PMID- 17114809
OWN - NLM
STAT- MEDLINE
DCOM- 20070307
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 282
IP  - 2
DP  - 2007 Jan 12
TI  - Tumor necrosis factor-alpha-stimulated cell proliferation is mediated through 
      sphingosine kinase-dependent Akt activation and cyclin D expression.
PG  - 863-70
AB  - Tumor necrosis factor-alpha (TNF-alpha) has been shown to activate sphingosine 
      kinase (SphK) in a variety of cell types. The extent to which SphK signaling 
      mediates the pleiotropic effects of TNF-alpha is not entirely clear. The current 
      study examined the role of SphK activity in TNF-alpha-stimulated cell 
      proliferation in 1321N1 glioblastoma cells. We first demonstrated that 
      pharmacological inhibitors of SphK markedly decrease TNF-alpha-stimulated DNA 
      synthesis. Signaling mechanisms through which SphK mediated the effect of 
      TNF-alpha on DNA synthesis were then examined. Inhibition of Rho proteins with C3 
      exoenzyme or of Rho kinase with Y27632 attenuated TNF-alpha-stimulated DNA 
      synthesis. However, RhoA activation by TNF-alpha was not blocked by SphK 
      inhibition. ERK activation was also required for TNF-alpha-stimulated DNA 
      synthesis but likewise TNF-alpha-induced ERK activation was not blocked by 
      inhibition of SphK. Thus, neither RhoA nor ERK activation are the SphK-dependent 
      transducers of TNF-alpha-induced proliferation. In contrast, TNF-alpha-stimulated 
      Akt phosphorylation, which was also required for DNA synthesis, was attenuated by 
      SphK inhibition or SphK1 knockdown by small interfering RNA. Furthermore, cyclin 
      D expression was increased by TNF-alpha in a SphK- and Akt-dependent manner. 
      Additional studies demonstrated that TNF-alpha effects on DNA synthesis, ERK, and 
      Akt phosphorylation are not mediated through cell surface Gi -coupled S1P 
      receptors, because none of these responses were inhibited by pertussis toxin. We 
      conclude that SphK-dependent Akt activation plays a significant role in 
      TNF-alpha-induced cyclin D expression and cell proliferation.
FAU - Radeff-Huang, Julie
AU  - Radeff-Huang J
AD  - Department of Pharmacology, University of California, San Diego, La Jolla, 
      California 92093, USA.
FAU - Seasholtz, Tammy M
AU  - Seasholtz TM
FAU - Chang, Jenny W
AU  - Chang JW
FAU - Smith, Jeffrey M
AU  - Smith JM
FAU - Walsh, Colin T
AU  - Walsh CT
FAU - Brown, Joan Heller
AU  - Brown JH
LA  - eng
GR  - GM36927/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20061119
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Cyclin D)
RN  - 0 (Cyclins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Receptors, Lysosphingolipid)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 9007-49-2 (DNA)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.- (sphingosine kinase)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.6.5.2 (rho GTP-Binding Proteins)
SB  - IM
MH  - Brain Neoplasms
MH  - Cell Division/drug effects/physiology
MH  - Cell Line, Tumor
MH  - Cyclin D
MH  - Cyclins/*metabolism
MH  - DNA/biosynthesis
MH  - Enzyme Activation/drug effects/physiology
MH  - Glioblastoma
MH  - Humans
MH  - Phosphotransferases (Alcohol Group Acceptor)/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - RNA, Small Interfering
MH  - Receptors, Cell Surface/metabolism
MH  - Receptors, Lysosphingolipid/metabolism
MH  - Signal Transduction/drug effects/*physiology
MH  - Tumor Necrosis Factor-alpha/*metabolism/pharmacology
MH  - rho GTP-Binding Proteins/metabolism
EDAT- 2006/11/23 09:00
MHDA- 2007/03/08 09:00
CRDT- 2006/11/23 09:00
PHST- 2006/11/23 09:00 [pubmed]
PHST- 2007/03/08 09:00 [medline]
PHST- 2006/11/23 09:00 [entrez]
AID - S0021-9258(20)73511-8 [pii]
AID - 10.1074/jbc.M601698200 [doi]
PST - ppublish
SO  - J Biol Chem. 2007 Jan 12;282(2):863-70. doi: 10.1074/jbc.M601698200. Epub 2006 
      Nov 19.