday, V.A., Whitelaw, S.C., Ginsberg, A., Atkin, W.S., Lynch, H.T., Southey, M.C., Debinski, H., Eng, C., Bodmer, W.F., Talbot, I.C., Hodgson, S.V., Thomas, H.J., Tomlinson, I.P. Am. J. Hum. Genet. (2003) [Pubmed]
  3. Hypoxia modulates early events in T cell receptor-mediated activation in human T lymphocytes via Kv1.3 channels. Robbins, J.R., Lee, S.M., Filipovich, A.H., Szigligeti, P., Neumeier, L., Petrovic, M., Conforti, L. J. Physiol. (Lond.) (2005) [Pubmed]
  4. Inhibition of neutrophil function by hydrogen peroxide. Effect of SH-group-containing compounds. Rajkovic, I.A., Williams, R. Biochem. Pharmacol. (1985) [Pubmed]
  5. Sulfotransferase-mediated chlorination of 1-hydroxymethylpyrene to a mutagen capable of penetrating indicator cells. Glatt, H., Henschler, R., Phillips, D.H., Blake, J.W., Steinberg, P., Seidel, A., Oesch, F. Environ. Health Perspect. (1990) [Pubmed]
  6. Calcium signaling mechanisms in T lymphocytes. Lewis, R.S. Annu. Rev. Immunol. (2001) [Pubmed]
  7. Single-channel recording of a store-operated Ca2+ channel in Jurkat T lymphocytes. Kerschbaum, H.H., Cahalan, M.D. Science (1999) [Pubmed]
  8. Molecular characteristics of serrated adenomas of the colorectum. Sawyer, E.J., Cerar, A., Hanby, A.M., Gorman, P., Arends, M., Talbot, I.C., Tomlinson, I.P. Gut (2002) [Pubmed]
  9. Allelic imbalance in colorectal cancer at the CRAC1 locus in early-onset colorectal cancer. Popat, S., Stone, J., Houlston, R.S. Cancer Genet. Cytogenet. (2003) [Pubmed]
  10. Defective oxidative metabolic responses of neutrophils from stressed neonates. Shigeoka, A.O., Charette, R.P., Wyman, M.L., Hill, H.R. J. Pediatr. (1981) [Pubmed]
  11. Oxidation of salicylates by stimulated granulocytes: evidence that these drugs act as free radical scavengers in biological systems. Sagone, A.L., Husney, R.M. J. Immunol. (1987) [Pubmed]
  12. Caveolin scaffolding region and cholesterol-rich domains in membranes. Epand, R.M., Sayer, B.G., Epand, R.F. J. Mol. Biol. (2005) [Pubmed]
  13. CaT1 knock-down strategies fail to affect CRAC channels in mucosal-type mast cells. Kahr, H., Schindl, R., Fritsch, R., Heinze, B., Hofbauer, M., Hack, M.E., Mörtelmaier, M.A., Groschner, K., Peng, J.B., Takanaga, H., Hediger, M.A., Romanin, C. J. Physiol. (Lond.) (2004) [Pubmed]
  14. Cholesterol and the interaction of proteins with membrane domains. Epand, R.M. Prog. Lipid Res. (2006) [Pubmed]
  15. The effects of the anti-tumor agent mezerein on the cytotoxic capacity and oxidative metabolism of human blood cells. Barton, K., Randall, G., Sagone, A.L. Investigational new drugs. (1989) [Pubmed]
  16. Defects in gliding motility in mutants of Cytophaga johnsonae lacking a high-molecular-weight cell surface polysaccharide. Godchaux, W., Lynes, M.A., Leadbetter, E.R. J. Bacteriol. (1991) [Pubmed]
  17. Inhibition of capacitative Ca2+ entry by a Cl- channel blocker in human endothelial cells. Gericke, M., Oike, M., Droogmans, G., Nilius, B. Eur. J. Pharmacol. (1994) [Pubmed]
  18. The effectiveness of chiropractic for treatment of low back pain: an update and attempt at statistical pooling. Assendelft, W.J., Koes, B.W., van der Heijden, G.J., Bouter, L.M. Journal of manipulative and physiological therapeutics. (1996) [Pubmed]
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