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

Abstract

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 Cisplatin is a widely used anticancer agent, and DNA damage is believed to be the main basis of the antitumor effect of cisplatin. Since cisplatin resistance is a major obstacle to the treatment of solid tumors, understanding the molecular basis of the DNA damage response and of cisplatin resistance is important for clinical protocols. Cisplatin resistance is thought to involve several mechanisms, including increased drug efflux, the presence of cellular thiols, increased nucleotide excision repair activity and decreased mismatch repair activity. [1][2][3][4] In addition, several mechanisms are thought to contribute to the DNA damage response associated with cisplatin resistance. To understand fully these molecular mechanisms, it is desirable to identify and characterize all the transcription factors that are activated by DNA damage. We have previously shown that transcription factors such as Y-box binding protein (YB-1) and the CCAAT-binding transcription factor 2 (CTF2) are overexpressed in human cancer cell lines resistant to cisplatin. 5,6 YB-1 has been shown to bind preferentially to cisplatin-modified DNA 5 and is activated by nuclear translocation and by transcriptional mechanisms. Oct1 participates in the cellular response to DNA damage, 7,8 and its induction involves posttranscriptional mechanisms. Both c-Myc and AP-1 are also activated and involved in cellular responses to cisplatin. 8 One cisplatininducible cDNA clone has been shown to encode the vacuolar H ϩ -ATPase subunit c (ATP6L), 9,10 and analysis of its expression revealed that both Sp1 and Oct1 are critical for its activation by anticancer agents. 11 In order to identify novel mechanisms involved in the DNA damage response, we have used differential display to compare gene expression between control and cisplatin-treated cells. Here, we characterize one cisplatin-inducible gene, MRP S11, whose product, MRP S11, is a component of the ribosomal small subunit and binds to 12S rRNA. 12 MRP S11 appears to have RNA binding but not DNA binding activity. We have isolated the promoter region of MRP S11 in order to identify its transcriptional activators. Functional analysis revealed a critical Staf binding site in the core of the promoter. The zinc finger transcription factor, Staf, originally identified in the frog, is involved in transcriptional regulation of snRNA type and mRNA promoters transcribed either by RNA polymerase II or III. 13 Two human homologues of Staf, ZNF 76 and ZNF 143, have been isolated. 14 Here we show that activation of the transcriptional activator ZNF 143 upregulates the transcription of MRP S11. We present evidence that ZNF 143, but not ZNF 76, is induced by DNA damage. We further demonstrate that ZN...

ZNF143 interacts with p73 and is involved in cisplatin resistance through the transcriptional regulation of DNA repair genes

“…ZNF143 is a human homolog of Xenopus Staf (Myslinski et al, 1998), and is involved in the transcriptional regulation of small nuclear RNA (snRNA) and snRNA-type genes by RNA polymerase II or III (Schaub et al, 1997;Rincon et al, 1998). It is induced by DNA-damaging agents and binds preferentially to cisplatin-modified DNA (Ishiguchi et al, 2004). In this study, we show that ZNF143 is upregulated in cisplatin-resistant cells.…”

“…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).…”

“…We have previously shown that ZNF143 expression was also induced by cisplatin treatment as well as p73 (Ishiguchi et al, 2004;Uramoto et al, 2002). Thus, we employed the stable transfectant for ChIP assay to avoid the effect of the enhanced expression of endogenous ZNF143 by cisplatin treatment on the binding to the promoters.…”

“…We identified the cisplatin-inducible genes such as activating transcription factor 4 (ATF4) (Tanabe et al, 2003) and Mitochondrial ribosomal protein S11 (MRP S11) (Ishiguchi et al, 2004) using differential display (Murakami et al, 2001). ATF4 is upregulated in cisplatin-resistant cells and its expression correlates with cisplatin resistance in lung cancer (Tanabe et al, 2003).…”

DNA Topoisomerase II Poison TAS-103 Transactivates GC-Box-dependent Transcription via Acetylation of Sp1

“…These data indicate that the acetylation of Sp1 via an interaction with p300 is involved in TAS-103-induced apoptosis in cancer cells. DISCUSSION We have previously identified several transcription factors involved in genomic responses to anticancer agents including Y-box-binding protein-1 (YB-1), activating transcription factor 4 (ATF4), zinc-finger factor 143 (ZNF143), and mitochondrial transcription factor A (mtTFA) (21)(22)(23)(24). This study provides evidence to support the novel finding that Sp1 contributes to the stress response of cancer cells following treatment with anticancer agents.…”