Identification of three novel members of the calcium‐dependent chloride channel (CaCC) family predominantly expressed in the digestive tract and trachea<sup>1</sup>

Agnel, Magali; Vermat, Thierry; Culouscou, Jean-Michel

doi:10.1016/s0014-5793(99)00891-1

Cited by 87 publications

(69 citation statements)

References 38 publications

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“…CLCA2 is primarily expressed in the breast and lung (Figure 1a). This result confirms the previously reported data (Agnel et al, 1999;. CLCA2 expression is also detected in the placenta (Figure 1a).…”

Section: Clca2 Is Downregulated In Breast Cancersupporting

confidence: 93%

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: Clca2 Is Downregulated In Breast Cancersupporting

confidence: 93%

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

Cowell

Sossey‐Alaoui

2004

Oncogene

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“…Positive signals were then confirmed using manually isolated tissues. Although most adult tissues were negative, mCLCA5 was detected in many of the same locations as hCLCA2, including lung, kidney, uterus, and endothelial cells (20,22) (Fig. 2A).…”

Section: Discovery and Cloning Of Mclca5-a Blast Search Of Thementioning

confidence: 98%

Re-expression of Detachment-inducible Chloride Channel mCLCA5 Suppresses Growth of Metastatic Breast Cancer Cells

Beckley

Pauli

Elble

2004

Journal of Biological Chemistry

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The calcium-activated chloride channel hCLCA2 has been identified as a candidate tumor suppressor in human breast cancer. It is greatly down-regulated in breast cancer, and its re-expression suppresses tumorigenesis by an unknown mechanism. To establish a mouse model, we identified the mouse ortholog of hCLCA2, termed mCLCA5, and investigated its behavior in mammary epithelial cell lines and tissues. Expression in the immortalized cell line HC11 correlated with slow or arrested growth. Although rapidly dividing, sparsely plated cells had low levels of expression, mCLCA5 was induced by 10-fold when cells became confluent and 30-fold when cells were deprived of growth factors or anchorage. The apoptosis effector Bax was induced in parallel. Like hCLCA2, mCLCA5 was down-regulated in metastatic mammary tumor cell lines such as 4T1 and CSML-100. Ectopic re-expression in 4T1 cells caused a 20-fold reduction in colony survival relative to vector control. High mCLCA5 expression in stable clones inhibited proliferation and enhanced sensitivity to detachment. Moreover, mCLCA5 was induced in lactating and involuting mammary gland, correlating with differentiation and onset of apoptosis. Together, these results establish mCLCA5 as the mouse ortholog of hCLCA2, demonstrate that mCLCA5 is a detachment-sensitive growth inhibitor, and suggest a mechanism whereby these channels may antagonize mammary tumor progression.

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“…Structurally, gob-5 belongs to a family of calcium-activated chloride channel (CaCCs) (15)(16)(17)(18)(19). The gob-5 protein shares 75% similarity with the human protein hCLCA1͞ hCaCC1, 55% with hCLCA4͞hCaCC2, and 38% with hCLCA2͞ hCaCC3.…”

Section: Mucus Production In Human Mucoepidermoid Cells Transfected Withmentioning

confidence: 99%

Role of gob-5 in mucus overproduction and airway hyperresponsiveness in asthma

Nakanishi

Morita

Iwashita

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

269

256

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Airway hyperresponsiveness (AHR), goblet cell metaplasia, and mucus overproduction are important features of bronchial asthma. To elucidate the molecular mechanisms behind these pulmonary pathologies, we examined for genes preferentially expressed in the lungs of a murine model of allergic asthma by using suppression subtractive hybridization (SSH). We identified a gene called gob-5 that had a selective expression pattern in the airway epithelium with AHR. Here, we show that gob-5, a member of the calcium-activated chloride channel family, is a key molecule in the induction of murine asthma. Intratracheal administration of adenovirus-expressing antisense gob-5 RNA into AHR-model mice efficiently suppressed the asthma phenotype, including AHR and mucus overproduction. In contrast, overexpression of gob-5 in airway epithelia by using an adenoviral vector exacerbated the asthma phenotype. Introduction of either gob-5 or hCLCA1, the human counterpart of gob-5, into the human mucoepidermoid cell line NCI-H292 induced mucus production as well as MUC5AC expression. Our results indicated that gob-5 may play a critical role in murine asthma, and its human counterpart hCLCA1 is therefore a potential target for asthma therapy.

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Identification of three novel members of the calcium‐dependent chloride channel (CaCC) family predominantly expressed in the digestive tract and trachea¹

Cited by 87 publications

References 38 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

Re-expression of Detachment-inducible Chloride Channel mCLCA5 Suppresses Growth of Metastatic Breast Cancer Cells

Role of gob-5 in mucus overproduction and airway hyperresponsiveness in asthma

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Identification of three novel members of the calcium‐dependent chloride channel (CaCC) family predominantly expressed in the digestive tract and trachea1

Cited by 87 publications

References 38 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

Re-expression of Detachment-inducible Chloride Channel mCLCA5 Suppresses Growth of Metastatic Breast Cancer Cells

Role of gob-5 in mucus overproduction and airway hyperresponsiveness in asthma

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Identification of three novel members of the calcium‐dependent chloride channel (CaCC) family predominantly expressed in the digestive tract and trachea¹