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Published on: December 19, 2019
CLIC4, skin homeostasis and cutaneous cancer: surprising connections
Kwang S Suh1, Mariam Malik, Anjali Shukla
1Laboratory of Cancer Biology and Genetics, Center for Cancer Research National Cancer Institute, Bethesda, Maryland 20892, USA.
Abstract:
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.
Insights
Chloride intracellular channel 4 (CLIC4) protein translocates to the nucleus under stress, influencing cell growth and apoptosis. Reduced CLIC4 in cancer cells impairs nuclear function, affecting tumor progression.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Chloride intracellular channel 4 (CLIC4) is a protein with diverse cellular roles beyond ion channel activity.
- CLIC4 localizes to mitochondria and cytoplasm in keratinocytes, with gene expression influenced by p53, TNF-alpha, and c-Myc.
- Cytoplasmic CLIC4 exhibits stress-induced nuclear translocation, impacting cell fate.
Purpose of the Study:
- To investigate the role of CLIC4 in cellular stress responses, nuclear translocation, and its implications in cancer.
- To explore the interaction of CLIC4 with nuclear proteins and its involvement in the TGF-beta pathway.
- To analyze CLIC4 expression patterns in human epithelial neoplasms and its contrasting roles in tumor cells and stroma.
Main Methods:
- Yeast two-hybrid screening and co-immunoprecipitation to identify nuclear protein interactions.
- Analysis of CLIC4 nuclear translocation in response to various cellular stress conditions.
- Examination of CLIC4 expression levels and localization in human and mouse cancer cell lines and epithelial neoplasms.
- In vivo studies involving overexpression of CLIC4 in cancer and stromal cells to assess tumor growth effects.
Main Results:
- CLIC4 translocates to the nucleus under stress, influencing growth arrest or apoptosis.
- Nuclear CLIC4 interacts with proteins and affects the TGF-beta pathway.
- CLIC4 levels are reduced and excluded from the nucleus in many cancers, potentially due to redox alterations.
- CLIC4 overexpression inhibits tumor growth in cancer cells but stimulates it in stromal cells.
Conclusions:
- CLIC4 plays a dual role in cancer, inhibiting growth when overexpressed in tumor cells but promoting it in stromal cells.
- Altered CLIC4 nuclear localization in cancer suggests a role in neoplastic transformation and homeostasis disturbances.
- CLIC4 represents a potential therapeutic target for cancer and other diseases involving disrupted cellular processes.
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