PMID- 18719335
OWN - NLM
STAT- MEDLINE
DCOM- 20081020
LR  - 20211203
IS  - 1349-3329 (Electronic)
IS  - 0040-8727 (Linking)
VI  - 216
IP  - 1
DP  - 2008 Sep
TI  - Ras-mediated up-regulation of survivin expression in cytokine-dependent murine 
      pro-B lymphocytic cells.
PG  - 25-34
AB  - 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.
FAU - Shinjyo, Tetsuharu
AU  - Shinjyo T
AD  - Department of Endocrinology and Metabolism, University of the Ryukyus, School of 
      Medicine, Okinawa, Japan. tshinjo@ryudai2nai.com
FAU - Kurosawa, Hidemitsu
AU  - Kurosawa H
FAU - Miyagi, Jun-ichi
AU  - Miyagi J
FAU - Ohama, Kiyoto
AU  - Ohama K
FAU - Masuda, Masato
AU  - Masuda M
FAU - Nagasaki, Akitoshi
AU  - Nagasaki A
FAU - Matsui, Hirotaka
AU  - Matsui H
FAU - Inaba, Toshiya
AU  - Inaba T
FAU - Furukawa, Yusuke
AU  - Furukawa Y
FAU - Takasu, Nobuyuki
AU  - Takasu N
LA  - eng
PT  - Journal Article
PL  - Japan
TA  - Tohoku J Exp Med
JT  - The Tohoku journal of experimental medicine
JID - 0417355
RN  - 0 (Birc5 protein, mouse)
RN  - 0 (Carrier Proteins)
RN  - 0 (Chromones)
RN  - 0 (Flavonoids)
RN  - 0 (Inhibitor of Apoptosis Proteins)
RN  - 0 (Interleukin-3)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Repressor Proteins)
RN  - 0 (Survivin)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Akt1 protein, mouse)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.5.2 (Oncogene Protein p21(ras))
RN  - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects/physiology
MH  - B-Lymphocytes/drug effects/*metabolism
MH  - Carrier Proteins/physiology
MH  - Cell Cycle/physiology
MH  - Cell Line/drug effects/metabolism
MH  - Chromones/pharmacology
MH  - Enhancer Elements, Genetic
MH  - Flavonoids/pharmacology
MH  - *Gene Expression Regulation
MH  - *Genes, ras
MH  - Humans
MH  - Inhibitor of Apoptosis Proteins
MH  - Interleukin-3/pharmacology
MH  - MAP Kinase Signaling System/drug effects
MH  - Mice
MH  - Microtubule-Associated Proteins/*biosynthesis/genetics
MH  - Morpholines/pharmacology
MH  - Oncogene Protein p21(ras)/genetics/*physiology
MH  - Phosphatidylinositol 3-Kinases/physiology
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphotransferases (Alcohol Group Acceptor)/physiology
MH  - Point Mutation
MH  - Proto-Oncogene Proteins c-akt/physiology
MH  - Recombinant Fusion Proteins/physiology
MH  - Repressor Proteins
MH  - Signal Transduction/drug effects/*physiology
MH  - Sirolimus/pharmacology
MH  - Survivin
MH  - TOR Serine-Threonine Kinases
MH  - Transfection
EDAT- 2008/08/23 09:00
MHDA- 2008/10/22 09:00
CRDT- 2008/08/23 09:00
PHST- 2008/08/23 09:00 [pubmed]
PHST- 2008/10/22 09:00 [medline]
PHST- 2008/08/23 09:00 [entrez]
AID - JST.JSTAGE/tjem/216.25 [pii]
AID - 10.1620/tjem.216.25 [doi]
PST - ppublish
SO  - Tohoku J Exp Med. 2008 Sep;216(1):25-34. doi: 10.1620/tjem.216.25.