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

Autor: Nobuyuki Takasu, Tetsuharu Shinjyo, Hirotaka Matsui, Akitoshi Nagasaki, Yusuke Furukawa, Jun-ichi Miyagi, Kiyoto Ohama, Masato Masuda, Hidemitsu Kurosawa, Toshiya Inaba
Rok vydání: 2008
Předmět:
MAPK/ERK pathway
MAP Kinase Signaling System
Morpholines
Recombinant Fusion Proteins
Survivin
Apoptosis
Oncogene Protein p21(ras)
Transfection
Inhibitor of apoptosis
General Biochemistry
Genetics and Molecular Biology
Cell Line
Inhibitor of Apoptosis Proteins
Mice
Phosphatidylinositol 3-Kinases
Anti-apoptotic Ras signalling cascade
Animals
Humans
Point Mutation
Protein kinase B
PI3K/AKT/mTOR pathway
Phosphoinositide-3 Kinase Inhibitors
Flavonoids
Sirolimus
B-Lymphocytes
Chemistry
Kinase
TOR Serine-Threonine Kinases
Cell Cycle
General Medicine
Repressor Proteins
Phosphotransferases (Alcohol Group Acceptor)
Enhancer Elements
Genetic
Genes
ras
Gene Expression Regulation
Chromones
Cancer research
Interleukin-3
Signal transduction
Carrier Proteins
Microtubule-Associated Proteins
Proto-Oncogene Proteins c-akt
Signal Transduction
Zdroj: The Tohoku Journal of Experimental Medicine. 216:25-34
ISSN: 1349-3329
0040-8727
Popis: 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.
Databáze: OpenAIRE
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