Matches in SemOpenAlex for { <https://semopenalex.org/work/W1993897258> ?p ?o ?g. }
- W1993897258 endingPage "2990" @default.
- W1993897258 startingPage "2978" @default.
- W1993897258 abstract "Checkpoint kinase 1 (CHK1) is a key component of the ATR (ataxia telangiectasia-mutated and Rad3-related)-dependent DNA damage response pathway that protect cells from replication stress, a cell intrinsic phenomenon enhanced by oncogenic transformation. Here, we show that CHK1 is overexpressed and hyperactivated in T-cell acute lymphoblastic leukemia (T-ALL). CHEK1 mRNA is highly abundant in patients of the proliferative T-ALL subgroup and leukemia cells exhibit constitutively elevated levels of the replication stress marker phospho-RPA32 and the DNA damage marker γH2AX. Importantly, pharmacologic inhibition of CHK1 using PF-004777736 or CHK1 short hairpin RNA-mediated silencing impairs T-ALL cell proliferation and viability. CHK1 inactivation results in the accumulation of cells with incompletely replicated DNA, ensuing DNA damage, ATM/CHK2 activation and subsequent ATM- and caspase-3-dependent apoptosis. In contrast to normal thymocytes, primary T-ALL cells are sensitive to therapeutic doses of PF-004777736, even in the presence of stromal or interleukin-7 survival signals. Moreover, CHK1 inhibition significantly delays in vivo growth of xenotransplanted T-ALL tumors. We conclude that CHK1 is critical for T-ALL proliferation and viability by downmodulating replication stress and preventing ATM/caspase-3-dependent cell death. Pharmacologic inhibition of CHK1 may be a promising therapeutic alternative for T-ALL treatment." @default.
- W1993897258 created "2016-06-24" @default.
- W1993897258 creator A5001332107 @default.
- W1993897258 creator A5005841369 @default.
- W1993897258 creator A5020146952 @default.
- W1993897258 creator A5038469796 @default.
- W1993897258 creator A5041231390 @default.
- W1993897258 creator A5044035206 @default.
- W1993897258 creator A5051553596 @default.
- W1993897258 creator A5054255908 @default.
- W1993897258 creator A5059506499 @default.
- W1993897258 creator A5077388131 @default.
- W1993897258 creator A5079785844 @default.
- W1993897258 creator A5089692175 @default.
- W1993897258 date "2014-08-18" @default.
- W1993897258 modified "2023-10-15" @default.
- W1993897258 title "CHK1 overexpression in T-cell acute lymphoblastic leukemia is essential for proliferation and survival by preventing excessive replication stress" @default.
- W1993897258 cites W1553367038 @default.
- W1993897258 cites W1594035260 @default.
- W1993897258 cites W1966249371 @default.
- W1993897258 cites W1974249811 @default.
- W1993897258 cites W1976955442 @default.
- W1993897258 cites W1984065010 @default.
- W1993897258 cites W1994791278 @default.
- W1993897258 cites W1995766341 @default.
- W1993897258 cites W2000589976 @default.
- W1993897258 cites W2003560510 @default.
- W1993897258 cites W2004017449 @default.
- W1993897258 cites W2008440310 @default.
- W1993897258 cites W2009596701 @default.
- W1993897258 cites W2010731453 @default.
- W1993897258 cites W2011595404 @default.
- W1993897258 cites W2015061258 @default.
- W1993897258 cites W2016426158 @default.
- W1993897258 cites W2018684077 @default.
- W1993897258 cites W2024231564 @default.
- W1993897258 cites W2030646897 @default.
- W1993897258 cites W2033983791 @default.
- W1993897258 cites W2039433529 @default.
- W1993897258 cites W2039616075 @default.
- W1993897258 cites W2043034924 @default.
- W1993897258 cites W2043895957 @default.
- W1993897258 cites W2050104597 @default.
- W1993897258 cites W2059971436 @default.
- W1993897258 cites W2063124444 @default.
- W1993897258 cites W2065434335 @default.
- W1993897258 cites W2067693418 @default.
- W1993897258 cites W2075707444 @default.
- W1993897258 cites W2076406418 @default.
- W1993897258 cites W2078842115 @default.
- W1993897258 cites W2082018870 @default.
- W1993897258 cites W2082559623 @default.
- W1993897258 cites W2082861064 @default.
- W1993897258 cites W2083101590 @default.
- W1993897258 cites W2087369559 @default.
- W1993897258 cites W2099673075 @default.
- W1993897258 cites W2101930901 @default.
- W1993897258 cites W2105435030 @default.
- W1993897258 cites W2116468279 @default.
- W1993897258 cites W2116675584 @default.
- W1993897258 cites W2116964110 @default.
- W1993897258 cites W2123366765 @default.
- W1993897258 cites W2130003099 @default.
- W1993897258 cites W2131607964 @default.
- W1993897258 cites W2134493631 @default.
- W1993897258 cites W2135946515 @default.
- W1993897258 cites W2140154966 @default.
- W1993897258 cites W2145264022 @default.
- W1993897258 cites W2149795092 @default.
- W1993897258 cites W2152057278 @default.
- W1993897258 cites W2154141161 @default.
- W1993897258 cites W2160538256 @default.
- W1993897258 cites W2163018106 @default.
- W1993897258 cites W2163280499 @default.
- W1993897258 cites W2164660906 @default.
- W1993897258 cites W2167196101 @default.
- W1993897258 cites W4248537801 @default.
- W1993897258 doi "https://doi.org/10.1038/onc.2014.248" @default.
- W1993897258 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/25132270" @default.
- W1993897258 hasPublicationYear "2014" @default.
- W1993897258 type Work @default.
- W1993897258 sameAs 1993897258 @default.
- W1993897258 citedByCount "56" @default.
- W1993897258 countsByYear W19938972582015 @default.
- W1993897258 countsByYear W19938972582016 @default.
- W1993897258 countsByYear W19938972582017 @default.
- W1993897258 countsByYear W19938972582018 @default.
- W1993897258 countsByYear W19938972582019 @default.
- W1993897258 countsByYear W19938972582020 @default.
- W1993897258 countsByYear W19938972582021 @default.
- W1993897258 countsByYear W19938972582022 @default.
- W1993897258 countsByYear W19938972582023 @default.
- W1993897258 crossrefType "journal-article" @default.
- W1993897258 hasAuthorship W1993897258A5001332107 @default.
- W1993897258 hasAuthorship W1993897258A5005841369 @default.
- W1993897258 hasAuthorship W1993897258A5020146952 @default.
- W1993897258 hasAuthorship W1993897258A5038469796 @default.
- W1993897258 hasAuthorship W1993897258A5041231390 @default.