2019 Fiscal Year Final Research Report
A better understanding of p53 network for cancer therapy
| Project/Area Number |
16K07122
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Tumor biology
|
|---|
| Research Institution | Sapporo Medical University |
|---|
Principal Investigator |
|
|---|
| Project Period (FY) |
2016-04-01 – 2020-03-31
|
| Keywords | p53 / がん抑制遺伝子 |
|---|
| Outline of Final Research Achievements |
p53 is one of the most important tumor suppressor genes. Thus, understanding p53 network is an important issue. In this study, we identified BRMS1L and ARVCF as novel p53-target genes. Functional analysis showed that ectopic expression of BRMS1L inhibited cancer cell invasion and migration; knockdown of BRMS1L by siRNA induced the opposite effects. Importantly, clinical databases revealed that reduced BRMS1L expression correlated with poor prognosis in patients with breast and brain cancer. We found that BRMS1L is one of the mediators downstream of the p53 pathway, such as p21 activation and survivin suppression. We also revealed the knockdown of ARVCF inhibited p53-induced apoptosis. Our results suggest that p53-induced ARVCF indirectly, but not directly, regulates p53 target selectivity through splicing alterations of specific genes. Our study indicates that BRMS1L and ARVCF are involved in tumor suppression, and could be therapeutic targets for human cancer.
|
| Free Research Field |
腫瘍生物学
|
| Academic Significance and Societal Importance of the Research Achievements |
新規p53標的としてBRMS1L，ARVCFを同定した．BRMS1Lは転移抑制遺伝子BRMS1, mSds3とファミリを形成しているが，その差異については不明な点が多かった．本研究で，BRMS1Lがp53経路とつながったことで，p53による腫瘍細胞の浸潤・遊走抑制におけるメカニズムの解明が進むことが期待できる．また，ARVCFの機能について，細胞接着・運動および選択的mRNAスプライシングへの関与が報告されていた．本研究において，ARVCFがp53誘導性細胞死およびp53変異をもつ患者の予後不良・生存率低下に関与していることが示された．ARVCFは新しいがん治療標的になる可能性がある．
|
