| Budget Amount *help |
¥16,510,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥1,710,000)
Fiscal Year 2007: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Fiscal Year 2006: ¥9,100,000 (Direct Cost: ¥9,100,000)
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| Research Abstract |
Ubiquitination is a versatile post-translational modification mechanism used by eukaryotic cells mainly to control protein levels through proteasome-mediated proteolysis. Ubiquitin conjugation is achieved by several enzymes that act in concert, a ubiquitin-protein ligase (E3). E3 is thought to be the component of the ubiquitin conjugation system that is most directly responsible for substrate recognition. Enzymes belonging to class E3 that have so far been identified include members of the HECT (homologous to E6-AP carboxyl terminus), RING-finger and U-box families of proteins. So far; we have published many articles about ubiquitination and oncogenesis.
Tripartite motif (TRIM) proteins are characterized by the presence of a RING finger, one or two zinc-binding motifs named B-boxes and an associated coiled-coil region (BBRC357: 245, 2007; Mal Cell Biochem 307, 73, 2008; Mol Immunol 45 2045, 2008, Cancer Res, in press).
We found that the putative E3 ubiquitin ligase TRIM68, which is prefe
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rentially expressed in prostate cancer cells, interacts with androgen receptor (AR) and enhances transcriptional activity of the AR in the presence of dihydrotestosterone (DHT). Overexpression of TRIM68 in prostate cancer cells caused an increase in secretion of prostate-specific antigen (PSA), one of the most reliable diagnostic markers for prostate cancer. Moreover, we showed that TRIM68 expression is significantly upregulated in human prostate cancers (Cancer Res, in press).
Furthermore, we found by using yeast two-hybrid screening that TRIM32 binds to Abl-interactor 2 (Abi2), which is known as a tumor suppressor gene and a cell migration inhibitor Overexpression of TRIM32 promoted degradation of Abi2, resulting in enhancement of cell growth, transforming activity and cell motility In addition, we found that TRIM32 suppresses apoptosis induced by cis-diamminedichloroplatinum (II) (cDDP) in HEp2 cell lines. These findings suggest that TRIM32 is a novel oncogene that promotes tumor growth, metastasis and resistance to anti-cancer drugs. Less
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