mtCLIC/CLIC4, an Organellular Chloride Channel Protein, Is Increased by DNA Damage and Participates in the Apoptotic Response to p53

Fernández‐Salas, Ester; Suh, Kwang S.; Speransky, V. V.; Bowers, Wendy L.; Levy, Joshua M.; Adams, Tracey; Pathak, Kamal; Edwards, Lindsay E.; Hayes, Denise A.; Cheng, Christina; Steven, Alasdair C.; Weinberg, Wendy C.; Yuspa, Stuart H.

doi:10.1128/mcb.22.11.3610-3620.2002

Cited by 164 publications

(167 citation statements)

References 58 publications

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“…If this is by mediating apoptosis, as is often argued, we must recognize that the mechanism by which p53 mediates apoptosis has become increasingly less clear in recent years as the list of p53-regulated proapoptotic candidates has grown sharply. Included among these are: Bax, CD95/Fas, Noxa, Pidd, PIG3, p53AIP1, PUMA, mtCLIC/CLIC4 and Scotin (Miyashita and Reed, 1995;Owen-Schaub et al, 1995;Polyak et al, 1997;Lin et al, 2000;Oda E et al, 2000;Oda K et al, 2000;Nakano and Vousden, 2001;Yu et al, 2001;Bourdon et al, 2002;Fernandez-Salas et al, 2002). Importantly, we lack data on whether these various proteins are coregulated, and how they might interact.…”

Section: Targeting P53mentioning

confidence: 99%

Strategies for reversing drug resistance

2003

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Section: Targeting P53mentioning

confidence: 99%

Strategies for reversing drug resistance

2003

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“…The nuclear channel NCC27 is expressed at G 2 /M, and specific blockade of the channel arrests cells at G 2 /M (65). On the other hand, CLIC4 is a p53-and stress-inducible channel that potentiates apoptosis by an unknown mechanism (66). Since members of both the CLCA and the CLIC families are expressed in many of the same cell types, it is possible that they perform similar functions for different cellular compartments.…”

Section: Fig 6 Decrease In Colony Formation Upon Transfection Of MCmentioning

confidence: 99%

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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“…CLIC4 was described as a mitochondrial and cytoplasmic protein in mouse keratinocytes and localized to the inner mitochondrial membrane in human keratinocytes (9). Other reports indicate CLIC4 is also localized in the trans-Golgi network in pancreatic cells, endoplasmic reticulum (ER) in rat hippocampal HT-4 cells, and large dense core vesicles in neurosecretory cells (10 -12).…”

mentioning

confidence: 99%

The Organellular Chloride Channel Protein CLIC4/mtCLIC Translocates to the Nucleus in Response to Cellular Stress and Accelerates Apoptosis

Suh¹,

Mutoh²,

Nagashima

et al. 2004

Journal of Biological Chemistry

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CLIC4/mtCLIC, a chloride intracellular channel protein, localizes to the mitochondria and cytoplasm of keratinocytes and participates in the apoptotic response to stress. We now show that multiple stress inducers cause the translocation of cytoplasmic CLIC4 to the nucleus. Immunogold electron microscopy and confocal analyses indicate that nuclear CLIC4 is detected prior to the apoptotic phenotype. CLIC4 associates with the Ran, NTF2, and Importin-␣ nuclear import complexes in immunoprecipitates of lysates from cells treated with apoptotic/stress-inducing agents. Deletion or mutation of the nuclear localization signal in the C terminus of CLIC4 eliminates nuclear translocation, whereas N terminus deletion enhances nuclear localization. Targeting CLIC4 to the nucleus via adenoviral transduction accelerates apoptosis when compared with cytoplasmic CLIC4, and only nuclear-targeted CLIC4 causes apoptosis in Apaf null mouse fibroblasts or in Bcl-2-overexpressing keratinocytes. These results indicate that CLIC4 nuclear translocation is an integral part of the cellular response to stress and may contribute to the initiation of nuclear alterations that are associated with apoptosis.

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mtCLIC/CLIC4, an Organellular Chloride Channel Protein, Is Increased by DNA Damage and Participates in the Apoptotic Response to p53

Cited by 164 publications

References 58 publications

Strategies for reversing drug resistance

Strategies for reversing drug resistance

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

The Organellular Chloride Channel Protein CLIC4/mtCLIC Translocates to the Nucleus in Response to Cellular Stress and Accelerates Apoptosis

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