| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
Our purpose is to elucidate the mechanism of acquisition of cancer cell invasiveness during tumor progression. Previously we found that a small GTPase, Arf6, and its effector, AMAP1, both play pivotal roles in the invasiveness of different breast cancer cells. We also showed that protein expression of Arf6 and AMAP1 in breast cancer cells correlate well with their invasive phenotypes, while expression in non-invasive cells and normal mammary epithelia is marginal.
During this research period, we obtained the following results:
1. Study of the molecular mechanisms regulating protein levels of Arf6 and AMAP1 in highly invasive breast cancer cells.
Arf6 and AMAP1 were ubiquitinated, but there was no correlation between their ubiquitination and their protein levels. On the other hand, in MDA-MB-231, AMAP1 protein levels were found to be translationally regulated through the mTOR pathway. We also found that AMAP1 is monoubiquitinated by Cbl and provide evidence that the ability of AMAP1 to be monoubiquitinated is important for its involvement in invasion.
2. Clarification of the signaling mechanisms of Arf6 activation in tumor invasion.
Expression or overexpression of several growth factor receptors, such as EGFR, ErbB2, and c-Met, often correlate with invasion and metastasis of different types of tumors. We identified that GEP100, but not other guanine nucleotide exchanging factors for Arf GTPases, is responsible for Arf6 activation to induce tumor invasion. GEP100 bound directly to phosphorylated EGFR to activate Arf6. Interfaces involved in the binding of GEP100 and EGFR may provide drug targets for tumor therapeutics.
3. Analysis of the correlation of the Arf6/AMAP1 pathway with invasiveness in other tumors.
We found that Arf6/AMAP1 signaling is also employed in the invasion of several kinds of cancer cell lines, derived from glioblastomas and lung tumors. We are now planning to perform immunohistochemical analyses of surgical specimens of these tumors.
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