ZNF143 activates gene expression in response to DNA damage and binds to cisplatin-modified DNA

Department of Molecular Biology, University of Occupational and Environmental Health, School of Medicine, Fukuoka, Japan.
International Journal of Cancer (Impact Factor: 5.09). 10/2004; 111(6):900-9. DOI: 10.1002/ijc.20358
Source: PubMed


We have identified a cisplatin-inducible gene, the mitochondrial ribosomal protein S11 (MRP S11) gene, by means of mRNA differential display. Functional analysis of the MRP S11 promoter showed that a Staf binding site in the promoter is required for both basal promoter activity and cisplatin-inducible activity. We also found that Staf binding activity is significantly increased in nuclear extracts from cells treated with cisplatin. ZNF 143 and ZNF 76 are human homologues of the Xenopus transcriptional activator, Staf. ZNF 143 expression is induced by cisplatin but ZNF 76 expression is not. However, ZNF 143 expression is not induced by transplatin, which is clinically ineffective. ZNF143 is an inducible gene by other DNA damaging agents such as gamma-irradiation, etoposide and adriamycin. ZNF 143 also binds preferentially to cisplatin-modified DNA. These results suggest that ZNF 143 participates in cellular responses to DNA damage.

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Available from: Kimitoshi Kohno, Sep 23, 2014
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    • "Notably, however, a considerable proportion of the Chk1 substrates we identified have been assigned roles in transcription and/or RNA processing, cellular functions that are being increasingly linked to the control of genome stability [46]. In line with this, we found that several of the newly identified Chk1 substrates functionally clustered around transcription factor ZNF143, which is known to control expression of DNA repair- and cell-cycle-related genes [47,48], and around SARNP, a protein linked to transcription and RNA export with a suggested role in cell growth and carcinogenesis [49,50] (Additional file 6). Further work will be required to validate such factors as true Chk1 substrates and determine whether and how Chk1 - and possibly Chk2 and MK2, which have similar consensus motifs to Chk1 [4] - regulate the events that they control. "
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    ABSTRACT: The cell-cycle checkpoint kinase Chk1 is essential in mammalian cells due to its roles in controlling processes such as DNA replication, mitosis and DNA-damage responses. Despite its paramount importance, how Chk1 controls these functions remains unclear, mainly because very few Chk1 substrates have hitherto been identified. Here, we combine a chemical genetics approach with high-resolution mass spectrometry to identify novel Chk1 substrates and their phosphorylation sites. The list of targets produced reveals the potential impact of Chk1 function not only on processes where Chk1 was already known to be involved, but also on other key cellular events such as transcription, RNA splicing and cell fate determination. In addition, we validate and explore the phosphorylation of transcriptional co-repressor KAP1 Ser473 as a novel DNA-damage-induced Chk1 site. By providing a substantial set of potential Chk1 substrates, we present opportunities for studying unanticipated functions for Chk1 in controlling a wide range of cellular processes. We also refine the Chk1 consensus sequence, facilitating the future prediction of Chk1 target sites. In addition, our identification of KAP1 Ser473 phosphorylation as a robust readout for Chk1 activity could be used to explore the in vivo effects of Chk1 inhibitors that are being developed for clinical evaluation.
    Genome biology 08/2011; 12(8):R78. DOI:10.1186/gb-2011-12-8-r78 · 10.81 Impact Factor
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    • "ZNF143 binds cisplatin-modified DNA and is upregulated in cisplatin-resistant ovarian cancer cells. Furthermore, knockdown of ZNF143 increases the sensitivity of cancer cells to cisplatin, implying a role for ZNF143 in cisplatin resistance in cancer cells (Ishiguchi et al., 2004; Wakasugi et al., 2007). Here, we investigated whether knockdown of ZNF143 expression would affect the cisplatin sensitivity of cancer cells. "
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    ABSTRACT: Expression of zinc-finger protein 143 (ZNF143), a human homolog of the Xenopus transcriptional activator protein Staf, is induced by various DNA-damaging agents including etoposide, doxorubicin, and gamma-irradiation. ZNF143 binds to cisplatin-modified DNA, and its levels are increased in cancer cells that are resistant to anticancer drugs, including cisplatin, suggesting that it plays a role in carcinogenesis and cancer cell survival. However, the mechanism of ZNF143 induction in cancer cells remains unclear. Both insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) have been reported to be overexpressed in cancer cells and to be related to anticancer drug resistance, but the identity of the relevant signaling mediators is still being investigated. In the present study, we observed that IGF-1 was able to induce ZNF143 expression in HCT116 human colon cancer cells and that wortmannin, an inhibitor of phosphatidylinositide 3- kinase (PI3-kinase), inhibited this induction, as did diphenyleneiodonium (DPI), an NADPH oxidase inhibitor, and monodansylcardavarine (MDC), a receptor internalization inhibitor. Treatment with MDC decreased the IGF-1-stimulated generation of reactive oxygen species. Taken together, these data suggest that IGF-1 induces ZNF143 expression in cancer cells via PI3-kinase and reactive oxygen species generation during receptor internalization.
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    • "And we also verified that the complex contained 3 Â Flag-ZNF143 when HA-p73 was reciprocally immunoprecipitated using HA antibody (Figure 3b). p73 stimulates the DNA binding of ZNF143 We previously reported that ZNF143 preferentially binds to cisplatin-modified DNA (Ishiguchi et al., 2004). To examine the effect of p73 on ZNF143 binding to oligonucleotide containing ZNF143 binding site of human U6 RNA promoter and cisplatin-modified DNA, we performed electrophoretic mobility shift assay (EMSA). "
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    ABSTRACT: Zinc-finger protein 143 (ZNF143) is a human homolog of Xenopus transcriptional activator staf that is involved in selenocystyl tRNA transcription. We previously showed that ZNF143 expression is induced by treatment with DNA-damaging agents and that it preferentially binds to cisplatin-modified DNA. In this study, the potential function of ZNF143 was investigated. ZNF143 was overexpressed in cisplatin-resistant cells. ZNF143 knockdown in prostate cancer caused increased sensitivity for cisplatin, but not for oxaliplatin, etoposide and vincristine. We also showed that ZNF143 is associated with tumor suppressor gene product p73 but not with p53. p73 could stimulate the binding of ZNF143 to both ZNF143 binding site and cisplatin-modified DNA, and modulate the function of ZNF143. We provide a direct evidence that both Rad51 and flap endonuclease-1 are target genes of ZNF143 and overexpressed in cisplatin-resistant cells. Taken together, these experiments demonstrate that an interplay of ZNF143, p73 and ZNF143 target genes is involved in DNA repair gene expression and cisplatin resistance.
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