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This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/L702    most recent 00016.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Gui, Y. Articles by Zheng, X.-L. Search for Related Content PubMed PubMed Citation Articles by Gui, Y. Articles by Zheng, X.-L.

Predisposition to tetraploidy in pulmonary vascular smooth muscle cells derived from the Eker rats

Smooth Muscle Research Group, Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada

Submitted 11 January 2007 ; accepted in final form 12 June 2007

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 4N DNA content (4N cells) and in the bromodeoxyuridine (BrdU) incorporation of 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 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.

tuberous sclerosis complex-2; smooth muscle cell cycle; lymphangioleiomyomatosis