| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Research Abstract |
Nuclear stabilization of β-catenin and its interaction with TCF/LEF factors are key events in transduction of the Wnt/ β-catenin signal pathway. We show here that β-catenin can directly induce transcription from the TCF4 promoter, the effect being enhanced by the p300 coactivator. In clinical cases, nuclear β-catenin accumulation was found to frequently overlap with TCF4 immunoreactivity in morules and surrounding glandular carcinoma lesions, showing a significant positive correlation (r=0.82, p<0.0001), in contrast to areas of squamous metaplasia (SqM) within Em Cas. The TCF4 promoter contains a single consensus TCF binding site that is critical for activation by β-catenin. The p300 coactivator appears sufficient to enhance β-catenin-dependent transcription, again with TCF4-dependence, indicating that a positive feedback loop of TCF4 expression mediated by β-catenin/p300 may be important for initial steps during trans-differentiation of Em Ca cells. In addition, transcriptional activation of p16^<INK4A> promoter by active form β-catenin occurred in a TCF4-independent manner. Moreover, cell proliferation was accompanied with phosphorylation of pRb and increased p16^<INK4A>, expression, while its inhibition by serum starvation caused decreased expression of total pRb but not p16^<INK4A>, resulting in high relative amounts of the latter, indicating that induction of p16^<INK4A> mediated by nuclear β-catenin and p21^<WAF1>, along with loss of pRb expression, may be important for initial steps during trans-differentiation of Em Ca cells.
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