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Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential.

Abstract
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.
AuthorsS Semba, F Trapasso, M Fabbri, K A McCorkell, S Volinia, T Druck, D Iliopoulos, Y Pekarsky, H Ishii, P N Garrison, L D Barnes, C M Croce, K Huebner
JournalOncogene (Oncogene) Vol. 25 Issue 20 Pg. 2860-72 (May 11 2006) ISSN: 0950-9232 [Print] England
PMID16407838 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • BIRC5 protein, human
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • Neoplasm Proteins
  • RNA, Small Interfering
  • fragile histidine triad protein
  • Tyrosine
  • Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • Proto-Oncogene Proteins c-akt
  • Acid Anhydride Hydrolases
Topics
  • Acid Anhydride Hydrolases (genetics)
  • Adenoviridae (genetics)
  • Blotting, Western
  • Flow Cytometry
  • Gene Expression Profiling
  • Gene Expression Regulation (physiology)
  • Genes, Tumor Suppressor (physiology)
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Lung Neoplasms (genetics, metabolism)
  • Microtubule-Associated Proteins (genetics, metabolism)
  • Neoplasm Proteins (genetics, metabolism)
  • Oligonucleotide Array Sequence Analysis
  • Phosphatidylinositol 3-Kinases (genetics, metabolism)
  • Proto-Oncogene Proteins c-akt (genetics, metabolism)
  • RNA, Small Interfering (pharmacology)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Tumor Cells, Cultured
  • Tyrosine (genetics, metabolism)

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