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Direct Protein Delivery to Mammalian Cells Using Cell-permeable Cys2-His2 Zinc-finger Domains
Published on: March 25, 2015
Zinc finger protein 598 inhibits cell survival by promoting UV-induced apoptosis
1Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
Abstract:
UV is one of the major causes of DNA damage induced apoptosis. However, cancer cells adopt alternative mechanisms to evade UV-induced apoptosis. To identify factors that protect cancer cells from UV-induced apoptosis, we performed a genome wide short-hairpin RNA (shRNA) screen, which identified Zinc finger protein 598 (ZNF598) as a key regulator of UV-induced apoptosis. Here, we show that UV irradiation transcriptionally upregulates ZNF598 expression. Additionally, ZNF598 knockdown in cancer cells inhibited UV-induced apoptosis. In our study, we observe that ELK1 mRNA level as well as phosphorylated ELK1 levels was up regulated upon UV irradiation, which was necessary for UV irradiation induced upregulation of ZNF598. Cells expressing ELK1 shRNA were also resistant to UV-induced apoptosis, and phenocopy ZNF598 knockdown. Upon further investigation, we found that ZNF598 knockdown inhibits UV-induced apoptotic gene expression, which matches with decrease in percentage of annexin V positive cell. Similarly, ectopic expression of ZNF598 promoted apoptotic gene expression and also increased annexin V positive cells. Collectively, these results demonstrate that ZNF598 is a UV irradiation regulated gene and its loss results in resistance to UV-induced apoptosis.
Insights
Zinc finger protein 598 (ZNF598) protects cancer cells from UV-induced apoptosis by upregulating apoptotic gene expression. Loss of ZNF598 confers resistance to UV-induced apoptosis, highlighting its role in cancer cell survival.
Area of Science:
- Molecular Biology
- Cancer Research
- Cellular Stress Response
Background:
- Ultraviolet (UV) radiation is a significant inducer of DNA damage and apoptosis.
- Cancer cells frequently develop mechanisms to evade apoptosis, contributing to tumor progression and treatment resistance.
Purpose of the Study:
- To identify novel factors that confer resistance to UV-induced apoptosis in cancer cells.
- To elucidate the role of Zinc finger protein 598 (ZNF598) in regulating UV-induced apoptosis.
Main Methods:
- Genome-wide short-hairpin RNA (shRNA) screening to identify key regulators of UV-induced apoptosis.
- Analysis of ZNF598 and ELK1 expression and phosphorylation levels following UV irradiation.
- Assessment of apoptosis using annexin V staining and apoptotic gene expression analysis.
Main Results:
- UV irradiation transcriptionally upregulates ZNF598 expression in cancer cells.
- ZNF598 knockdown inhibits UV-induced apoptosis, while its ectopic expression promotes it.
- UV-induced ZNF598 upregulation is dependent on ELK1 activation, and ELK1 knockdown also confers resistance to UV-induced apoptosis.
Conclusions:
- ZNF598 is a critical mediator of UV-induced apoptosis, acting downstream of ELK1.
- ZNF598 plays a protective role in cancer cells against UV-induced cell death.
- Targeting ZNF598 may represent a therapeutic strategy to enhance cancer cell sensitivity to UV-based treatments.
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