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The Role of Cdk5 in Neuroendocrine Thyroid Cancer
Medullary thyroid carcinoma (MTC) is a neuroendocrine cancer that originates from calcitonin-secreting parafollicular cells, or C cells. We found that Cdk5 and its cofactors p35 and p25 are highly expressed in human MTC and that Cdk5 activity promotes MTC proliferation. A conditional MTC mouse model...
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| Published in: | Cancer cell 2013-10, Vol.24 (4), p.499-511 |
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| creator | Pozo, Karine Castro-Rivera, Emely Tan, Chunfeng Plattner, Florian Schwach, Gert Siegl, Veronika Meyer, Douglas Guo, Ailan Gundara, Justin Mettlach, Gabriel Richer, Edmond Guevara, Jonathan A. Ning, Li Gupta, Anjali Hao, Guiyang Tsai, Li-Huei Sun, Xiankai Antich, Pietro Sidhu, Stanley Robinson, Bruce G. Chen, Herbert Nwariaku, Fiemu E. Pfragner, Roswitha Richardson, James A. Bibb, James A. |
| description | Medullary thyroid carcinoma (MTC) is a neuroendocrine cancer that originates from calcitonin-secreting parafollicular cells, or C cells. We found that Cdk5 and its cofactors p35 and p25 are highly expressed in human MTC and that Cdk5 activity promotes MTC proliferation. A conditional MTC mouse model was generated and corroborated the role of aberrant Cdk5 activation in MTC. C cell-specific overexpression of p25 caused rapid C cell hyperplasia leading to lethal MTC, which was arrested by repressing p25 overexpression. A comparative phosphoproteomic screen between proliferating and arrested MTC identified the retinoblastoma protein (Rb) as a crucial Cdk5 downstream target. Prevention of Rb phosphorylation at Ser807/Ser811 attenuated MTC proliferation. These findings implicate Cdk5 signaling via Rb as critical to MTC tumorigenesis and progression.
•Cdk5 and its activators are expressed in human MTC•Cdk5 activity drives proliferation of sporadic human MTC cell lines•Transgenic expression of the Cdk5 cofactor p25 rapidly induces lethal MTC in mice•Rb phosphorylation at Ser807/Ser811 is critical for MTC progression |
| doi_str_mv | 10.1016/j.ccr.2013.08.027 |
| format | article |
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•Cdk5 and its activators are expressed in human MTC•Cdk5 activity drives proliferation of sporadic human MTC cell lines•Transgenic expression of the Cdk5 cofactor p25 rapidly induces lethal MTC in mice•Rb phosphorylation at Ser807/Ser811 is critical for MTC progression</description><identifier>ISSN: 1535-6108</identifier><identifier>EISSN: 1878-3686</identifier><identifier>DOI: 10.1016/j.ccr.2013.08.027</identifier><identifier>PMID: 24135281</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Carcinoma, Medullary - metabolism ; Carcinoma, Neuroendocrine - metabolism ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival ; Cyclin-Dependent Kinase 5 - metabolism ; Disease Progression ; Gene Expression Regulation, Neoplastic ; Humans ; Mice ; Mice, Transgenic ; Phosphorylation ; Retinoblastoma Protein - metabolism ; Signal Transduction ; Thyroid Neoplasms - metabolism ; Time Factors ; Transgenes</subject><ispartof>Cancer cell, 2013-10, Vol.24 (4), p.499-511</ispartof><rights>2013 Elsevier Inc.</rights><rights>Copyright © 2013 Elsevier Inc. All rights reserved.</rights><rights>2013 Elsevier Inc. All rights reserved. 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c451t-766efb7323a4838e6ba2100dd6103678170bf45c06c3f8c664dafd698612cf993</citedby><cites>FETCH-LOGICAL-c451t-766efb7323a4838e6ba2100dd6103678170bf45c06c3f8c664dafd698612cf993</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24135281$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pozo, Karine</creatorcontrib><creatorcontrib>Castro-Rivera, Emely</creatorcontrib><creatorcontrib>Tan, Chunfeng</creatorcontrib><creatorcontrib>Plattner, Florian</creatorcontrib><creatorcontrib>Schwach, Gert</creatorcontrib><creatorcontrib>Siegl, Veronika</creatorcontrib><creatorcontrib>Meyer, Douglas</creatorcontrib><creatorcontrib>Guo, Ailan</creatorcontrib><creatorcontrib>Gundara, Justin</creatorcontrib><creatorcontrib>Mettlach, Gabriel</creatorcontrib><creatorcontrib>Richer, Edmond</creatorcontrib><creatorcontrib>Guevara, Jonathan A.</creatorcontrib><creatorcontrib>Ning, Li</creatorcontrib><creatorcontrib>Gupta, Anjali</creatorcontrib><creatorcontrib>Hao, Guiyang</creatorcontrib><creatorcontrib>Tsai, Li-Huei</creatorcontrib><creatorcontrib>Sun, Xiankai</creatorcontrib><creatorcontrib>Antich, Pietro</creatorcontrib><creatorcontrib>Sidhu, Stanley</creatorcontrib><creatorcontrib>Robinson, Bruce G.</creatorcontrib><creatorcontrib>Chen, Herbert</creatorcontrib><creatorcontrib>Nwariaku, Fiemu E.</creatorcontrib><creatorcontrib>Pfragner, Roswitha</creatorcontrib><creatorcontrib>Richardson, James A.</creatorcontrib><creatorcontrib>Bibb, James A.</creatorcontrib><title>The Role of Cdk5 in Neuroendocrine Thyroid Cancer</title><title>Cancer cell</title><addtitle>Cancer Cell</addtitle><description>Medullary thyroid carcinoma (MTC) is a neuroendocrine cancer that originates from calcitonin-secreting parafollicular cells, or C cells. We found that Cdk5 and its cofactors p35 and p25 are highly expressed in human MTC and that Cdk5 activity promotes MTC proliferation. A conditional MTC mouse model was generated and corroborated the role of aberrant Cdk5 activation in MTC. C cell-specific overexpression of p25 caused rapid C cell hyperplasia leading to lethal MTC, which was arrested by repressing p25 overexpression. A comparative phosphoproteomic screen between proliferating and arrested MTC identified the retinoblastoma protein (Rb) as a crucial Cdk5 downstream target. Prevention of Rb phosphorylation at Ser807/Ser811 attenuated MTC proliferation. These findings implicate Cdk5 signaling via Rb as critical to MTC tumorigenesis and progression.
•Cdk5 and its activators are expressed in human MTC•Cdk5 activity drives proliferation of sporadic human MTC cell lines•Transgenic expression of the Cdk5 cofactor p25 rapidly induces lethal MTC in mice•Rb phosphorylation at Ser807/Ser811 is critical for MTC progression</description><subject>Animals</subject><subject>Carcinoma, Medullary - metabolism</subject><subject>Carcinoma, Neuroendocrine - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Cell Survival</subject><subject>Cyclin-Dependent Kinase 5 - metabolism</subject><subject>Disease Progression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Phosphorylation</subject><subject>Retinoblastoma Protein - metabolism</subject><subject>Signal Transduction</subject><subject>Thyroid Neoplasms - metabolism</subject><subject>Time Factors</subject><subject>Transgenes</subject><issn>1535-6108</issn><issn>1878-3686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNp9kE9LAzEQxYMoWqsfwIvs0cuumU02m0UQpPgPioLUc0iTWZu63dSkFfrtjVRFL55mYN578_gRcgK0AArifF4YE4qSAiuoLGhZ75AByFrmTEixm_aKVbkAKg_IYYxzmjxQN_vkoOTAqlLCgMBkhtmT7zDzbTayr1Xm-uwB18Fjb70JrsdsMtsE72w20r3BcET2Wt1FPP6aQ_J8cz0Z3eXjx9v70dU4N7yCVV4Lge20ZiXTXDKJYqpLoNTa1IeJWkJNpy2vDBWGtdIIwa1urWikgNK0TcOG5HKbu1xPF2gN9qugO7UMbqHDRnnt1N9L72bqxb8rJnnDSpoCzr4Cgn9bY1yphYsGu0736NdRAeeMQ9NIlqSwlZrgYwzY_rwBqj5Rq7lKqNUnakWlSqiT5_R3vx_HN9skuNgKMFF6dxhUNA4TQusCmpWy3v0T_wEbMI2K</recordid><startdate>20131014</startdate><enddate>20131014</enddate><creator>Pozo, Karine</creator><creator>Castro-Rivera, Emely</creator><creator>Tan, Chunfeng</creator><creator>Plattner, Florian</creator><creator>Schwach, Gert</creator><creator>Siegl, Veronika</creator><creator>Meyer, Douglas</creator><creator>Guo, Ailan</creator><creator>Gundara, Justin</creator><creator>Mettlach, Gabriel</creator><creator>Richer, Edmond</creator><creator>Guevara, Jonathan A.</creator><creator>Ning, Li</creator><creator>Gupta, Anjali</creator><creator>Hao, Guiyang</creator><creator>Tsai, Li-Huei</creator><creator>Sun, Xiankai</creator><creator>Antich, Pietro</creator><creator>Sidhu, Stanley</creator><creator>Robinson, Bruce G.</creator><creator>Chen, Herbert</creator><creator>Nwariaku, Fiemu E.</creator><creator>Pfragner, Roswitha</creator><creator>Richardson, James A.</creator><creator>Bibb, James A.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><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>5PM</scope></search><sort><creationdate>20131014</creationdate><title>The Role of Cdk5 in Neuroendocrine Thyroid Cancer</title><author>Pozo, Karine ; Castro-Rivera, Emely ; Tan, Chunfeng ; Plattner, Florian ; Schwach, Gert ; Siegl, Veronika ; Meyer, Douglas ; Guo, Ailan ; Gundara, Justin ; Mettlach, Gabriel ; Richer, Edmond ; Guevara, Jonathan A. ; Ning, Li ; Gupta, Anjali ; Hao, Guiyang ; Tsai, Li-Huei ; Sun, Xiankai ; Antich, Pietro ; Sidhu, Stanley ; Robinson, Bruce G. ; Chen, Herbert ; Nwariaku, Fiemu E. ; Pfragner, Roswitha ; Richardson, James A. ; Bibb, James A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c451t-766efb7323a4838e6ba2100dd6103678170bf45c06c3f8c664dafd698612cf993</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Carcinoma, Medullary - metabolism</topic><topic>Carcinoma, Neuroendocrine - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Cell Survival</topic><topic>Cyclin-Dependent Kinase 5 - metabolism</topic><topic>Disease Progression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Phosphorylation</topic><topic>Retinoblastoma Protein - metabolism</topic><topic>Signal Transduction</topic><topic>Thyroid Neoplasms - metabolism</topic><topic>Time Factors</topic><topic>Transgenes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pozo, Karine</creatorcontrib><creatorcontrib>Castro-Rivera, Emely</creatorcontrib><creatorcontrib>Tan, Chunfeng</creatorcontrib><creatorcontrib>Plattner, Florian</creatorcontrib><creatorcontrib>Schwach, Gert</creatorcontrib><creatorcontrib>Siegl, Veronika</creatorcontrib><creatorcontrib>Meyer, Douglas</creatorcontrib><creatorcontrib>Guo, Ailan</creatorcontrib><creatorcontrib>Gundara, Justin</creatorcontrib><creatorcontrib>Mettlach, Gabriel</creatorcontrib><creatorcontrib>Richer, Edmond</creatorcontrib><creatorcontrib>Guevara, Jonathan A.</creatorcontrib><creatorcontrib>Ning, Li</creatorcontrib><creatorcontrib>Gupta, Anjali</creatorcontrib><creatorcontrib>Hao, Guiyang</creatorcontrib><creatorcontrib>Tsai, Li-Huei</creatorcontrib><creatorcontrib>Sun, Xiankai</creatorcontrib><creatorcontrib>Antich, Pietro</creatorcontrib><creatorcontrib>Sidhu, Stanley</creatorcontrib><creatorcontrib>Robinson, Bruce G.</creatorcontrib><creatorcontrib>Chen, Herbert</creatorcontrib><creatorcontrib>Nwariaku, Fiemu E.</creatorcontrib><creatorcontrib>Pfragner, Roswitha</creatorcontrib><creatorcontrib>Richardson, James A.</creatorcontrib><creatorcontrib>Bibb, James A.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pozo, Karine</au><au>Castro-Rivera, Emely</au><au>Tan, Chunfeng</au><au>Plattner, Florian</au><au>Schwach, Gert</au><au>Siegl, Veronika</au><au>Meyer, Douglas</au><au>Guo, Ailan</au><au>Gundara, Justin</au><au>Mettlach, Gabriel</au><au>Richer, Edmond</au><au>Guevara, Jonathan A.</au><au>Ning, Li</au><au>Gupta, Anjali</au><au>Hao, Guiyang</au><au>Tsai, Li-Huei</au><au>Sun, Xiankai</au><au>Antich, Pietro</au><au>Sidhu, Stanley</au><au>Robinson, Bruce G.</au><au>Chen, Herbert</au><au>Nwariaku, Fiemu E.</au><au>Pfragner, Roswitha</au><au>Richardson, James A.</au><au>Bibb, James A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Role of Cdk5 in Neuroendocrine Thyroid Cancer</atitle><jtitle>Cancer cell</jtitle><addtitle>Cancer Cell</addtitle><date>2013-10-14</date><risdate>2013</risdate><volume>24</volume><issue>4</issue><spage>499</spage><epage>511</epage><pages>499-511</pages><issn>1535-6108</issn><eissn>1878-3686</eissn><abstract>Medullary thyroid carcinoma (MTC) is a neuroendocrine cancer that originates from calcitonin-secreting parafollicular cells, or C cells. We found that Cdk5 and its cofactors p35 and p25 are highly expressed in human MTC and that Cdk5 activity promotes MTC proliferation. A conditional MTC mouse model was generated and corroborated the role of aberrant Cdk5 activation in MTC. C cell-specific overexpression of p25 caused rapid C cell hyperplasia leading to lethal MTC, which was arrested by repressing p25 overexpression. A comparative phosphoproteomic screen between proliferating and arrested MTC identified the retinoblastoma protein (Rb) as a crucial Cdk5 downstream target. Prevention of Rb phosphorylation at Ser807/Ser811 attenuated MTC proliferation. These findings implicate Cdk5 signaling via Rb as critical to MTC tumorigenesis and progression.
•Cdk5 and its activators are expressed in human MTC•Cdk5 activity drives proliferation of sporadic human MTC cell lines•Transgenic expression of the Cdk5 cofactor p25 rapidly induces lethal MTC in mice•Rb phosphorylation at Ser807/Ser811 is critical for MTC progression</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>24135281</pmid><doi>10.1016/j.ccr.2013.08.027</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Carcinoma, Medullary - metabolism Carcinoma, Neuroendocrine - metabolism Cell Line, Tumor Cell Proliferation Cell Survival Cyclin-Dependent Kinase 5 - metabolism Disease Progression Gene Expression Regulation, Neoplastic Humans Mice Mice, Transgenic Phosphorylation Retinoblastoma Protein - metabolism Signal Transduction Thyroid Neoplasms - metabolism Time Factors Transgenes |
| title | The Role of Cdk5 in Neuroendocrine Thyroid Cancer |
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