PMID- 17575014
OWN - NLM
STAT- MEDLINE
DCOM- 20071017
LR  - 20211203
IS  - 1040-0605 (Print)
IS  - 1040-0605 (Linking)
VI  - 293
IP  - 3
DP  - 2007 Sep
TI  - Predisposition to tetraploidy in pulmonary vascular smooth muscle cells derived 
      from the Eker rats.
PG  - L702-11
AB  - Somatic mutations in the tuberous sclerosis complex-2 (TSC2) gene are associated 
      with pulmonary lymphangioleiomyomatosis (LAM), a disorder characterized by benign 
      lesions of smooth muscle and/or smooth muscle-like cells in the lung. However, 
      the cellular mechanisms underlying LAM disease are largely unknown. Given that 
      the TSC2 gene product tuberin is involved in the regulation of cell growth and 
      proliferation, the present study was designed to investigate the potential roles 
      of TSC2 in regulation of the cell cycle. We studied cell cycle profiles of 
      pulmonary vascular smooth muscle cells (SMCs) derived from Eker rats 
      (Tsc2(+/EK)), a genetic model carrying a germline insertional deletion in one 
      copy of the Tsc2 gene, and the wild-type rats (Tsc2(+/+)), a noncarrier 
      counterpart. We found that Tsc2(+/EK), but not Tsc2(+/+), SMCs displayed 
      increases in cells with > or =4N DNA content (> or =4N cells) and in the 
      bromodeoxyuridine (BrdU) incorporation of > or =4N cells. Centrosome number was 
      also increased in Tsc2(+/EK) SMCs, but the mitotic index was comparable between 
      Tsc2(+/+) and Tsc2(+/EK) SMCs. Furthermore, Tsc2(+/EK) SMCs showed elevated 
      phosphorylation of p70S6K and increased expression of cell cycle regulatory 
      proteins Cdk1, cyclin B, Cdk2, and cyclin E. Inhibition of the mammalian target 
      of rapamycin (mTOR) pathway by rapamycin not only inhibited the phosphorylation 
      of p70(S6K) and the expression of cell cycle regulatory proteins but also reduced 
      accumulation of > or =4N cells and BrdU incorporation of >4N cells. Therefore, 
      our results demonstrate that Tsc2(+/EK) SMCs are predisposed to undergo 
      tetraploidization, involving activation of the mTOR pathway. These findings 
      suggest an important role of Tsc2 in regulation of the cell cycle.
FAU - Gui, Yu
AU  - Gui Y
AD  - Smooth Muscle Research Group, Department of Biochemistry & Molecular Biology, 
      University of Calgary, Calgary, Alberta, Canada.
FAU - He, Gordon H
AU  - He GH
FAU - Walsh, Michael P
AU  - Walsh MP
FAU - Zheng, Xi-Long
AU  - Zheng XL
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070615
PL  - United States
TA  - Am J Physiol Lung Cell Mol Physiol
JT  - American journal of physiology. Lung cellular and molecular physiology
JID - 100901229
RN  - 0 (Cyclin B)
RN  - 0 (Cyclin E)
RN  - 0 (Tsc2 protein, rat)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 9007-49-2 (DNA)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Cell Cycle
MH  - Centrosome/metabolism
MH  - Cyclin B/genetics
MH  - Cyclin E/genetics
MH  - Cyclin-Dependent Kinases/genetics
MH  - DNA/biosynthesis
MH  - Female
MH  - Male
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Muscle, Smooth, Vascular/*cytology/enzymology/*metabolism
MH  - Myocytes, Smooth Muscle/cytology/enzymology/*metabolism
MH  - *Polyploidy
MH  - Protein Kinases/metabolism
MH  - Pulmonary Artery/*cytology/*metabolism
MH  - Rats
MH  - Rats, Inbred Strains
MH  - Rats, Long-Evans
MH  - Ribosomal Protein S6 Kinases/metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/metabolism
MH  - Up-Regulation/genetics
EDAT- 2007/06/19 09:00
MHDA- 2007/10/18 09:00
CRDT- 2007/06/19 09:00
PHST- 2007/06/19 09:00 [pubmed]
PHST- 2007/10/18 09:00 [medline]
PHST- 2007/06/19 09:00 [entrez]
AID - 00016.2007 [pii]
AID - 10.1152/ajplung.00016.2007 [doi]
PST - ppublish
SO  - Am J Physiol Lung Cell Mol Physiol. 2007 Sep;293(3):L702-11. doi: 
      10.1152/ajplung.00016.2007. Epub 2007 Jun 15.