Aminothiol WR1065 induces differential gene expression in the presence of wild-type p53

Abstract

The aminothiol WR1065 exerts selective cytoprotective effects in normal cells compared to cancer cells and has clinical applications for the protection of normal cells in cancer patients undergoing radio-or chemotherapy. There is evidence that p53 is activated in response to WR1065. To examine the effects of WR1065 on the signalling pathways controlled by p53, isogeneic human colon carcinoma cell lines (HCT116) differing only in the presence or absence of wild-type p53 were used. Treatment with WR1065 resulted in G1 cell cycle arrest in the p53-positive cell line but not in the p53-negative cell line. Long-term exposure resulted in minimal apoptosis of either cell line. Changes in gene expression in p53-positive or -negative cells treated with WR1065 were examined using commercial human stress and cancer gene arrays (Clontech Atlas arrays). Genes found to be specifically upregulated in a p53-dependent manner included coproporphyrinogen oxidase, ICErel-II cysteine protease, macrophage inhibitory cytokine-1 (also known as placental transforming growth factor beta), S100A4, and Waf1/ p21. However, most proapoptotic genes typically upregulated by p53 in response to DNA damage were not activated. These studies show that WR1065 specifically modulates a subset of p53 target genes in a colon carcinoma cell line, consistent with the observation that this agent elicits essentially p53-dependent, cell cycle arrest responses.

Improving gene set analysis of microarray data by SAM-GS

“…It catalyzes a rate-limiting step in heme biosynthesis and may contribute to mitochondrial redox balance. It has recently been shown to be regulated by p53 [15]. Finally, the Wnt and p53 pathways have also been shown to be linked via pro-apoptotic Dkk1, a wnt antagonist [16].…”

The TGF-β superfamily cytokine, MIC-1/GDF15: A pleotrophic cytokine with roles in inflammation, cancer and metabolism

“…Since then many in vitro studies have demonstrated the strong relationship of MIC-1/ GDF15 expression with p53 pathway activation and the modulation of molecules with tumour growth regulatory effects (Baek et al 2002;Yang et al 2003;Eling et al 2006;Kadara et al 2006;Zimmers et al 2006;Osada et al 2007). MIC-1/GDF15 expression is also regulated by a number of other pathways (Mann and Hainaut 2005;Schmittgen et al 2005). Where the p53 pathway is mutated, Egr-1 and NFkB pathways up-regulate MIC-1/ GDF15 (Shim and Eling 2005).…”

S100 family signaling network and related proteins in pancreatic cancer (Review)

“…For example, S100A11 has been shown to be involved since TGF-β induces S100A11 gene expression and translocation into the nucleus, where it interacts with p21/WaF1 (56,57). S100A4 target genes comprise p21/WAF, Bax, thrombospondin-1 and MDM2 (16,58,59). S100 proteins: role in the degradation of the extracellular matrix (ECM) and metastasis.…”