| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Human papillomavirus(HPV) is thought to have a causal role in cervical carcinogenesis. Approximately, in 95% of cervical cancer tissues, infection of HPV in found by wing DNA extracted from cancer tissues. HPV type 16 is the type of HPV most frequently identified from allover cervical cancer tissues, while HPV type 18 is the HPV type most frequently found in cervical adeno carcinoma, which represent about 10-20% of cervical cancer. Cervical adenocarcinoma is known to occur in younger women comparing with squamous cell carcinoma and to have poorer prognosis than squamous cell carcinoma. Given that each types of HPV infect to the cervical epithelia at the same age, HPV type 18 is thought to have stronger transforming ability than HPV type 16. HPV has two oncogenes, E6 and E7. E7 oncoprotein interacts with tumor suppressor pRb. While E6 oncoprotein interacts with tumor suppresser p53, it also degrade p53 through the ubiquitin-mediated pathway depending on the expression of E6AP, the cellu
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lar ubiquitin-protein ligase. Dr.Shunsuke Nakagawa, who is a member of this research, identified a new tumor suppressor protein human Scribble. Human Scribble is a human homologue of Drosophila tumor suppressor protein, which has a role in control of cellular apical-basolateral polarity. Loss of scribble mutation leads to the disruption of epithelial polarity and overgrowth of epithelia. Hunan Scribble has almost equivalent protein structure to its Drosophila homologue. The expression of human Scribble in Drosophila scribble mutant recovers phenotype of loss of cellular polarity and overgrowth of epithelia. These results indicate that human Scribble has a role in suppression of tumorgenesis. We tried to identify a new tumor suppressor protein related to the development of cervical adenocarcinoma. We identified the product of dbc-1(deleted in breast cancer-1) gene, which localizes on 8p21 and is frequently deleted among breast cancers, as a now ubiqituin-mediated degradation target of E6 oncoprotein. DBC1 possesses a Leucine Zipper domain, E6 binding consensus motif and a Ca binding EF-hand motif. DBC-1 bound with both low risk type E6, type 11, and with high risk E6s, type 16 and 18, but the binding with low risk 11E6 was weaker than with high risk 16 and 18E6. We also revealed that E6 oncoprotein degrades DBC-1 in the presence of E6AP. DBC-1 localized in nucleus, but concentrated on mitochondria during apoptosis.
Our data suggest the possibility that degradation of DBC-1 by E6-E6AP might have some effect on the apoptotic signal pathway in mitochondria, which takes part in the cervical carcinogenesis Less
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