PMID- 12861025
OWN - NLM
STAT- MEDLINE
DCOM- 20030829
LR  - 20231105
IS  - 0270-7306 (Print)
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Linking)
VI  - 23
IP  - 15
DP  - 2003 Aug
TI  - Thrombospondin 2 regulates cell proliferation induced by Rac1 redox-dependent 
      signaling.
PG  - 5401-8
AB  - Thrombospondin 2 (TSP2) is a matricellular protein controlling the 
      apoptosis-proliferation balance in endothelial cells. Little is known about its 
      transcriptional regulation compared with that of TSP1. We found that 
      overexpression of a constitutively active mutant of Rac (Rac(V12)) specifically 
      increases TSP2 mRNA levels without affecting TSP1 in human aortic endothelial 
      cells (HAEC). Moreover, TSP2 induction by Rac(V12) is dependent upon reactive 
      oxygen species (ROS) production, as gp91ds-tat peptide, an inhibitor of NADPH 
      oxidase, and the flavoprotein inhibitor diphenylene iodinium (DPI) block TSP2 
      synthesis. Furthermore, we found that increasing Rac(V12) expression results in a 
      biphasic proliferative curve, with proliferation initially increasing as Rac(V12) 
      expression increases and then returning to levels less than that of control cells 
      at higher expression. This growth inhibition is mediated by TSP2, as either DPI 
      treatment, which blocks TSP2 synthesis, or pan-TSP blocking antibodies restore 
      the proliferative ability of HAEC with high expression. Mechanistically, we show 
      that the effect of TSP2 on cell proliferation is independent of the 
      antiangiogenic TSP2 Hep1 sequence, which is capable of altering actin 
      cytoskeletal reorganization but not proliferation in our experimental conditions. 
      Finally, we show in vivo that Rac-induced TSP2 expression is observed in the 
      aorta of transgenic mice selectively expressing Rac(V12) in smooth muscle cells. 
      These results identify Rac-induced ROS as a new pathway involved in the 
      regulation of TSP2 expression.
FAU - Lopes, Neuza
AU  - Lopes N
AD  - Division of Cardiology, Department of Medicine, Duke University Medical Center, 
      Durham, NC 27710, USA.
FAU - Gregg, David
AU  - Gregg D
FAU - Vasudevan, Sanjay
AU  - Vasudevan S
FAU - Hassanain, Hamdy
AU  - Hassanain H
FAU - Goldschmidt-Clermont, Pascal
AU  - Goldschmidt-Clermont P
FAU - Kovacic, Herve
AU  - Kovacic H
LA  - eng
GR  - R01 HL071536/HL/NHLBI NIH HHS/United States
GR  - R01 HL 71536/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Actins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Onium Compounds)
RN  - 0 (RNA, Messenger)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Thrombospondins)
RN  - 0 (thrombospondin 2)
RN  - 63231-63-0 (RNA)
RN  - 6HJ411TU98 (diphenyleneiodonium)
RN  - 9007-49-2 (DNA)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 3.6.5.2 (rac1 GTP-Binding Protein)
SB  - IM
MH  - Actins/metabolism
MH  - Animals
MH  - Aorta/cytology
MH  - Apoptosis
MH  - Cell Cycle
MH  - Cell Division
MH  - Cell Line
MH  - Cells, Cultured
MH  - Cytoskeleton/metabolism
MH  - DNA/biosynthesis
MH  - Endothelium, Vascular/cytology
MH  - Enzyme Inhibitors/pharmacology
MH  - Gene Expression Regulation
MH  - Humans
MH  - Immunoblotting
MH  - Mice
MH  - Mice, Transgenic
MH  - Muscle, Smooth/cytology
MH  - NADPH Oxidases/metabolism
MH  - Onium Compounds/pharmacology
MH  - *Oxidation-Reduction
MH  - RNA/metabolism
MH  - RNA, Messenger/metabolism
MH  - Reactive Oxygen Species
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - *Signal Transduction
MH  - Thrombospondins/*physiology
MH  - Time Factors
MH  - Tissue Distribution
MH  - Transcription, Genetic
MH  - Up-Regulation
MH  - rac1 GTP-Binding Protein/*metabolism
PMC - PMC165731
EDAT- 2003/07/16 05:00
MHDA- 2003/08/30 05:00
PMCR- 2003/08/01
CRDT- 2003/07/16 05:00
PHST- 2003/07/16 05:00 [pubmed]
PHST- 2003/08/30 05:00 [medline]
PHST- 2003/07/16 05:00 [entrez]
PHST- 2003/08/01 00:00 [pmc-release]
AID - 1650 [pii]
AID - 10.1128/MCB.23.15.5401-5408.2003 [doi]
PST - ppublish
SO  - Mol Cell Biol. 2003 Aug;23(15):5401-8. doi: 10.1128/MCB.23.15.5401-5408.2003.