mtCLIC/CLIC4, an organellular chloride channel protein, is increased by DNA damage and participates in the apoptotic response to p53.
mtCLIC/CLIC4 (referred to here as mtCLIC) is a p53- and tumor necrosis factor alpha-regulated cytoplasmic and mitochondrial protein that belongs to the CLIC family of intracellular chloride channels. mtCLIC associates with the inner mitochondrial membrane. Dual regulation of mtCLIC by two stress response pathways suggested that this chloride channel protein might contribute to the cellular response to cytotoxic stimuli. DNA damage or overexpression of p53 upregulates mtCLIC and induces apoptosis. Overexpression of mtCLIC by transient transfection reduces mitochondrial membrane potential, releases cytochrome c into the cytoplasm, activates caspases, and induces apoptosis. mtCLIC is additive with Bax in inducing apoptosis without a physical association of the two proteins. Antisense mtCLIC prevents the increase in mtCLIC levels and reduces apoptosis induced by p53 but not apoptosis induced by Bax, suggesting that the two proapoptotic proteins function through independent pathways. Our studies indicate that mtCLIC, like Bax, Noxa, p53AIP1, and PUMA, participates in a stress-induced death pathway converging on mitochondria and should be considered a target for cancer therapy through genetic or pharmacologic approaches.
Fernández-Salas
Ester
E
Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Suh
Kwang S
KS
Speransky
Vladislav V
VV
Bowers
Wendy L
WL
Levy
Joshua M
JM
Adams
Tracey
T
Pathak
Kamal R
KR
Edwards
Lindsay E
LE
Hayes
Daniel D
DD
Cheng
Christina
C
Steven
Alasdair C
AC
Weinberg
Wendy C
WC
Yuspa
Stuart H
SH
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D015870:Gene Expression; D016158:Genes, p53; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D018118:Chloride Channels; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein