Gene Set: GALI_TP53_TARGETS_APOPTOTIC_DN

Standard name GALI_TP53_TARGETS_APOPTOTIC_DN
Systematic name M17309
Brief description Apoptosis genes down-regulated by TP53 [GeneID=7157] in HCT116 cells (colon cancer) treated with thymoquinone [PubChem=10281].
Full description or abstract There are few reports describing the role of p53-dependent gene repression in apoptotic cell death. To identify such apoptosis-associated p53 target genes, we used the pro-oxidant plant-derived drug thymoquinone and compared p53+/+ and p53-/- colon cancer cells HCT116. The p53 wild-type (wt) status correlated with more pronounced DNA damage and higher apoptosis after thymoquinone treatment. A significant up-regulation of the survival gene CHEK1 was observed in p53-/- cells in response to thymoquinone due to the lack of transcriptional repression of p53. In p53-/- cells, transfection with p53-wt vector and CHEK1 small interfering RNA treatment decreased CHEK1 mRNA and protein levels and restored apoptosis to the levels of the p53+/+ cells. p53-/- cells transplanted to nude mice treated with thymoquinone up-regulated CHEK1 expression and did not undergo apoptosis unlike p53+/+ cells. Immunofluorescence analysis revealed that the apoptosis resistance in p53-/- cells after thymoquinone treatment might be conveyed by shuttling of CHEK1 into the nucleus. We confirmed the in vivo existence of this CHEK1/p53 link in human colorectal cancer, showing that tumors lacking p53 had higher levels of CHEK1, which was accompanied by poorer apoptosis. CHEK1 overexpression was correlated with advanced tumor stages (P = 0.03), proximal tumor localization (P = 0.02), and worse prognosis (1.9-fold risk, univariate Cox regression; Kaplan-Meier, P = 0.04). We suggest that the inhibition of the stress response sensor CHEK1 might contribute to the antineoplastic activity of specific DNA-damaging drugs.
Collection C2: curated gene sets
      CGP: chemical and genetic perturbations
Source publication Pubmed 18632613   Authors: Gali-Muhtasib H,Kuester D,Mawrin C,Bajbouj K,Diestel A,Ocker M,Habold C,Foltzer-Jourdainne C,Schoenfeld P,Peters B,Diab-Assaf M,Pommrich U,Itani W,Lippert H,Roessner A,Schneider-Stock R
Exact source Table 1S: p53 repressed
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Organism Homo sapiens
Contributed by Jessica Robertson (Broad Institute)
Source platform SEQ_ACCESSION
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