PMID- 20019183
OWN - NLM
STAT- MEDLINE
DCOM- 20100315
LR  - 20211203
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Print)
IS  - 0002-9440 (Linking)
VI  - 176
IP  - 1
DP  - 2010 Jan
TI  - Mammalian target of rapamycin (mTOR) induces proliferation and de-differentiation 
      responses to three coordinate pathophysiologic stimuli (mechanical strain, 
      hypoxia, and extracellular matrix remodeling) in rat bladder smooth muscle.
PG  - 304-19
LID - 10.2353/ajpath.2010.080834 [doi]
AB  - Maladaptive bladder muscle overgrowth and de-differentiation in human bladder 
      obstructive conditions is instigated by coordinate responses to three stimuli: 
      mechanical strain, tissue hypoxia, and extracellular matrix remodeling.( 1,2) 
      Pathway analysis of genes induced by obstructive models of injury in bladder 
      smooth muscle cells (BSMCs) identified a mammalian target of rapamycin 
      (mTOR)-specific inhibitor as a potential pharmacological inhibitor. 
      Strain-induced mTOR-specific S6K activation segregated differently from ERK1/2 
      activation in intact bladder ex vivo. Though rapamycin's antiproliferative 
      effects in vascular smooth muscle cells are well known, its effects on BSMCs were 
      previously unknown. Rapamycin significantly inhibited proliferation of BSMCs in 
      response to mechanical strain, hypoxia, and denatured collagen. Rapamycin 
      inhibited S6K at mTOR-sensitive phosphorylation sites in response to strain and 
      hypoxia. Rapamycin also supported smooth muscle actin expression in response to 
      strain or hypoxia-induced de-differentiation. Importantly, strain plus hypoxia 
      synergistically augmented mTOR-dependent S6K activation, Mmp7 expression and 
      proliferation. Forced expression of wild-type and constitutively active S6K 
      resulted in loss of smooth muscle actin expression. Decreased smooth muscle 
      actin, increased Mmp7 levels and mTOR pathway activation during in vivo partial 
      bladder obstruction paralleled our in vitro studies. These results point to a 
      coordinate role for mTOR in BSMCs responses to the three stimuli and a potential 
      new therapeutic target for myopathic bladder disease.
FAU - Aitken, Karen J
AU  - Aitken KJ
AD  - Developmental & Stem Cell Biology, The Hospital For Sick Children Research 
      Institute, Toronto, ON M5G 1X8, Canada.
FAU - Tolg, Cornelia
AU  - Tolg C
FAU - Panchal, Trupti
AU  - Panchal T
FAU - Leslie, Bruno
AU  - Leslie B
FAU - Yu, Jeffery
AU  - Yu J
FAU - Elkelini, Mohamed
AU  - Elkelini M
FAU - Sabha, Nesrin
AU  - Sabha N
FAU - Tse, Derrick J
AU  - Tse DJ
FAU - Lorenzo, Armando J
AU  - Lorenzo AJ
FAU - Hassouna, Magdy
AU  - Hassouna M
FAU - Bagli, Darius J
AU  - Bagli DJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20091217
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - 0 (Actins)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Mitogens)
RN  - 0 (smooth muscle actin, rat)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (Rps6kb1 protein, rat)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.24.23 (Matrix Metalloproteinase 7)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Actins/metabolism
MH  - Animals
MH  - Cattle
MH  - *Cell Dedifferentiation/drug effects
MH  - Cell Hypoxia/drug effects
MH  - Cell Proliferation/drug effects
MH  - Enzyme Activation/drug effects
MH  - Extracellular Matrix/drug effects/metabolism/*pathology
MH  - Intracellular Signaling Peptides and Proteins/*metabolism
MH  - Matrix Metalloproteinase 7/metabolism
MH  - Mitogens/pharmacology
MH  - Models, Biological
MH  - Myocytes, Smooth Muscle/drug effects/*enzymology/*pathology
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Ribosomal Protein S6 Kinases/metabolism
MH  - Signal Transduction/drug effects
MH  - Sirolimus/pharmacology
MH  - *Stress, Mechanical
MH  - TOR Serine-Threonine Kinases
MH  - Urinary Bladder/drug effects/*pathology
PMC - PMC2797892
EDAT- 2009/12/19 06:00
MHDA- 2010/03/17 06:00
PMCR- 2011/01/01
CRDT- 2009/12/19 06:00
PHST- 2009/12/19 06:00 [entrez]
PHST- 2009/12/19 06:00 [pubmed]
PHST- 2010/03/17 06:00 [medline]
PHST- 2011/01/01 00:00 [pmc-release]
AID - S0002-9440(10)60347-1 [pii]
AID - AJPA60347 [pii]
AID - 10.2353/ajpath.2010.080834 [doi]
PST - ppublish
SO  - Am J Pathol. 2010 Jan;176(1):304-19. doi: 10.2353/ajpath.2010.080834. Epub 2009 
      Dec 17.