Abstract
The transcription factor p53 is a key player in the tumour suppressive DNA damage response and a growing number of target genes involved in these pathways has been identified. p53 has been shown to be implicated in controlling cell motility and its mutant form enhances metastasis by loss of cell directionality, but the p53 role in this context has not yet being investigated. Here, we report that ZNF185, an actin cytoskeleton-associated protein from LIM-family of Zn-finger proteins, is induced following DNA-damage. ChIP-seq analysis, chromatin crosslinking immune-precipitation experiments and luciferase assays demonstrate that ZNF185 is a bona fide p53 target gene. Upon genotoxic stress, caused by DNA-damaging drug etoposide and UVB irradiation, ZNF185 expression is up-regulated and in etoposide-treated cells, ZNF185 depletion does not affect cell proliferation and apoptosis, but interferes with actin cytoskeleton remodelling and cell polarization. Bioinformatic analysis of different types of epithelial cancers from both TCGA and GTEx databases showed a significant decrease in ZNF185 mRNA level compared to normal tissues. These findings are confirmed by tissue micro-array IHC staining. Our data highlight the involvement of ZNF185 and cytoskeleton changes in p53-mediated cellular response to genotoxic stress and indicate ZNF185 as potential biomarker for epithelial cancer diagnosis.
Highlights
To counteract DNA damage, specific mechanisms have been evolved, these are activated by specific signal transduction pathways, such as the phosphatidylinositol 3-kinase-like protein kinases (PIKKs) family, ATM, ATR and DNA-PK, and the members of the poly(ADP)ribose polymerase (PARP) family [1,2,3,4,5,6,7]
The transcription factor p53 is a key player in the tumour suppressive DNA damage response and a growing number of target genes involved in these pathways has been identified. p53 has been shown to be implicated in controlling cell motility and its mutant form enhances metastasis by loss of cell directionality, but the p53 role in this context has not yet being investigated
To investigate whether p53 could regulate ZNF185 expression and expand the p53 target genes involved in cytoskeleton regulation and cell polarity, we further analysed ZNF185 promoter region using UCSC genome browser (Fig 1A)
Summary
To counteract DNA damage, specific mechanisms have been evolved, these are activated by specific signal transduction pathways, such as the phosphatidylinositol 3-kinase-like protein kinases (PIKKs) family, ATM, ATR and DNA-PK, and the members of the poly(ADP)ribose polymerase (PARP) family [1,2,3,4,5,6,7]. In addition to its roles in cell death, p53 has been implicated in cytoskeleton assembly, cell motility and mechanosignaling, as negative regulator of cancer cell mobility, invasion and metastasis [18,19,20]. Integrin expression and signalling pathways, which play a key www.aging-us.com role in tumour cell invasion and metastasis, have been reported to be regulated indirectly by p53 [18]. F-actin formation is negatively or positively regulated by p53 in response to DNA damage depending on the anti-tumour drug used and cell type. Cytoskeleton remodelling and cell migration in cancer is a complex process and is controlled by many proteins and pathways, the specific role of p53 in these mechanisms is not yet completely understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
