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

• CRAC1 LOH occurred in 23% of tumours [8].
• A susceptibility gene to colorectal adenomas and carcinoma (CRAC1) on chromosome region 15q14 approximately q22 has been proposed on the basis of linkage in a single family [9].
• To determine whether CRAC1 plays a role in colorectal carcinogenesis in general, we have studied 277 cases of early-onset colorectal cancers for allele loss at 15q14 approximately q22 using four microsatellite markers (D15S970, D15S117, D15S971, and D15S1028) that define the region of maximal linkage [9].
• Allelic imbalance in colorectal cancer at the CRAC1 locus in early-onset colorectal cancer [9].
• The oxidative metabolic abnormalities of neonates' PMNs are consistent with either a defect in HMPS activity, a defect in functioning of the later portions of the respiratory burst, or a stimulus-specific abnormality in respiratory burst activity [10].

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

• We have studied the interaction of two peptides containing the CRAC motif of caveolin-1 by differential scanning calorimetry, fluorescence, circular dichroism and magic angle spinning NMR [12].
• We have used the patch clamp technique in combination with intracellular calcium measurements to measure simultaneously Ca2+ entry and ionic currents activated by emptying of intracellular Ca2+ stores (capacitative Ca2+ entry and Ca2+ release-activated Ca2+ currents, CRAC) in human endothelial cells from umbilical veins [17].
• DATA SOURCES: Randomized clinical trials (RCTs) on chiropractic were identified with a Medline and Embase search (1966-1995), by citation tracking, and by hand searching of the relevant chiropractic reference systems (CRAC and Index to Chiropractic Literature) [18].

References