Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo
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 (Pten(FV)), fo...
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| Veröffentlicht in: | Genes & development 2015-08, Vol.29 (16), p.1707-1720 |
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| creator | Caserta, Enrico Egriboz, Onur Wang, Hui Martin, Chelsea Koivisto, Christopher Pecót, Thierry Kladney, Raleigh D Shen, Changxian Shim, Kang-Sup Pham, Thac Karikomi, Matthew K Mauntel, Melissa J Majumder, Sarmila Cuitino, Maria C Tang, Xing Srivastava, Arunima Yu, Lianbo Wallace, Julie Mo, Xiaokui Park, Morag Fernandez, Soledad A Pilarski, Robert La Perle, Krista M D Rosol, Thomas J Coppola, Vincenzo Castrillon, Diego H Timmers, Cynthia Cohn, David E O'Malley, David M Backes, Floor Suarez, Adrian A Goodfellow, Paul Chamberlin, Helen M Macrae, Erin R Shapiro, Charles L Ostrowski, Michael C Leone, Gustavo |
| description | 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 (Pten(FV)), found in human cancer. Despite having reduced levels of PTEN protein, homozygous Pten(FV/FV) embryos have intact AKT signaling, develop normally, and are carried to term. Heterozygous Pten(FV/+) 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. |
| doi_str_mv | 10.1101/gad.262568.115 |
| format | Article |
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Here we generated and analyzed Pten knock-in mice harboring a C2 domain missense mutation at phenylalanine 341 (Pten(FV)), found in human cancer. Despite having reduced levels of PTEN protein, homozygous Pten(FV/FV) embryos have intact AKT signaling, develop normally, and are carried to term. Heterozygous Pten(FV/+) 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.</description><identifier>ISSN: 0890-9369</identifier><identifier>EISSN: 1549-5477</identifier><identifier>DOI: 10.1101/gad.262568.115</identifier><identifier>PMID: 26302789</identifier><language>eng</language><publisher>United States: Cold Spring Harbor Laboratory Press</publisher><subject>Animal genetics ; Animals ; Biochemistry, Molecular Biology ; Cancer ; Carcinoma - enzymology ; Carcinoma - genetics ; Carcinoma - physiopathology ; Cell Nucleus - metabolism ; Cells, Cultured ; Embryo, Mammalian ; Enzyme Activation ; Female ; Gene Knock-In Techniques ; Genetics ; Life Sciences ; Mice ; Molecular biology ; Mutation, Missense - genetics ; Oncogene Protein v-akt - genetics ; Oncogene Protein v-akt - metabolism ; Protein Stability ; PTEN Phosphohydrolase - genetics ; PTEN Phosphohydrolase - metabolism ; Research Paper ; Signal Transduction</subject><ispartof>Genes & development, 2015-08, Vol.29 (16), p.1707-1720</ispartof><rights>2015 Caserta et al.; Published by Cold Spring Harbor Laboratory Press.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c523t-861625eff2c6e90e87fda12f8a2c9f2a22b33b696898ca2a4ac9d90c11422a5e3</citedby><cites>FETCH-LOGICAL-c523t-861625eff2c6e90e87fda12f8a2c9f2a22b33b696898ca2a4ac9d90c11422a5e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561480/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561480/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26302789$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://inria.hal.science/hal-01244933$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Caserta, Enrico</creatorcontrib><creatorcontrib>Egriboz, Onur</creatorcontrib><creatorcontrib>Wang, Hui</creatorcontrib><creatorcontrib>Martin, Chelsea</creatorcontrib><creatorcontrib>Koivisto, Christopher</creatorcontrib><creatorcontrib>Pecót, Thierry</creatorcontrib><creatorcontrib>Kladney, Raleigh D</creatorcontrib><creatorcontrib>Shen, Changxian</creatorcontrib><creatorcontrib>Shim, Kang-Sup</creatorcontrib><creatorcontrib>Pham, Thac</creatorcontrib><creatorcontrib>Karikomi, Matthew K</creatorcontrib><creatorcontrib>Mauntel, Melissa J</creatorcontrib><creatorcontrib>Majumder, Sarmila</creatorcontrib><creatorcontrib>Cuitino, Maria C</creatorcontrib><creatorcontrib>Tang, Xing</creatorcontrib><creatorcontrib>Srivastava, Arunima</creatorcontrib><creatorcontrib>Yu, Lianbo</creatorcontrib><creatorcontrib>Wallace, Julie</creatorcontrib><creatorcontrib>Mo, Xiaokui</creatorcontrib><creatorcontrib>Park, Morag</creatorcontrib><creatorcontrib>Fernandez, Soledad A</creatorcontrib><creatorcontrib>Pilarski, Robert</creatorcontrib><creatorcontrib>La Perle, Krista M D</creatorcontrib><creatorcontrib>Rosol, Thomas J</creatorcontrib><creatorcontrib>Coppola, Vincenzo</creatorcontrib><creatorcontrib>Castrillon, Diego H</creatorcontrib><creatorcontrib>Timmers, Cynthia</creatorcontrib><creatorcontrib>Cohn, David E</creatorcontrib><creatorcontrib>O'Malley, David M</creatorcontrib><creatorcontrib>Backes, Floor</creatorcontrib><creatorcontrib>Suarez, Adrian A</creatorcontrib><creatorcontrib>Goodfellow, Paul</creatorcontrib><creatorcontrib>Chamberlin, Helen M</creatorcontrib><creatorcontrib>Macrae, Erin R</creatorcontrib><creatorcontrib>Shapiro, Charles L</creatorcontrib><creatorcontrib>Ostrowski, Michael C</creatorcontrib><creatorcontrib>Leone, Gustavo</creatorcontrib><title>Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo</title><title>Genes & development</title><addtitle>Genes Dev</addtitle><description>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 (Pten(FV)), found in human cancer. Despite having reduced levels of PTEN protein, homozygous Pten(FV/FV) embryos have intact AKT signaling, develop normally, and are carried to term. Heterozygous Pten(FV/+) 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.</description><subject>Animal genetics</subject><subject>Animals</subject><subject>Biochemistry, Molecular Biology</subject><subject>Cancer</subject><subject>Carcinoma - enzymology</subject><subject>Carcinoma - genetics</subject><subject>Carcinoma - physiopathology</subject><subject>Cell Nucleus - metabolism</subject><subject>Cells, Cultured</subject><subject>Embryo, Mammalian</subject><subject>Enzyme Activation</subject><subject>Female</subject><subject>Gene Knock-In Techniques</subject><subject>Genetics</subject><subject>Life Sciences</subject><subject>Mice</subject><subject>Molecular biology</subject><subject>Mutation, Missense - genetics</subject><subject>Oncogene Protein v-akt - genetics</subject><subject>Oncogene Protein v-akt - metabolism</subject><subject>Protein Stability</subject><subject>PTEN Phosphohydrolase - genetics</subject><subject>PTEN Phosphohydrolase - metabolism</subject><subject>Research Paper</subject><subject>Signal Transduction</subject><issn>0890-9369</issn><issn>1549-5477</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkT1vFDEQhi0EIkegpUQuodjDH2uv3SBFUSBIpyRFKJHl885ejHbtxfatlH-Po0uikCrVaMbPvDPjF6GPlKwpJfTrzvZrJpmQqubiFVpR0epGtF33Gq2I0qTRXOoj9C7nP4QQSaR8i46Y5IR1Sq_Q74sYnC12vC3e4avrsws8-ZwhZMDTvtjiY8Bzgt7nOWbIuEQc086GJsMIrvgFsLPBQcI9LDDGeYJQsA948Ut8j94Mdszw4T4eo1_fz65Pz5vN5Y-fpyebxgnGS6MkrSfAMDAnQRNQ3dBbygZlmdMDs4xtOd9KLZVWzjLbWqd7TRylLWNWAD9G3w668347Qe_qCsmOZk5-sunWROvN_y_B35hdXEwrJG0VqQJfDgI3z9rOTzbmrkYoa1vN-UIr-_l-WIp_95CLqT_mYBxtgLjPhnZcaMq5fglKOiEEkbqi6wPqUsw5wfC4BiXmzmpTrTYHq2suasOnpzc_4g_e8n9LrKX5</recordid><startdate>20150815</startdate><enddate>20150815</enddate><creator>Caserta, Enrico</creator><creator>Egriboz, Onur</creator><creator>Wang, Hui</creator><creator>Martin, Chelsea</creator><creator>Koivisto, Christopher</creator><creator>Pecót, Thierry</creator><creator>Kladney, Raleigh D</creator><creator>Shen, Changxian</creator><creator>Shim, Kang-Sup</creator><creator>Pham, Thac</creator><creator>Karikomi, Matthew K</creator><creator>Mauntel, Melissa J</creator><creator>Majumder, Sarmila</creator><creator>Cuitino, Maria C</creator><creator>Tang, Xing</creator><creator>Srivastava, Arunima</creator><creator>Yu, Lianbo</creator><creator>Wallace, Julie</creator><creator>Mo, Xiaokui</creator><creator>Park, Morag</creator><creator>Fernandez, Soledad A</creator><creator>Pilarski, Robert</creator><creator>La Perle, Krista M D</creator><creator>Rosol, Thomas J</creator><creator>Coppola, Vincenzo</creator><creator>Castrillon, Diego H</creator><creator>Timmers, Cynthia</creator><creator>Cohn, David E</creator><creator>O'Malley, David M</creator><creator>Backes, Floor</creator><creator>Suarez, Adrian A</creator><creator>Goodfellow, Paul</creator><creator>Chamberlin, Helen M</creator><creator>Macrae, Erin R</creator><creator>Shapiro, Charles L</creator><creator>Ostrowski, Michael C</creator><creator>Leone, Gustavo</creator><general>Cold Spring Harbor Laboratory Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>1XC</scope><scope>5PM</scope></search><sort><creationdate>20150815</creationdate><title>Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo</title><author>Caserta, Enrico ; Egriboz, Onur ; Wang, Hui ; Martin, Chelsea ; Koivisto, Christopher ; Pecót, Thierry ; Kladney, Raleigh D ; Shen, Changxian ; Shim, Kang-Sup ; Pham, Thac ; Karikomi, Matthew K ; Mauntel, Melissa J ; Majumder, Sarmila ; Cuitino, Maria C ; Tang, Xing ; Srivastava, Arunima ; Yu, Lianbo ; Wallace, Julie ; Mo, Xiaokui ; Park, Morag ; Fernandez, Soledad A ; Pilarski, Robert ; La Perle, Krista M D ; Rosol, Thomas J ; Coppola, Vincenzo ; Castrillon, Diego H ; Timmers, Cynthia ; Cohn, David E ; O'Malley, David M ; Backes, Floor ; Suarez, Adrian A ; Goodfellow, Paul ; Chamberlin, Helen M ; Macrae, Erin R ; Shapiro, Charles L ; Ostrowski, Michael C ; Leone, Gustavo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c523t-861625eff2c6e90e87fda12f8a2c9f2a22b33b696898ca2a4ac9d90c11422a5e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animal genetics</topic><topic>Animals</topic><topic>Biochemistry, Molecular Biology</topic><topic>Cancer</topic><topic>Carcinoma - enzymology</topic><topic>Carcinoma - genetics</topic><topic>Carcinoma - physiopathology</topic><topic>Cell Nucleus - metabolism</topic><topic>Cells, Cultured</topic><topic>Embryo, Mammalian</topic><topic>Enzyme Activation</topic><topic>Female</topic><topic>Gene Knock-In Techniques</topic><topic>Genetics</topic><topic>Life Sciences</topic><topic>Mice</topic><topic>Molecular biology</topic><topic>Mutation, Missense - genetics</topic><topic>Oncogene Protein v-akt - genetics</topic><topic>Oncogene Protein v-akt - metabolism</topic><topic>Protein Stability</topic><topic>PTEN Phosphohydrolase - genetics</topic><topic>PTEN Phosphohydrolase - metabolism</topic><topic>Research Paper</topic><topic>Signal Transduction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Caserta, Enrico</creatorcontrib><creatorcontrib>Egriboz, Onur</creatorcontrib><creatorcontrib>Wang, Hui</creatorcontrib><creatorcontrib>Martin, Chelsea</creatorcontrib><creatorcontrib>Koivisto, Christopher</creatorcontrib><creatorcontrib>Pecót, Thierry</creatorcontrib><creatorcontrib>Kladney, Raleigh D</creatorcontrib><creatorcontrib>Shen, Changxian</creatorcontrib><creatorcontrib>Shim, Kang-Sup</creatorcontrib><creatorcontrib>Pham, Thac</creatorcontrib><creatorcontrib>Karikomi, Matthew K</creatorcontrib><creatorcontrib>Mauntel, Melissa J</creatorcontrib><creatorcontrib>Majumder, Sarmila</creatorcontrib><creatorcontrib>Cuitino, Maria C</creatorcontrib><creatorcontrib>Tang, Xing</creatorcontrib><creatorcontrib>Srivastava, Arunima</creatorcontrib><creatorcontrib>Yu, Lianbo</creatorcontrib><creatorcontrib>Wallace, Julie</creatorcontrib><creatorcontrib>Mo, Xiaokui</creatorcontrib><creatorcontrib>Park, Morag</creatorcontrib><creatorcontrib>Fernandez, Soledad A</creatorcontrib><creatorcontrib>Pilarski, Robert</creatorcontrib><creatorcontrib>La Perle, Krista M D</creatorcontrib><creatorcontrib>Rosol, Thomas J</creatorcontrib><creatorcontrib>Coppola, Vincenzo</creatorcontrib><creatorcontrib>Castrillon, Diego H</creatorcontrib><creatorcontrib>Timmers, Cynthia</creatorcontrib><creatorcontrib>Cohn, David E</creatorcontrib><creatorcontrib>O'Malley, David M</creatorcontrib><creatorcontrib>Backes, Floor</creatorcontrib><creatorcontrib>Suarez, Adrian A</creatorcontrib><creatorcontrib>Goodfellow, Paul</creatorcontrib><creatorcontrib>Chamberlin, Helen M</creatorcontrib><creatorcontrib>Macrae, Erin R</creatorcontrib><creatorcontrib>Shapiro, Charles L</creatorcontrib><creatorcontrib>Ostrowski, Michael C</creatorcontrib><creatorcontrib>Leone, Gustavo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - 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Here we generated and analyzed Pten knock-in mice harboring a C2 domain missense mutation at phenylalanine 341 (Pten(FV)), found in human cancer. Despite having reduced levels of PTEN protein, homozygous Pten(FV/FV) embryos have intact AKT signaling, develop normally, and are carried to term. Heterozygous Pten(FV/+) 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.</abstract><cop>United States</cop><pub>Cold Spring Harbor Laboratory Press</pub><pmid>26302789</pmid><doi>10.1101/gad.262568.115</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Genes & development, 2015-08, Vol.29 (16), p.1707-1720 |
| issn | 0890-9369 1549-5477 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Animal genetics Animals Biochemistry, Molecular Biology Cancer Carcinoma - enzymology Carcinoma - genetics Carcinoma - physiopathology Cell Nucleus - metabolism Cells, Cultured Embryo, Mammalian Enzyme Activation Female Gene Knock-In Techniques Genetics Life Sciences Mice Molecular biology Mutation, Missense - genetics Oncogene Protein v-akt - genetics Oncogene Protein v-akt - metabolism Protein Stability PTEN Phosphohydrolase - genetics PTEN Phosphohydrolase - metabolism Research Paper Signal Transduction |
| title | Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo |
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