STANDARD_NAME	SEMBA_FHIT_TARGETS_DN
SYSTEMATIC_NAME	M10504
COLLECTION	C2:CGP
MSIGDB_URL	https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/SEMBA_FHIT_TARGETS_DN
NAMESPACE	HUMAN_SEQ_ACCESSION
DESCRIPTION_BRIEF	Genes down-regulated in H1299 cells (non-small cell lung cancer, NSCLC) expressing the Y144F mutant form of FHIT [GeneID=2272].
DESCRIPTION_FULL	The Fhit tumor suppressor binds and hydrolyses diadenosine polyphosphates and the Fhit-substrate complex has been proposed as a proapoptotic effector, as determined by infection of susceptible cancer cells with adenoviruses carrying wild-type fragile histidine triad (FHIT) or catalytic site mutants. The highly conserved Fhit tyrosine 114 (Y114), within the unstructured loop C-terminal of the catalytic site, can be phosphorylated by Src family tyrosine kinases, although endogenous phospho-Fhit is rarely detected. To explore the importance of Y114 and identify Fhit-mediated signaling events, wild-type and Y114 mutant FHIT-expressing adenoviruses were introduced into two human lung cancer cell lines. Caspase-dependent apoptosis was effectively induced only by wild-type but not Y114 mutant Fhit proteins. By expression profiling of FHIT versus mutant FHIT-infected cells, we found that survivin, an Inhibitor of Apoptosis Protein (IAP) family member, was significantly decreased by wild-type Fhit. In addition, Fhit inhibited activity of Akt, a key effector in the phosphatidylinositol 3-OH kinase (PI3K) pathway; loss of endogenous Fhit expression caused increased Akt activity in vitro and in vivo, and overexpression of constitutively active Akt inhibited Fhit-induced apoptosis. The results indicate that the Fhit Y114 residue plays a critical role in Fhit-induced apoptosis, occurring through inactivation of the PI3K-Akt-survivin signal pathway.
PMID	16407838
GEOID	
AUTHORS	Semba S,Trapasso F,Fabbri M,McCorkell KA,Volinia S,Druck T,Iliopoulos D,Pekarsky Y,Ishii H,Garrison PN,Barnes LD,Croce CM,Huebner K
CONTRIBUTOR	Leona Saunders
CONTRIBUTOR_ORG	MSigDB Team
EXACT_SOURCE	Table 1: Fold change < 1
FILTERED_BY_SIMILARITY	
EXTERNAL_NAMES_FOR_SIMILAR_TERMS	
EXTERNAL_DETAILS_URL	
SOURCE_MEMBERS	BC019922,NM_001168,NM_006461,NM_012145,NM_014264,NM_016343,NM_017882,NM_018098,NM_018136,NM_018365
GENE_SYMBOLS	ZNF252P,BIRC5,SPAG5,DTYMK,PLK4,CENPF,CLN6,ECT2,ASPM,MNS1
FOUNDER_NAMES