| Project/Area Number |
17K14983
|
|---|
| Research Category |
Grant-in-Aid for Young Scientists (B)
|
| Allocation Type | Multi-year Fund |
|---|
| Research Field |
Tumor biology
|
|---|
| Research Institution | Chiba University |
|---|
Principal Investigator |
Mano Yasunobu 千葉大学, 大学院医学研究院, 特任助教 (80577362)
|
|---|
| Research Collaborator |
MATSUSAKA Keisuke
OKABE Atsushi
FUKUYO Masaki
|
|---|
| Project Period (FY) |
2017-04-01 – 2019-03-31
|
| Project Status |
Completed (Fiscal Year 2018)
|
| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
|
|---|
| Keywords | 癌 / 早期細胞老化 / Notchシグナル / 細胞老化 / 老化 |
|---|
| Outline of Final Research Achievements |
Premature senescence is known as a potent tumor suppressive mechanism that can be triggered by various stresses such as oncogene activation, oxidative stress, and DNA damage. Disruption of premature senescence by genetic and epigenetic aberrations can contribute to tumor progression, but its mechanism is not clear. To identify the molecular mechanism of Ras/Raf-induced senescence, we here performed RNA-Seq and ChIP-Seq analysis focusing JAG1 gene, a ligand in Notch signaling pathway. As a result, JAG1 knockdown caused repression of p21 and p15, leading to bypass of Ras/Raf-induced senescence. In contrast, overexpression of JAG1 could induce senescence via p21 and p15 activation in normal cells. These results suggest that activation of JAG1-Notch signaling plays an important role mediated by up-regulating p21 and p15 in Ras/Raf-induced senescence. We also identify that normal cells were induced senescence in co-culture of JAG1-activated cells and normal cells.
|
| Academic Significance and Societal Importance of the Research Achievements |
Notchシグナルは、発生、分化、増殖などの様々な細胞の運命決定において重要な役割を果たす事が知られている。癌においては、Notchシグナルは発癌性及び抗腫瘍性の両面性を持つ可能性が示唆されているが、今回の解析によって正常線維芽細胞においては、Notchシグナルの活性化が老化を誘導する事が明らかとなった。またNotchシグナル活性化細胞と正常細胞を共培養する事で、周囲の正常細胞にも老化が誘導される事を見出した。この様なNotchシグナルの機能は、癌細胞(自身の早期細胞老化誘導機構が破綻した細胞)の転移・浸潤機構にも関与している可能性があり、今後の研究の発展が期待される。
|
