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- Title
Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential.
- Authors
Semba, S.; Trapasso, F.; Fabbri, M.; McCorkell, K. A.; Volinia, S.; Druck, T.; Iliopoulos, D.; Pekarsky, Y.; Ishii, H.; Garrison, P. N.; Barnes, L. D.; Croce, C. M.; Huebner, K.
- 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.Oncogene (2006) 25, 2860–2872. doi:10.1038/sj.onc.1209323; published online 16 January 2006
- Subjects
LUNG cancer; APOPTOSIS; TUMOR suppressor genes; POLYPHOSPHATES; CANCER cells; ADENOVIRUSES; PROTEIN-tyrosine kinases
- Publication
Oncogene, 2006, Vol 25, Issue 20, p2860
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1209323