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Perception and transduction of salt stress signals are critical for plant survival, growth, and propagation. Thus, identification of components of the salt stress-signaling pathway is important for rice () molecular breeding of salt stress resistance. Here, we report the identification of an apetala2/ethylene response factor transcription factor INDETERMINATE SPIKELET1 (IDS1) and its roles in the regulation of rice salt tolerance. By genetic screening and phenotype analysis, we demonstrated that IDS1 conferred transcriptional repression activity and acted as a negative regulator of salt tolerance in rice. To identify potential downstream target genes regulated by IDS1, we conducted chromatin immunoprecipitation (ChIP) sequencing and ChIP-quantitative PCR assays and found that IDS1 may directly associate with the GCC-box-containing motifs in the promoter regions of abiotic stress-responsive genes, including () and (), which are key genes regulating rice salt tolerance. IDS1 physically interacted with the transcriptional corepressor topless-related 1 and the histone deacetylase HDA1, contributing to the repression of and expression. Analyses of histone H3 acetylation status and RNA polymerase II occupation on the promoters of and further defined the molecular foundation of the transcriptional repression activity of IDS1. Our findings illustrate an epigenetic mechanism by which IDS1 modulates salt stress signaling as well as salt tolerance in rice.

Gemcitabine is widely used for pancreatic, lung, and bladder cancer. However, drug resistance against gemcitabine is a large obstacle to effective chemotherapy. Nucleoside transporters, nucleoside and nucleotide metabolic enzymes, and efflux transporters have been reported to be involved in gemcitabine resistance. Although most of the resistant factors are supposed to be related to each other, it is unclear how one factor can affect the other one. In this study, we established gemcitabine-resistant pancreatic cancer cell lines. Gemcitabine resistance in these cells is caused by two major processes: a decrease in gemcitabine uptake and overexpression of ribonucleotide reductase large subunit (RRM1). Knockdown of RRM1, but not the overexpression of concentrative nucleoside transporter 1 (CNT1), could completely overcome the gemcitabine resistance. RRM1 knockdown in gemcitabine-resistant cells could increase the intracellular accumulation of gemcitabine by increasing the nucleoside transporter expression. Furthermore, a synergistic effect was observed between hydroxyurea, a ribonucleotide reductase (RR) inhibitor, and gemcitabine on the gemcitabine-resistant cells. Here we indicate that RR is one of the most promising targets to overcome gemcitabine resistance in gemcitabine-resistant cells with dual resistant factors.

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5-Fluorouracil (5-FU) is one of the most commonly used anticancer drugs in chemotherapy against various solid tumors. 5-FU dose-dependently increased the expression levels of intrinsic antiangiogenic factor thrombospondin-1 (TSP-1) in human colon carcinoma KM12C cells and human breast cancer MCF7 cells. We investigated the molecular basis for the induction of TSP-1 by 5-FU in KM12C cells. Promoter assays showed that the region with the Egr-1 binding site is critical for the induction of TSP-1 promoter activity by 5-FU. The binding of Egr-1 to the TSP-1 promoter was increased in KM12C cells treated with 5-FU. Immunofluorescence staining revealed that 5-FU significantly increased the level of Egr-1 in the nuclei of KM12C cells. The suppression of Egr-1 expression by small interfering RNA decreased the expression level of TSP-1. Furthermore, 5-FU induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and heat shock protein 27 (HSP27). Blockade of the p38 MAPK pathway by SB203580 remarkably inhibited the phosphorylation of HSP27 induced by 5-FU and decreased the induction of Egr-1 and TSP-1 by 5-FU in KM12C cells. These findings suggest that the p38 MAPK pathway plays a crucial role in the induction of Egr-1 by 5-FU and that induced Egr-1 augments TSP-1 promoter activity, with the subsequent production of TSP-1 mRNA and protein. [Cancer Res 2008;68(17):7035-41]