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Ras-mediated Up-regulation of Survivin Expression in Cytokine-dependent Murine Pro-B Lymphocytic Cells

Authors :
Nobuyuki Takasu
Tetsuharu Shinjyo
Hirotaka Matsui
Akitoshi Nagasaki
Yusuke Furukawa
Jun-ichi Miyagi
Kiyoto Ohama
Masato Masuda
Hidemitsu Kurosawa
Toshiya Inaba
Source :
The Tohoku Journal of Experimental Medicine. 216:25-34
Publication Year :
2008
Publisher :
Tohoku University Medical Press, 2008.

Abstract

Survivin, a member of the inhibitor of apoptosis protein (IAP) family, has been widely studied because of its aberrant expression in human cancer. Survivin has multiple functions, including cell-cycle regulation at mitosis, inhibition of apoptosis and caspase-independent cytoprotection. Clinical studies have shown that survivin is associated with resistance to treatment and its expression is linked to poor prognosis. Recent studies indicated that Ras pathways up-regulate survivin expression in hematopoietic cells. Here we analyzed downstream pathways of Ras in interleukin-3 (IL-3)-dependent Baf-3 murine-derived pro-B lymphocytic cells that express constitutively active Ras mutants, using signaling pathway-specific inhibitors. Both mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3-K) pathways are involved in the induction of survivin. Downstream of PI3-K, the signaling pathway is composed of two kinases, Akt and mammalian target of rapamycin (mTOR) pathways. In the downstream targets of PI3-K, mTOR but not Akt is responsible for survivin expression. Using a counterflow centrifugal elutriator, we observed G2/M phase-dominant survivin expression in Baf-3 cells. Interestingly, constitutively active Ras mutants also induced survivin in a cell cycle-dependent manner. Reporter assays of the survivin gene promoter revealed a transcriptional regulatory cis-acting region that is responsible for Ras signaling, indicating that Ras increases the transcription of the survivin gene through specific enhancer elements. These data illustrate the pathways regulating survivin expression by Ras. Ras activates the MAPK, PI3-K and mTOR pathways, and these signals enhance survivin transcription. Our data will provide the new information about mechanisms of survivin expression by Ras-signalling pathways.

Details

ISSN :
13493329 and 00408727
Volume :
216
Database :
OpenAIRE
Journal :
The Tohoku Journal of Experimental Medicine
Accession number :
edsair.doi.dedup.....760a7cb651f9facd1adff3e7fa3bcc27
Full Text :
https://doi.org/10.1620/tjem.216.25