| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
1)ARF-mediated p53-independent tumor suppression occurs in part through BCL6.
The ARF tumor' suppressor gene antagonizes generation of various tumors. ARF-mediated tumor suppression occurs in a p53-independent manner as well as in a p53-dependent manner. In this study, we demonstrate that BCL6 is a target of the ARF tumor suppressor. Either mouse p19^<ARF> or human p14^<ARF> binds to BCL6 and downregulates BCL6-induced transcriptional repression. The N-terminal 37 amino acids of p19^<ARF> are necessary and sufficient for ARF-mediated downregulation of BCL6 transcriptional repression. Thus, we have concluded that ARF-mediated downregulation of the BCL6 activity may account in part for ARF-mediated tumor suppression. In addition, we have found that Bax is the main mediator of ARF-induced p53-independent apoptosis.
2)p53-independent apoptosis induced by ik3-1/ik3-2 is mediated in part by mediated by CR.
CR(Cdc7 expression repressor)/periphilin has been originally cloned as an interactor with periplakin, a precursor of the cornified cell envelope, and suggested to constitute a new type of nuclear matrix. We have found that CR/periphilin is a ubiquitously expressed nuclear protein with speckled distribution. Overexpression of CR/periphiilin induces S-phase arrest. Analysis of expression of regulators involved in DNA replication, has revealed that both mRNA and protein expression of Cdc7, a regulator of the initiation and continuation of DNA replication, are markedly downregulated by overexpression of CR/periphilin. In addition, we have found that CR associates with histone deacetylase I and mSin3A that act as co-reppressors for various transcriptional reppressors, suggesting that CR is also a co-repressor. In conclusion, it appears that CR mediates p53-independent apoptosis induced by ik3-1/ik3-2 by acting as a transcriptional co-repressor.
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