CLIC4, skin homeostasis and cutaneous cancer: surprising connections.
Chloride intracellular channel 4 (CLIC4) is a putative chloride channel for intracellular organelles. CLIC4 has biological activities in addition to or because of its channel activity. In keratinocytes, CLIC4 resides in the mitochondria and cytoplasm, and CLIC4 gene expression is regulated by p53, TNF-alpha, and c-Myc. Cytoplasmic CLIC4 translocates to the nucleus in response to cellular stress conditions including DNA damage, metabolic inhibition, senescence, and exposure to certain trophic factors such as TNF-alpha and LPS. Nuclear translocation is associated with growth arrest or apoptosis, depending on the level of expression. In the nucleus CLIC4 interacts with several nuclear proteins as demonstrated by yeast two-hybrid screening and co-immunoprecipitation. Nuclear CLIC4 appears to act on the TGF-beta pathway, and TGF-beta also causes CLIC4 nuclear translocation. In human and mouse cancer cell lines, CLIC4 levels are reduced, and CLIC4 is excluded from the nucleus. CLIC4 soluble or membrane-inserted status is dependent on redox state, and redox alterations in cancer cells could underly the defect in nuclear translocation. CLIC4 is reduced and excluded from the nucleus of many human epithelial neoplasms. Paradoxically, CLIC4 is reciprocally upregulated in tumor stroma in conjunction with the expression of alpha-smooth muscle actin in the fibroblast to myofibroblast transition. Overexpression of CLIC4 in cancer cells inhibits tumor growth in vivo. Conversely, overexpression of CLIC4 in tumor stromal cells stimulates tumor growth in vivo. Thus, CLIC4 participates in normal and pathological processes and may serve as a useful target for therapies in disturbances of homeostasis and neoplastic transformation.
Suh
Kwang S
KS
Laboratory of Cancer Biology and Genetics, Center for Cancer Research National Cancer Institute, Bethesda, Maryland 20892, USA.
Malik
Mariam
M
Shukla
Anjali
A
Yuspa
Stuart H
SH
D000818:Animals; D002454:Cell Differentiation; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006706:Homeostasis; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology
C464459:CLIC4 protein, human; D018118:Chloride Channels; D016376:Oligonucleotides, Antisense