PMID- 15047702
OWN - NLM
STAT- MEDLINE
DCOM- 20040729
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 279
IP  - 22
DP  - 2004 May 28
TI  - Mammalian target of rapamycin positively regulates collagen type I production via 
      a phosphatidylinositol 3-kinase-independent pathway.
PG  - 23166-75
AB  - The mammalian target of rapamycin (mTOR) is a multifunctional protein involved in 
      the regulation of cell growth, proliferation, and differentiation. The goal of 
      this study was to determine the role of mTOR in type I collagen regulation. The 
      pharmacological inhibitor of phosphatidylinositol (PI) 3-kinase, LY294002, 
      significantly inhibited collagen type I protein and mRNA levels. The effects of 
      LY294002 were more pronounced on the collagen alpha1(I) chain, which was 
      inhibited at the transcriptional and mRNA stability levels versus collagen 
      alpha2(I) chain, which was inhibited through a decrease in mRNA stability. In 
      contrast, addition of the PI 3-kinase inhibitor, wortmannin, did not alter type I 
      collagen steady-state mRNA levels. This observation and further experiments using 
      an inactive LY294002 analogue suggested that collagen mRNA levels are inhibited 
      independent of PI 3-kinase. Additional experiments have established that mTOR 
      positively regulates collagen type I synthesis in human fibroblasts. These 
      conclusions are based on results demonstrating that inhibition of mTOR activity 
      using a specific inhibitor, rapamycin, reduced collagen mRNA levels. Furthermore, 
      decreasing mTOR expression by about 50% by using small interfering RNA resulted 
      in a significant decrease of collagen mRNA (75% COL1A1 decrease and 28% COL1A2 
      decrease) and protein levels. Thus, mTOR plays an essential role in regulating 
      basal expression of collagen type I gene in dermal fibroblasts. Together, our 
      data suggest that the classical PI 3-kinase pathway, which places mTOR downstream 
      of PI 3-kinase, is not involved in mTOR-dependent regulation of type I collagen 
      synthesis in dermal fibroblasts. Because collagen overproduction is a main 
      feature of fibrosis, identification of mTOR as a critical mediator of its 
      regulation may provide a suitable target for drug or gene therapy.
FAU - Shegogue, Daniel
AU  - Shegogue D
AD  - Division of Rheumatology and Immunology, Medical University of South Carolina, 
      Charleston, South Carolina 29425, USA.
FAU - Trojanowska, Maria
AU  - Trojanowska M
LA  - eng
GR  - AR42334/AR/NIAMS NIH HHS/United States
GR  - AR44883/AR/NIAMS NIH HHS/United States
GR  - HL07260-25/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20040326
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Androstadienes)
RN  - 0 (Chromones)
RN  - 0 (Collagen Type I)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Cell Line
MH  - Chromones/pharmacology
MH  - Collagen Type I/*biosynthesis
MH  - Enzyme Inhibitors/pharmacology
MH  - Fibroblasts/*metabolism
MH  - Humans
MH  - Morpholines/pharmacology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Kinase Inhibitors
MH  - Protein Kinases/*metabolism
MH  - *Signal Transduction/drug effects
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Wortmannin
EDAT- 2004/03/30 05:00
MHDA- 2004/07/30 05:00
CRDT- 2004/03/30 05:00
PHST- 2004/03/30 05:00 [pubmed]
PHST- 2004/07/30 05:00 [medline]
PHST- 2004/03/30 05:00 [entrez]
AID - S0021-9258(20)66682-0 [pii]
AID - 10.1074/jbc.M401238200 [doi]
PST - ppublish
SO  - J Biol Chem. 2004 May 28;279(22):23166-75. doi: 10.1074/jbc.M401238200. Epub 2004 
      Mar 26.