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A more recent version of this article appeared on February 1, 2002
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Submitted on July 20, 2001
Revised on October 24, 2001
Accepted on November 8, 2001
1 Laboratory of Molecular Cardiology, National Heart, Lung, and Blood Institute National Institutes of Health, Bethesda, MD 20892
2 Laboratory of Molecular Cardiology, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 8N202, 10 Center Dr., MSC 1762, Bethesda, MD 20892-1762
* Corresponding author. E-mail address: AdelsteR{at}NHLBI.NIH.GOV.
We ectopically expressed the transcription factor Pitx2a, one of the Pitx2 isoforms, in HeLa cells using a tetracycline-inducible expression system and examined whether Pitx2a was capable of modulating Rho GTPase signaling and altering the cell's cytoskeleton. Ectopic expression of Pitx2a induced actin-myosin reorganization, leading to increased cell spreading, suppression of cell migration and the strengthening of cell-cell adhesion, marked by the accumulation and localization of beta-catenin and N-cadherin to the sites of cell-cell contacts. Moreover, Pitx2a expression resulted in activation of the Rho GTPases, Rac1 and RhoA, and the dominant negative Rac1 mutant N17Rac1 inhibited cell spreading and disrupted localization of beta-catenin to the sites of cell-cell contacts. Both reorganization of actin-myosin and cell spreading require PI 3-kinase activity, which is also necessary for activation of the Rho GTPase proteins. Pitx2a induced the expression of Trio, a guanine nucleotide exchange factor for Rac1 and RhoA, which preceded cell spreading and the expression of Trio protein was downregulated after the changes in cell spreading and cell morphology were initiated. In addition, Pitx2a also induces cell cycle arrest at G0/G1, most likely due to the accumulation of the tumor suppressor proteins p53 and p21. Our data indicate that the transcriptional activities initiated in the nucleus by Pitx2a result in profound changes in HeLa cell morphology, migration and proliferation.
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