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- W2003309498 abstract "Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FLDNA damage is a hallmark of malignantly transformed cells. Accordingly, overexpression of the DNA damage activated kinases has been observed in different human cancers. However, it is unclear whether constitutive DNA damage present in unperturbed cancer cells promotes tumourigenesis.Here we show that increased activity of DNA damage sensitive kinase Chk1 promotes proliferation of several cancer cell types by stimulating expression of CIP2A protein. Either chemical or genetic inhibition of Chk1, and not of ATM-ATR, results in potent inhibition of CIP2A protein expression levels. Importantly, Chk1 siRNA-elicited inhibition of cell proliferation and clonogenic growth is rescued by overexpression of CIP2A from a heterologous promoter. Moreover, in clinical (human) tumor samples there is a significant association between CIP2A and Chk1 expression in both ovarian and gastric cancers. Intriguingly, meta-analysis of seventeen published genome wide studies on different types of cancers unveils a striking similarity in the gene expression patterns of both CIP2A and Chk1. Amongst these, 12/17 studies show overexpression (top 10%) of both these proteins. Additionally, similarly to CIP2A, increased Chk1 expression is shown to correlate with tumor progression in human cancer.In summary, these results identify a novel function for DNA damage kinase Chk1 in regulation of the human oncoprotein CIP2A. In general, these results provide an unprecented molecular mechanism by which constitutive DNA damage present in cancer cells promotes tumourigenesis. Additionally, as CIP2A is not significantly expressed in most of the normal human tissues, it is proposed that targeting of CIP2A might abrogate the Chk1-mediated support of proliferation without concerns related to anticancer therapy directly targeting Chk1.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4194. doi:10.1158/1538-7445.AM2011-4194" @default.
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- W2003309498 date "2011-04-15" @default.
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- W2003309498 title "Abstract 4194: Constitutive DNA-damage signaling promotes cancer cell proliferation through Chk1-CIP2A pathway independent of ATM-ATR" @default.
- W2003309498 doi "https://doi.org/10.1158/1538-7445.am2011-4194" @default.
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