Molecular Characteristics And Functional Diversity Of Clca Family Members

Pauli, Bendicht U.; Abdel-Ghany, Mossaad; Cheng, Hsiu Chi; Gruber, Achim D.; Archibald, Heather A.; Elble, Randolph C.

doi:10.1046/j.1440-1681.2000.03358.x

Cited by 92 publications

(79 citation statements)

References 34 publications

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“…The CLCA2 gene family is a novel family of calciumactivated chloride channels (Pauli et al, 2002). Several members of this family have been cloned from different mammalian species with distinct, highly specific expression patterns (Gruber et al, 1998.…”

Section: Discussionmentioning

confidence: 99%

CLCA2 tumour suppressor gene in 1p31 is epigenetically regulated in breast cancer

Cowell

Sossey‐Alaoui

2004

Oncogene

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The calcium-activated chloride channel gene family is clustered in the 1p31 region, which is frequently deleted in sporadic breast cancer. Recent studies have indicated the association of the second member of this gene family (CLCA2) with the development of breast cancer and metastasis. We have now shown the absence of expression of CLCA2 in several breast cancer tumours and cell lines, which confirms the results from other reports. When overexpressed in CLCA2-negative cell lines, their tumorigenicity and metastasis capability were significantly reduced, suggesting a tumour suppressor role for CLCA2 in breast cancer. The mechanisms behind the silencing of CLCA2 in breast cancer, however, have not been elucidated to date. Although we were able to identify CLCA2 mutations in breast cancers, somatic mutations are not the major cause of CLCA2 gene silencing. On the other hand, treatment of breast cancer CLCA2-negative cell lines with demethylating agents was able to restore CLCA2 expression, suggesting an epigenetic inactivation of this gene. Bisulphite-sequencing of the promoterassociated CpG island of the CLCA2 gene in breast tumours demonstrated that the absence of expression in these tumours was caused by hypermethylation of the promoter CpG island. In contrast, in breast cancer cell lines, tumours, and control cell lines that express CLCA2, a much lower level, and often absence, of methylation of the promoter were demonstrated. These findings demonstrate that CLCA2 is frequently inactivated in breast cancer by promoter region hypermethylation, which makes it an excellent candidate for the 1p31 breast cancer tumour suppressor gene.

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Section: Discussionmentioning

confidence: 99%

CLCA2 tumour suppressor gene in 1p31 is epigenetically regulated in breast cancer

Cowell

Sossey‐Alaoui

2004

Oncogene

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“…The expression, processing and primary structure of CLCA proteins have recently been studied (Pauli et al, 2000). The initial translation product of the open reading frame is about 100 kDa, which is glycosylated into a 125 kDa glycoprotein, and then immediately proteolytically cleaved into 90 kDa and 35 kDa subunits.…”

Section: Characterization Of Bclca1 Antibodymentioning

confidence: 99%

“…The initial translation product of the open reading frame is about 100 kDa, which is glycosylated into a 125 kDa glycoprotein, and then immediately proteolytically cleaved into 90 kDa and 35 kDa subunits. The proteolytic cleavage site is assumed to be around 709 aa (Pauli et al, 2000). The peptide sequence used to induce our anti-bCLCA1 antibody is upstream to the cleavage site.…”

Section: Characterization Of Bclca1 Antibodymentioning

confidence: 99%

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Molecular expression and functional involvement of the bovine calcium-activated chloride channel 1 (bCLCA1) in apical HCO3− permeability of bovine corneal endothelium

Zhang

Xie

et al. 2006

Experimental Eye Research

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Corneal endothelium secretes from basolateral (stroma) to apical (anterior chamber) compartments. Apical permeability can be enhanced by increasing [Ca 2+ ] i . We hypothesized that the bovine calcium-activated chloride channel 1 (bCLCA1), shown previously by PCR screening to be expressed in corneal endothelium, is involved in Ca 2+ activated apical permeability. bCLCA1 expression in cultured bovine corneal endothelial cells (CBCEC) was examined by in situ hybridization analysis, immunoblotting, immunofluorescence and confocal microscopy. Rabbit polyclonal antibodies were generated using a 14 aa polypeptide (417-430) from the predicted sequence of bCLCA1. The small interference RNA (siRNA) knock down technique was used to evaluate the functional involvement of bCLCA1 in apical permeability. In situ hybridization confirmed prominent bCLCA1-specific mRNA expression in CBCEC. bCLCA1 antiserum detected the heterologously expressed bCLCA1 in HEK293 cells and a 90 kDa band in CBCEC, which was absent when using the pre-immune serum or antigen absorption of serum. Immunofluoresence staining with anti-bCLCA1 antibody and confocal microscopy indicates an apical membrane location in CBCEC. In CBCEC transfected with bCLCA1 specific siRNA, bCLCA1 expression was reduced by 80%, while transfection with siControl scrambled sequence had no effect. Increasing [ ] by application of ATPγS or cyclopiazonic acid (CPA) increased apical permeability in siControl transfected CBCEC, while having no effect on apical permeability in bCLCA1 specific siRNA transfected cells. Baseline permeability, however, was not different between controls and siRNA treated cells. We conclude that the calcium-activated chloride channel (bCLCA1) is expressed in bovine corneal endothelial cells and can contribute to Ca 2+ dependent apical permeability, but not resting permeability, across the corneal endothelium.

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“…The hCLCA1 enhances mucus secretion by mediating the active transport of chloride ions. 10 Currently, the family includes two bovine homologues (bCLCA1 and bCLCA2), [17][18][19] four murine homologues (mCLCA1, mCLCA2, mCLCA3 (gob-5), mCLCA4), [20][21][22][23][24] and four human homologues (hCLCA1, hCLCA2, hCLCA3, hCLCA4 (hCaCC2)). 15,16,25,26 All human CLCA genes identified are clustered on the short arm of chromosome 1 (1p22-31).…”

Section: Introductionmentioning

confidence: 99%

Association of the hCLCA1 gene with childhood and adult asthma

et al. 2004

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Asthma is caused by bronchial inflammation. This inflammation involves mucus overproduction and hypersecretion. Recently, a mouse model of asthma showed that gob-5 is involved in the pathogenesis of asthma. The gob-5 gene is involved in mucus secretion and its expression is upregulated upon antigen attack in sensitized mice. The observation suggests that human homologue of gob-5, hCLCA1 (human calcium-dependent chloride channel-1), may be involved in human disease. We screened for single-nucleotide polymorphisms (SNPs) in hCLCA1 in the Japanese population. We identified eight SNPs, and performed association studies using 384 child patients with asthma, 480 adult patients with asthma, and 672 controls. In haplotype analysis, we found a different haplotype distribution pattern between controls and childhood asthma (Po0.0001) and between controls and adult asthma (P ¼ 0.0031). We identified a high-risk haplotype (CATCAAGT haplotype; P ¼ 0.0014) and a low-risk haplotype (TGCCAAGT haplotype; P ¼ 0.00010) in cases of childhood asthma. In diplotype analysis, patients who had the CATCAAGT haplotype showed a higher risk for childhood asthma than those who did not (P ¼ 0.0011). Individuals who had the TGCCAAGT haplotype showed a lower risk for childhood asthma than those who did not (Po0.0001). Our data suggested that variation of the hCLCA1 gene affects patients' susceptibility for asthma.

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Molecular Characteristics And Functional Diversity Of Clca Family Members

Cited by 92 publications

References 34 publications

CLCA2 tumour suppressor gene in 1p31 is epigenetically regulated in breast cancer

CLCA2 tumour suppressor gene in 1p31 is epigenetically regulated in breast cancer

Molecular expression and functional involvement of the bovine calcium-activated chloride channel 1 (bCLCA1) in apical HCO3− permeability of bovine corneal endothelium

Association of the hCLCA1 gene with childhood and adult asthma

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