Fhit modulation of cell cycle progression and DMA damage response It has recently been proposedthat in early preneoplastic lesions, DNA replication stress leads tc the DNA Damage Response (DDR), which elicits growth arrest and cell death. Thus, before occurrence o-' genomic instability and transformation, cells activate DNA damage response networks that delay or prevent cancer; mutations that compromise the checkpoints, such as defects in Atm or Atr pathway proteins, allcw escape from the checkpoint block, leading to tumor progression. Importantly, for the research proposed here, the early hyperplasias showed allelic imbalance at common fragile sites, particularly the FRA3B/FH1T locus. """"""""Fragile site LOH was targeted during the period of maximal DDR and may be considered a """"""""signature"""""""" of stalled replicationforks"""""""" (Gorgoulis et at, Nature 434:907-913, 2005). The researchproposed is based on the hypothesis that loss of the Fhit tumor suppressorvery early in the preneoplastic process, coincident with activation of the DNA damage response (DDR) checkpoint, effects critical cellular processes, cell proliferation, DNA damage response and apoptosis, that can tip the tBalance toward genome instability and tumor progression. The hypothesis is based on preliminary data demonstrating that Fhit-deficient cells show altered expression of cell,cycle, DNA damage response andapoptosis associated proteins and that Fhit over-expression modulates expression of Cyclin D1, Hus1, Chk1 jind Akt/mTor/Survivin. ?; ? The goals of this project are to understand the mechanisms underlying Fhit modulation of these pathways by the following aims: 1) Examine the mechanism of Fhit down-modulation of Cyclin D1 level after infection of Fhit negsitive cells with AdenoFHIT and AdenoFHIT mutant viruses. ? 2) Determine the mechanisms through which Fhit modulates"""""""" the level of Hus1, pChkl and the CNA damage response pathway by manipulation of Fhit .expression in Fhit-deficient cells. 3) Examine the role of Fhit in induction of apoptosis after AdenoFHIT and AdenoFHIT mutant viius infection of Fhit-deficient cells and exposure to oxidative stress conditions. 4) Define the sequenceof modulation of expression of cell.cycle, DDR and apoptosis associated proteins in early oral and upper gastrointestinal tract lesions of Fhit-deficient mice before and after FHIT replacement by AdenoFHIT oral gene therapy. ,
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