Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo

Enrico Caserta 1, 2, 3 Onur Egriboz 1, 2, 3 Hui Wang 1, 2, 3 Chelsea Martin 1, 2, 3 Christopher Koivisto 1, 2, 3 Thierry Pécot 4 Raleigh Kladney 1, 2, 3 Changxian Shen 1, 2, 3 Kang-Sup Shim 1, 2, 3 Thac Pham 1, 2, 3 Matthew K. Karikomi 1, 2, 3 Melissa J. Mauntel 1, 2, 3 Sarmila Majumder 1, 2, 3 Maria Cecilia Cuitiño 1, 2, 3 Xing Tang 1, 2, 3 Arunima Srivastava 1, 2, 3 Lianbo Yu 5, 6 Julie Wallace 1, 2, 3 Xiaokui Mo 5, 6 Morag Park 7, 8, 9 Soledad A. Fernandez 5, 6 Robert Pilarski 1 Krista M. La Perle 10 Thomas J. Rosol 10 Vincenzo Coppola 1, 3 Diego H. Castrillon 11 Cynthia Timmers 1 David E. Cohn 12 David M. O'Malley 12 Floor Backes 12 Adrian A. Suarez 13 Paul Goodfellow 3, 12 Helen Chamberlin 2 Erin R. Macrae 14 Charles L. Shapiro 14 Michael C. Ostrowski 1, 3 Gustavo Leone 1, 2, 3
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.
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https://hal.inria.fr/hal-01244933
Contributor : Thierry Pécot <>
Submitted on : Wednesday, December 16, 2015 - 2:33:58 PM
Last modification on : Thursday, February 7, 2019 - 4:27:11 PM

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Enrico Caserta, Onur Egriboz, Hui Wang, Chelsea Martin, Christopher Koivisto, et al.. Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo. Genes and Development, Cold Spring Harbor Laboratory Press, 2015, ⟨10.1101/gad.262568.115⟩. ⟨hal-01244933⟩

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