Title |
RNA-Binding Protein Musashi1 Modulates Glioma Cell Growth through the Post-Transcriptional Regulation of Notch and PI3 Kinase/Akt Signaling Pathways
|
---|---|
Published in |
PLOS ONE, March 2012
|
DOI | 10.1371/journal.pone.0033431 |
Pubmed ID | |
Authors |
Jun Muto, Takao Imai, Daisuke Ogawa, Yoshinori Nishimoto, Yohei Okada, Yo Mabuchi, Takeshi Kawase, Akio Iwanami, Paul S. Mischel, Hideyuki Saya, Kazunari Yoshida, Yumi Matsuzaki, Hideyuki Okano |
Abstract |
Musashi1 (MSI1) is an RNA-binding protein that plays critical roles in nervous-system development and stem-cell self-renewal. Here, we examined its role in the progression of glioma. Short hairpin RNA (shRNA)-based MSI1-knock down (KD) in glioblastoma and medulloblastoma cells resulted in a significantly lower number of self renewing colony on day 30 (a 65% reduction), compared with non-silencing shRNA-treated control cells, indicative of an inhibitory effect of MSI1-KD on tumor cell growth and survival. Immunocytochemical staining of the MSI1-KD glioblastoma cells indicated that they ectopically expressed metaphase markers. In addition, a 2.2-fold increase in the number of MSI1-KD cells in the G2/M phase was observed. Thus, MSI1-KD caused the prolongation of mitosis and reduced the cell survival, although the expression of activated Caspase-3 was unaltered. We further showed that MSI1-KD glioblastoma cells xenografted into the brains of NOD/SCID mice formed tumors that were 96.6% smaller, as measured by a bioluminescence imaging system (BLI), than non-KD cells, and the host survival was longer (49.3±6.1 days vs. 33.6±3.6 days; P<0.01). These findings and other cell biological analyses suggested that the reduction of MSI1 in glioma cells prolonged the cell cycle by inducing the accumulation of Cyclin B1. Furthermore, MSI1-KD reduced the activities of the Notch and PI(3) kinase-Akt signaling pathways, through the up-regulation of Numb and PTEN, respectively. Exposure of glioma cells to chemical inhibitors of these pathways reduced the number of spheres and living cells, as did MSI1-KD. These results suggest that MSI1 increases the growth and/or survival of certain types of glioma cells by promoting the activation of both Notch and PI(3) kinase/Akt signaling. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Brazil | 1 | 2% |
Unknown | 63 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 14 | 22% |
Researcher | 11 | 17% |
Student > Doctoral Student | 6 | 9% |
Student > Master | 6 | 9% |
Student > Bachelor | 5 | 8% |
Other | 12 | 19% |
Unknown | 10 | 16% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 25 | 39% |
Medicine and Dentistry | 14 | 22% |
Biochemistry, Genetics and Molecular Biology | 10 | 16% |
Chemistry | 3 | 5% |
Neuroscience | 1 | 2% |
Other | 1 | 2% |
Unknown | 10 | 16% |