한빛사 논문
Mi Kyung Park1, Yixin Yao1, Weiya Xia1, Stephanie Rebecca Setijono2, Jae Hwan Kim1,3, Isabelle K. Vila1, Hui-Hsuan Chiu1, Yun Wu 4, Enrique Gonzalez Billalabeitia5, Min Gyu Lee1, Robert G. Kalb6, Mien-Chie Hung1,7,8, Pier Paolo Pandolfi 9, Su Jung Song2,* & Min Sup Song1,7,*
1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. 2 Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan-si, Chungcheongnam-do 31151, Republic of Korea. 3 Department of Biomedical Sciences, Seoul National University College of Medicine, Houston, Seoul 03080, Republic of Korea. 4Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. 5Department of Clinical Oncology, Hospital Universitario Morales Meseguer-IMIB, Universidad Catolica San Antonio de Murcia-UCAM, Murcia 30007, Spain. 6 Division of Neurology, Department of Pediatrics, Research Institute, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA. 7 Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. 8 Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan. 9 Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
*Correspondence and requests for materials should be addressed to S.J.S. or to M.S.S.
Abstract
PTEN is a lipid phosphatase that antagonizes the PI3K/AKT pathway and is recognized as a major dose-dependent tumor suppressor. The cellular mechanisms that control PTEN levels therefore offer potential routes to therapy, but these are as yet poorly defined. Here we demonstrate that PTEN plays an unexpected role in regulating its own stability through the transcriptional upregulation of the deubiquitinase USP11 by the PI3K/FOXO pathway, and further show that this feedforward mechanism is implicated in its tumor-suppressive role, as mice lacking Usp11 display increased susceptibility to PTEN-dependent tumor initiation, growth and metastasis. Notably, USP11 is downregulated in cancer patients, and correlates with PTEN expression and FOXO nuclear localization. Our findings therefore demonstrate that PTEN-PI3K-FOXO-USP11 constitute the regulatory feedforward loop that improves the stability and tumor suppressive activity of PTEN.
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