1. Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo
- Author
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Helen M. Chamberlin, Thac Pham, Paul J. Goodfellow, Robert Pilarski, David E. Cohn, Charles L. Shapiro, Onur Egriboz, Adrian A. Suarez, Julie A. Wallace, Raleigh D. Kladney, Xing Tang, Changxian Shen, Gustavo Leone, Cynthia Timmers, Maria C. Cuitiño, Chelsea K. Martin, Kang Sup Shim, Michael C. Ostrowski, David M. O'Malley, Arunima Srivastava, Vincenzo Coppola, Thierry Pécot, Diego H. Castrillon, Morag Park, Soledad Fernandez, Hui Wang, Matthew K. Karikomi, Melissa J. Mauntel, Floor J. Backes, Thomas J. Rosol, Krista M. D. La Perle, Erin Macrae, Xiaokui Mo, Enrico Caserta, Christopher Koivisto, Sarmila Majumder, Lianbo Yu, Comprehensive Cancer Center [Colombus], Ohio State University [Columbus] (OSU), Department of Molecular Genetics [Colombus], Department of Molecular Virology, Immunology and Medical Genetics [Colombus], Ohio State University [Columbus] (OSU)-College of Medicine and Public Health [Colombus], Space-timE RePresentation, Imaging and cellular dynamics of molecular COmplexes (SERPICO), Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Center for Biostatistics [Colombus], Department of Biomedical Informatics [Columbus], Department of Biochemistry [Montréal], McGill University = Université McGill [Montréal, Canada], Rosalind and Morris Goodman Cancer Center [Montreal], Department of Oncology [Montréal], Department of Veterinary Biosciences [Colombus], College of Veterinary Medicine [Colombus], Ohio State University [Columbus] (OSU)-Ohio State University [Columbus] (OSU), Department of Pathology [Dallas], University of Texas Southwestern Medical Center [Dallas], Department of Obstetrics and Gynecology [Colombus], Department of Pathology [Columbus], and Department of Internal Medicine [Colombus]
- Subjects
Phosphatase ,Mutation, Missense ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Mice ,Genetics ,Carcinoma ,medicine ,PTEN ,Missense mutation ,Tensin ,Animals ,Gene Knock-In Techniques ,Protein kinase B ,Cells, Cultured ,C2 domain ,Cell Nucleus ,biology ,Protein Stability ,PTEN Phosphohydrolase ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,medicine.disease ,Embryo, Mammalian ,Enzyme Activation ,Oncogene Protein v-akt ,[SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics ,biology.protein ,Cancer research ,Female ,Signal transduction ,Developmental Biology ,Research Paper ,Signal Transduction - Abstract
Inactivation of phosphatase and tensin homology deleted on chromosome 10 (PTEN) is linked to increased PI3K–AKT signaling, enhanced organismal growth, and cancer development. Here we generated and analyzed Pten knock-in mice harboring a C2 domain missense mutation at phenylalanine 341 (PtenFV), found in human cancer. Despite having reduced levels of PTEN protein, homozygous PtenFV/FV embryos have intact AKT signaling, develop normally, and are carried to term. Heterozygous PtenFV/+ mice develop carcinoma in the thymus, stomach, adrenal medulla, and mammary gland but not in other organs typically sensitive to Pten deficiency, including the thyroid, prostate, and uterus. Progression to carcinoma in sensitive organs ensues in the absence of overt AKT activation. Carcinoma in the uterus, a cancer-resistant organ, requires a second clonal event associated with the spontaneous activation of AKT and downstream signaling. In summary, this PTEN noncatalytic missense mutation exposes a core tumor suppressor function distinct from inhibition of canonical AKT signaling that predisposes to organ-selective cancer development in vivo.
- Published
- 2015