Prolyl 4-hydroxylase 2 promotes B-cell lymphoma progression via hydroxylation of Carabin
B-cell lymphomas are heterogeneous blood disorders with limited therapeutic options, largely because of their propensity to relapse and become refractory to treatments. Carabin, a key suppressor of B-cell receptor signaling and proliferation, is inactivated in B-cell lymphoma by unknown mechanisms....
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| Veröffentlicht in: | Blood 2018-03, Vol.131 (12), p.1325-1336 |
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| creator | Jiang, Wei Zhou, Xiaoyan Li, Zengxia Liu, Kaiyu Wang, Weige Tan, Renke Cong, Xiaoji Shan, Jiaoyu Zhan, Yanxia Cui, Zhaomeng Jiang, Lizhi Li, Quanfu Shen, Suqin Bai, Meirong Cheng, Yunfeng Li, Bin Tan, Minjia Ma, Dengke K. Liu, Jun O. Dang, Yongjun |
| description | B-cell lymphomas are heterogeneous blood disorders with limited therapeutic options, largely because of their propensity to relapse and become refractory to treatments. Carabin, a key suppressor of B-cell receptor signaling and proliferation, is inactivated in B-cell lymphoma by unknown mechanisms. Here, we identify prolyl 4-hydroxylase 2 (P4HA2) as a specific proline hydroxylase of Carabin. Carabin hydroxylation leads to its proteasomal degradation, thereby activating the Ras/extracellular signal-regulated kinase pathway and increasing B-cell lymphoma proliferation. P4HA2 is undetectable in normal B cells but upregulated in the diffuse large B-cell lymphoma (DLBCL), driving Carabin inactivation and lymphoma proliferation. Our results indicate that P4HA2 is a potential prognosis marker for DLBCL and a promising pharmacological target for developing treatment of molecularly stratified B-cell lymphomas.
•P4HA2, associated with progression and poor overall survival in DLBCL patients, could serve as a novel biomarker and therapeutic target.•P4HA2 counteracts the negative effect of Carabin on lymphoma by hydroxylation of Carabin at Pro306. |
| doi_str_mv | 10.1182/blood-2017-07-794875 |
| format | Article |
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•P4HA2, associated with progression and poor overall survival in DLBCL patients, could serve as a novel biomarker and therapeutic target.•P4HA2 counteracts the negative effect of Carabin on lymphoma by hydroxylation of Carabin at Pro306.</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2017-07-794875</identifier><identifier>PMID: 29437589</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adaptor Proteins, Signal Transducing - genetics ; Adaptor Proteins, Signal Transducing - metabolism ; Biomarkers, Tumor - genetics ; Biomarkers, Tumor - metabolism ; Cell Line, Tumor ; Cell Proliferation ; GTPase-Activating Proteins ; Humans ; Hydroxylation ; Lymphoid Neoplasia ; Lymphoma, Large B-Cell, Diffuse - genetics ; Lymphoma, Large B-Cell, Diffuse - metabolism ; Lymphoma, Large B-Cell, Diffuse - pathology ; MAP Kinase Signaling System ; Neoplasm Proteins - genetics ; Neoplasm Proteins - metabolism ; Prolyl Hydroxylases - genetics ; Prolyl Hydroxylases - metabolism ; Proteasome Endopeptidase Complex - genetics ; Proteasome Endopeptidase Complex - metabolism ; Proteolysis</subject><ispartof>Blood, 2018-03, Vol.131 (12), p.1325-1336</ispartof><rights>2018 American Society of Hematology</rights><rights>2018 by The American Society of Hematology.</rights><rights>2018 by The American Society of Hematology 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-c3a502625f74957049515e2e5cb1dda60b1fdf8b1632d97acb742a82d8d1e93b3</citedby><cites>FETCH-LOGICAL-c463t-c3a502625f74957049515e2e5cb1dda60b1fdf8b1632d97acb742a82d8d1e93b3</cites><orcidid>0000-0001-7237-1132</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,27928,27929</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29437589$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jiang, Wei</creatorcontrib><creatorcontrib>Zhou, Xiaoyan</creatorcontrib><creatorcontrib>Li, Zengxia</creatorcontrib><creatorcontrib>Liu, Kaiyu</creatorcontrib><creatorcontrib>Wang, Weige</creatorcontrib><creatorcontrib>Tan, Renke</creatorcontrib><creatorcontrib>Cong, Xiaoji</creatorcontrib><creatorcontrib>Shan, Jiaoyu</creatorcontrib><creatorcontrib>Zhan, Yanxia</creatorcontrib><creatorcontrib>Cui, Zhaomeng</creatorcontrib><creatorcontrib>Jiang, Lizhi</creatorcontrib><creatorcontrib>Li, Quanfu</creatorcontrib><creatorcontrib>Shen, Suqin</creatorcontrib><creatorcontrib>Bai, Meirong</creatorcontrib><creatorcontrib>Cheng, Yunfeng</creatorcontrib><creatorcontrib>Li, Bin</creatorcontrib><creatorcontrib>Tan, Minjia</creatorcontrib><creatorcontrib>Ma, Dengke K.</creatorcontrib><creatorcontrib>Liu, Jun O.</creatorcontrib><creatorcontrib>Dang, Yongjun</creatorcontrib><title>Prolyl 4-hydroxylase 2 promotes B-cell lymphoma progression via hydroxylation of Carabin</title><title>Blood</title><addtitle>Blood</addtitle><description>B-cell lymphomas are heterogeneous blood disorders with limited therapeutic options, largely because of their propensity to relapse and become refractory to treatments. Carabin, a key suppressor of B-cell receptor signaling and proliferation, is inactivated in B-cell lymphoma by unknown mechanisms. Here, we identify prolyl 4-hydroxylase 2 (P4HA2) as a specific proline hydroxylase of Carabin. Carabin hydroxylation leads to its proteasomal degradation, thereby activating the Ras/extracellular signal-regulated kinase pathway and increasing B-cell lymphoma proliferation. P4HA2 is undetectable in normal B cells but upregulated in the diffuse large B-cell lymphoma (DLBCL), driving Carabin inactivation and lymphoma proliferation. Our results indicate that P4HA2 is a potential prognosis marker for DLBCL and a promising pharmacological target for developing treatment of molecularly stratified B-cell lymphomas.
•P4HA2, associated with progression and poor overall survival in DLBCL patients, could serve as a novel biomarker and therapeutic target.•P4HA2 counteracts the negative effect of Carabin on lymphoma by hydroxylation of Carabin at Pro306.</description><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>GTPase-Activating Proteins</subject><subject>Humans</subject><subject>Hydroxylation</subject><subject>Lymphoid Neoplasia</subject><subject>Lymphoma, Large B-Cell, Diffuse - genetics</subject><subject>Lymphoma, Large B-Cell, Diffuse - metabolism</subject><subject>Lymphoma, Large B-Cell, Diffuse - pathology</subject><subject>MAP Kinase Signaling System</subject><subject>Neoplasm Proteins - genetics</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Prolyl Hydroxylases - genetics</subject><subject>Prolyl Hydroxylases - metabolism</subject><subject>Proteasome Endopeptidase Complex - genetics</subject><subject>Proteasome Endopeptidase Complex - metabolism</subject><subject>Proteolysis</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcFu1DAQhi0EotuWN0BVjlwMtmPH9qUSrIAiVYIDlXqzHHvSNXLirZ1dNW9P0i1buHAZSzPz_-OZD6G3lLynVLEPbUzJY0aoxERiqbmS4gVaUcEUJoSRl2hFCGkw15KeoNNSfhFCec3Ea3TCNK-lUHqFbn_kFKdYcbyZfE4PU7QFKlZtc-rTCKX6hB3EWMWp325Sb5fCXYZSQhqqfbDVUTYumdRVa5ttG4Zz9KqzscCbp_cM3Xz5_HN9ha-_f_22_niNHW_qEbvaCsIaJjrJtZBkDlQAA-Fa6r1tSEs736mWNjXzWlrXSs6sYl55Crpu6zN0efDd7toevINhzDaabQ69zZNJNph_K0PYmLu0N0I1gjE9G7x7MsjpfgdlNH0oy852gLQrhs3HZEQrubTyQ6vLqZQM3XEMJWaBYh6hmAWKIdIcoMyyi7-_eBT9ofC8A8yH2gfIprgAgwMfMrjR-BT-P-E3nmSgYg</recordid><startdate>20180322</startdate><enddate>20180322</enddate><creator>Jiang, Wei</creator><creator>Zhou, Xiaoyan</creator><creator>Li, Zengxia</creator><creator>Liu, Kaiyu</creator><creator>Wang, Weige</creator><creator>Tan, Renke</creator><creator>Cong, Xiaoji</creator><creator>Shan, Jiaoyu</creator><creator>Zhan, Yanxia</creator><creator>Cui, Zhaomeng</creator><creator>Jiang, Lizhi</creator><creator>Li, Quanfu</creator><creator>Shen, Suqin</creator><creator>Bai, Meirong</creator><creator>Cheng, Yunfeng</creator><creator>Li, Bin</creator><creator>Tan, Minjia</creator><creator>Ma, Dengke K.</creator><creator>Liu, Jun O.</creator><creator>Dang, Yongjun</creator><general>Elsevier Inc</general><general>American Society of Hematology</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><orcidid>https://orcid.org/0000-0001-7237-1132</orcidid></search><sort><creationdate>20180322</creationdate><title>Prolyl 4-hydroxylase 2 promotes B-cell lymphoma progression via hydroxylation of Carabin</title><author>Jiang, Wei ; Zhou, Xiaoyan ; Li, Zengxia ; Liu, Kaiyu ; Wang, Weige ; Tan, Renke ; Cong, Xiaoji ; Shan, Jiaoyu ; Zhan, Yanxia ; Cui, Zhaomeng ; Jiang, Lizhi ; Li, Quanfu ; Shen, Suqin ; Bai, Meirong ; Cheng, Yunfeng ; Li, Bin ; Tan, Minjia ; Ma, Dengke K. ; Liu, Jun O. ; Dang, Yongjun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-c3a502625f74957049515e2e5cb1dda60b1fdf8b1632d97acb742a82d8d1e93b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adaptor Proteins, Signal Transducing - genetics</topic><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>GTPase-Activating Proteins</topic><topic>Humans</topic><topic>Hydroxylation</topic><topic>Lymphoid Neoplasia</topic><topic>Lymphoma, Large B-Cell, Diffuse - genetics</topic><topic>Lymphoma, Large B-Cell, Diffuse - metabolism</topic><topic>Lymphoma, Large B-Cell, Diffuse - pathology</topic><topic>MAP Kinase Signaling System</topic><topic>Neoplasm Proteins - genetics</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Prolyl Hydroxylases - genetics</topic><topic>Prolyl Hydroxylases - metabolism</topic><topic>Proteasome Endopeptidase Complex - genetics</topic><topic>Proteasome Endopeptidase Complex - metabolism</topic><topic>Proteolysis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jiang, Wei</creatorcontrib><creatorcontrib>Zhou, Xiaoyan</creatorcontrib><creatorcontrib>Li, Zengxia</creatorcontrib><creatorcontrib>Liu, Kaiyu</creatorcontrib><creatorcontrib>Wang, Weige</creatorcontrib><creatorcontrib>Tan, Renke</creatorcontrib><creatorcontrib>Cong, Xiaoji</creatorcontrib><creatorcontrib>Shan, Jiaoyu</creatorcontrib><creatorcontrib>Zhan, Yanxia</creatorcontrib><creatorcontrib>Cui, Zhaomeng</creatorcontrib><creatorcontrib>Jiang, Lizhi</creatorcontrib><creatorcontrib>Li, Quanfu</creatorcontrib><creatorcontrib>Shen, Suqin</creatorcontrib><creatorcontrib>Bai, Meirong</creatorcontrib><creatorcontrib>Cheng, Yunfeng</creatorcontrib><creatorcontrib>Li, Bin</creatorcontrib><creatorcontrib>Tan, Minjia</creatorcontrib><creatorcontrib>Ma, Dengke K.</creatorcontrib><creatorcontrib>Liu, Jun O.</creatorcontrib><creatorcontrib>Dang, Yongjun</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>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jiang, Wei</au><au>Zhou, Xiaoyan</au><au>Li, Zengxia</au><au>Liu, Kaiyu</au><au>Wang, Weige</au><au>Tan, Renke</au><au>Cong, Xiaoji</au><au>Shan, Jiaoyu</au><au>Zhan, Yanxia</au><au>Cui, Zhaomeng</au><au>Jiang, Lizhi</au><au>Li, Quanfu</au><au>Shen, Suqin</au><au>Bai, Meirong</au><au>Cheng, Yunfeng</au><au>Li, Bin</au><au>Tan, Minjia</au><au>Ma, Dengke K.</au><au>Liu, Jun O.</au><au>Dang, Yongjun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prolyl 4-hydroxylase 2 promotes B-cell lymphoma progression via hydroxylation of Carabin</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2018-03-22</date><risdate>2018</risdate><volume>131</volume><issue>12</issue><spage>1325</spage><epage>1336</epage><pages>1325-1336</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><abstract>B-cell lymphomas are heterogeneous blood disorders with limited therapeutic options, largely because of their propensity to relapse and become refractory to treatments. Carabin, a key suppressor of B-cell receptor signaling and proliferation, is inactivated in B-cell lymphoma by unknown mechanisms. Here, we identify prolyl 4-hydroxylase 2 (P4HA2) as a specific proline hydroxylase of Carabin. Carabin hydroxylation leads to its proteasomal degradation, thereby activating the Ras/extracellular signal-regulated kinase pathway and increasing B-cell lymphoma proliferation. P4HA2 is undetectable in normal B cells but upregulated in the diffuse large B-cell lymphoma (DLBCL), driving Carabin inactivation and lymphoma proliferation. Our results indicate that P4HA2 is a potential prognosis marker for DLBCL and a promising pharmacological target for developing treatment of molecularly stratified B-cell lymphomas.
•P4HA2, associated with progression and poor overall survival in DLBCL patients, could serve as a novel biomarker and therapeutic target.•P4HA2 counteracts the negative effect of Carabin on lymphoma by hydroxylation of Carabin at Pro306.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>29437589</pmid><doi>10.1182/blood-2017-07-794875</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-7237-1132</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Cell Line, Tumor Cell Proliferation GTPase-Activating Proteins Humans Hydroxylation Lymphoid Neoplasia Lymphoma, Large B-Cell, Diffuse - genetics Lymphoma, Large B-Cell, Diffuse - metabolism Lymphoma, Large B-Cell, Diffuse - pathology MAP Kinase Signaling System Neoplasm Proteins - genetics Neoplasm Proteins - metabolism Prolyl Hydroxylases - genetics Prolyl Hydroxylases - metabolism Proteasome Endopeptidase Complex - genetics Proteasome Endopeptidase Complex - metabolism Proteolysis |
| title | Prolyl 4-hydroxylase 2 promotes B-cell lymphoma progression via hydroxylation of Carabin |
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