Regulation of inosine monophosphate dehydrogenase type I and type II isoforms in human lymphocytes
The enzyme inosine monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in the de novo biosynthesis of guanine nucleotides. Inhibition of IMPDH leads to immunosuppression by decreasing guanine nucleotides that are required for the proliferation of lymphocytes. IMPDH activity is media...
Gespeichert in:
| Veröffentlicht in: | Biochemical pharmacology 2004-02, Vol.67 (4), p.767-776 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 776 |
|---|---|
| container_issue | 4 |
| container_start_page | 767 |
| container_title | Biochemical pharmacology |
| container_volume | 67 |
| creator | Jain, Jugnu Almquist, Susan J. Ford, Pamella J. Shlyakhter, Dina Wang, Yongping Nimmesgern, Elmar Germann, Ursula A. |
| description | The enzyme inosine monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in the
de novo biosynthesis of guanine nucleotides. Inhibition of IMPDH leads to immunosuppression by decreasing guanine nucleotides that are required for the proliferation of lymphocytes. IMPDH activity is mediated by two highly conserved isoforms, type I and type II. We have characterized the mRNA and protein expression of the two isoforms in a variety of human tissues, peripheral blood mononuclear cells (PBMCs), and selected cell lines to investigate their regulation. Type I mRNA was expressed in most tissues with high expression in PBMCs and low expression in thymus. IMPDH type II transcript was also detected in most tissues with low expression in spleen and PBMCs. In PBMCs, induction of both type I and type II mRNAs was observed within 12
hr of mitogenic stimulation. Using type-selective IMPDH antibodies, an increase in the levels of type I and type II proteins was observed after mitogenic stimulation. The effect of two IMPDH inhibitors, MPA and VX-497, was investigated on the expression of type I and type II isoforms. VX-497 is an orally bioavailable, potent and reversible inhibitor of IMPDH, with broad applicability in many viral and immune system-mediated diseases. MPA and VX-497 inhibit both isoforms of IMPDH
in vitro. Prolonged treatment of lymphocytes with either VX-497 or MPA did not lead to an increase in type I or type II IMPDH protein levels. These results are discussed in the context of IMPDH being a target for immunosuppressive, anti-viral and anti-cancer therapy. |
| doi_str_mv | 10.1016/j.bcp.2003.09.043 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_80128939</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0006295203007962</els_id><sourcerecordid>80128939</sourcerecordid><originalsourceid>FETCH-LOGICAL-c445t-ccf18505f744a76ec8bffaccbf804e80d40559e7cc83c483fd640c0d3ef7e1893</originalsourceid><addsrcrecordid>eNp9kEGL1TAQx4Mo7nP1A3iRXPT26qRN2xRPsqj7YEEQPYd0OtmXR5vUpBX67W15hb3taf4Dv_8w_Bh7LyATIKrPl6zFMcsBigyaDGTxgh2Eqotj3lTqJTsAQLXmMr9hb1K6bKuqxGt2I2Rd1qKuD6z9RY9zbyYXPA-WOx-S88SH4MN4Dmk8m4l4R-eli-GRvEnEp2UkfuLGd3s8cZeCDXFIa5-f58F43i_D2sdlovSWvbKmT_Run7fsz_dvv-_ujw8_f5zuvj4cUcpyOiJaoUoobS2lqStC1VprEFurQJKCTkJZNlQjqgKlKmxXSUDoCrI1CdUUt-zT9e4Yw9-Z0qQHl5D63ngKc9IKRL5iGyiuIMaQUiSrx-gGExctQG9i9UWvYvUmVkOjV7Fr58N-fG4H6p4au8kV-LgDJqHpbTQeXXriyjIXEjbuy5WjVcU_R1EndOSROhcJJ90F98wb_wH-_pe5</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>80128939</pqid></control><display><type>article</type><title>Regulation of inosine monophosphate dehydrogenase type I and type II isoforms in human lymphocytes</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Jain, Jugnu ; Almquist, Susan J. ; Ford, Pamella J. ; Shlyakhter, Dina ; Wang, Yongping ; Nimmesgern, Elmar ; Germann, Ursula A.</creator><creatorcontrib>Jain, Jugnu ; Almquist, Susan J. ; Ford, Pamella J. ; Shlyakhter, Dina ; Wang, Yongping ; Nimmesgern, Elmar ; Germann, Ursula A.</creatorcontrib><description>The enzyme inosine monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in the
de novo biosynthesis of guanine nucleotides. Inhibition of IMPDH leads to immunosuppression by decreasing guanine nucleotides that are required for the proliferation of lymphocytes. IMPDH activity is mediated by two highly conserved isoforms, type I and type II. We have characterized the mRNA and protein expression of the two isoforms in a variety of human tissues, peripheral blood mononuclear cells (PBMCs), and selected cell lines to investigate their regulation. Type I mRNA was expressed in most tissues with high expression in PBMCs and low expression in thymus. IMPDH type II transcript was also detected in most tissues with low expression in spleen and PBMCs. In PBMCs, induction of both type I and type II mRNAs was observed within 12
hr of mitogenic stimulation. Using type-selective IMPDH antibodies, an increase in the levels of type I and type II proteins was observed after mitogenic stimulation. The effect of two IMPDH inhibitors, MPA and VX-497, was investigated on the expression of type I and type II isoforms. VX-497 is an orally bioavailable, potent and reversible inhibitor of IMPDH, with broad applicability in many viral and immune system-mediated diseases. MPA and VX-497 inhibit both isoforms of IMPDH
in vitro. Prolonged treatment of lymphocytes with either VX-497 or MPA did not lead to an increase in type I or type II IMPDH protein levels. These results are discussed in the context of IMPDH being a target for immunosuppressive, anti-viral and anti-cancer therapy.</description><identifier>ISSN: 0006-2952</identifier><identifier>EISSN: 1873-2968</identifier><identifier>DOI: 10.1016/j.bcp.2003.09.043</identifier><identifier>PMID: 14757177</identifier><identifier>CODEN: BCPCA6</identifier><language>eng</language><publisher>New York, NY: Elsevier Inc</publisher><subject>Biological and medical sciences ; Carbamates - pharmacology ; Enzyme Inhibitors - pharmacology ; Gene regulation ; Humans ; Immune ; IMP Dehydrogenase - antagonists & inhibitors ; IMP Dehydrogenase - genetics ; IMP Dehydrogenase - metabolism ; IMPDH ; Isoenzymes - genetics ; Isoenzymes - metabolism ; Leukocytes, Mononuclear - drug effects ; Leukocytes, Mononuclear - enzymology ; Lymphocytes ; Lymphocytes - enzymology ; Medical sciences ; Mycophenolic acid ; Mycophenolic Acid - pharmacology ; Pharmacology. Drug treatments ; Phenylurea Compounds - pharmacology ; RNA, Messenger - metabolism ; Tumor Cells, Cultured ; VX-497</subject><ispartof>Biochemical pharmacology, 2004-02, Vol.67 (4), p.767-776</ispartof><rights>2003 Elsevier Inc.</rights><rights>2004 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c445t-ccf18505f744a76ec8bffaccbf804e80d40559e7cc83c483fd640c0d3ef7e1893</citedby><cites>FETCH-LOGICAL-c445t-ccf18505f744a76ec8bffaccbf804e80d40559e7cc83c483fd640c0d3ef7e1893</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0006295203007962$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15521407$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14757177$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jain, Jugnu</creatorcontrib><creatorcontrib>Almquist, Susan J.</creatorcontrib><creatorcontrib>Ford, Pamella J.</creatorcontrib><creatorcontrib>Shlyakhter, Dina</creatorcontrib><creatorcontrib>Wang, Yongping</creatorcontrib><creatorcontrib>Nimmesgern, Elmar</creatorcontrib><creatorcontrib>Germann, Ursula A.</creatorcontrib><title>Regulation of inosine monophosphate dehydrogenase type I and type II isoforms in human lymphocytes</title><title>Biochemical pharmacology</title><addtitle>Biochem Pharmacol</addtitle><description>The enzyme inosine monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in the
de novo biosynthesis of guanine nucleotides. Inhibition of IMPDH leads to immunosuppression by decreasing guanine nucleotides that are required for the proliferation of lymphocytes. IMPDH activity is mediated by two highly conserved isoforms, type I and type II. We have characterized the mRNA and protein expression of the two isoforms in a variety of human tissues, peripheral blood mononuclear cells (PBMCs), and selected cell lines to investigate their regulation. Type I mRNA was expressed in most tissues with high expression in PBMCs and low expression in thymus. IMPDH type II transcript was also detected in most tissues with low expression in spleen and PBMCs. In PBMCs, induction of both type I and type II mRNAs was observed within 12
hr of mitogenic stimulation. Using type-selective IMPDH antibodies, an increase in the levels of type I and type II proteins was observed after mitogenic stimulation. The effect of two IMPDH inhibitors, MPA and VX-497, was investigated on the expression of type I and type II isoforms. VX-497 is an orally bioavailable, potent and reversible inhibitor of IMPDH, with broad applicability in many viral and immune system-mediated diseases. MPA and VX-497 inhibit both isoforms of IMPDH
in vitro. Prolonged treatment of lymphocytes with either VX-497 or MPA did not lead to an increase in type I or type II IMPDH protein levels. These results are discussed in the context of IMPDH being a target for immunosuppressive, anti-viral and anti-cancer therapy.</description><subject>Biological and medical sciences</subject><subject>Carbamates - pharmacology</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Gene regulation</subject><subject>Humans</subject><subject>Immune</subject><subject>IMP Dehydrogenase - antagonists & inhibitors</subject><subject>IMP Dehydrogenase - genetics</subject><subject>IMP Dehydrogenase - metabolism</subject><subject>IMPDH</subject><subject>Isoenzymes - genetics</subject><subject>Isoenzymes - metabolism</subject><subject>Leukocytes, Mononuclear - drug effects</subject><subject>Leukocytes, Mononuclear - enzymology</subject><subject>Lymphocytes</subject><subject>Lymphocytes - enzymology</subject><subject>Medical sciences</subject><subject>Mycophenolic acid</subject><subject>Mycophenolic Acid - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Phenylurea Compounds - pharmacology</subject><subject>RNA, Messenger - metabolism</subject><subject>Tumor Cells, Cultured</subject><subject>VX-497</subject><issn>0006-2952</issn><issn>1873-2968</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEGL1TAQx4Mo7nP1A3iRXPT26qRN2xRPsqj7YEEQPYd0OtmXR5vUpBX67W15hb3taf4Dv_8w_Bh7LyATIKrPl6zFMcsBigyaDGTxgh2Eqotj3lTqJTsAQLXmMr9hb1K6bKuqxGt2I2Rd1qKuD6z9RY9zbyYXPA-WOx-S88SH4MN4Dmk8m4l4R-eli-GRvEnEp2UkfuLGd3s8cZeCDXFIa5-f58F43i_D2sdlovSWvbKmT_Run7fsz_dvv-_ujw8_f5zuvj4cUcpyOiJaoUoobS2lqStC1VprEFurQJKCTkJZNlQjqgKlKmxXSUDoCrI1CdUUt-zT9e4Yw9-Z0qQHl5D63ngKc9IKRL5iGyiuIMaQUiSrx-gGExctQG9i9UWvYvUmVkOjV7Fr58N-fG4H6p4au8kV-LgDJqHpbTQeXXriyjIXEjbuy5WjVcU_R1EndOSROhcJJ90F98wb_wH-_pe5</recordid><startdate>20040215</startdate><enddate>20040215</enddate><creator>Jain, Jugnu</creator><creator>Almquist, Susan J.</creator><creator>Ford, Pamella J.</creator><creator>Shlyakhter, Dina</creator><creator>Wang, Yongping</creator><creator>Nimmesgern, Elmar</creator><creator>Germann, Ursula A.</creator><general>Elsevier Inc</general><general>Elsevier Science</general><scope>IQODW</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></search><sort><creationdate>20040215</creationdate><title>Regulation of inosine monophosphate dehydrogenase type I and type II isoforms in human lymphocytes</title><author>Jain, Jugnu ; Almquist, Susan J. ; Ford, Pamella J. ; Shlyakhter, Dina ; Wang, Yongping ; Nimmesgern, Elmar ; Germann, Ursula A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c445t-ccf18505f744a76ec8bffaccbf804e80d40559e7cc83c483fd640c0d3ef7e1893</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Biological and medical sciences</topic><topic>Carbamates - pharmacology</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Gene regulation</topic><topic>Humans</topic><topic>Immune</topic><topic>IMP Dehydrogenase - antagonists & inhibitors</topic><topic>IMP Dehydrogenase - genetics</topic><topic>IMP Dehydrogenase - metabolism</topic><topic>IMPDH</topic><topic>Isoenzymes - genetics</topic><topic>Isoenzymes - metabolism</topic><topic>Leukocytes, Mononuclear - drug effects</topic><topic>Leukocytes, Mononuclear - enzymology</topic><topic>Lymphocytes</topic><topic>Lymphocytes - enzymology</topic><topic>Medical sciences</topic><topic>Mycophenolic acid</topic><topic>Mycophenolic Acid - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Phenylurea Compounds - pharmacology</topic><topic>RNA, Messenger - metabolism</topic><topic>Tumor Cells, Cultured</topic><topic>VX-497</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jain, Jugnu</creatorcontrib><creatorcontrib>Almquist, Susan J.</creatorcontrib><creatorcontrib>Ford, Pamella J.</creatorcontrib><creatorcontrib>Shlyakhter, Dina</creatorcontrib><creatorcontrib>Wang, Yongping</creatorcontrib><creatorcontrib>Nimmesgern, Elmar</creatorcontrib><creatorcontrib>Germann, Ursula A.</creatorcontrib><collection>Pascal-Francis</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><jtitle>Biochemical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jain, Jugnu</au><au>Almquist, Susan J.</au><au>Ford, Pamella J.</au><au>Shlyakhter, Dina</au><au>Wang, Yongping</au><au>Nimmesgern, Elmar</au><au>Germann, Ursula A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Regulation of inosine monophosphate dehydrogenase type I and type II isoforms in human lymphocytes</atitle><jtitle>Biochemical pharmacology</jtitle><addtitle>Biochem Pharmacol</addtitle><date>2004-02-15</date><risdate>2004</risdate><volume>67</volume><issue>4</issue><spage>767</spage><epage>776</epage><pages>767-776</pages><issn>0006-2952</issn><eissn>1873-2968</eissn><coden>BCPCA6</coden><abstract>The enzyme inosine monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in the
de novo biosynthesis of guanine nucleotides. Inhibition of IMPDH leads to immunosuppression by decreasing guanine nucleotides that are required for the proliferation of lymphocytes. IMPDH activity is mediated by two highly conserved isoforms, type I and type II. We have characterized the mRNA and protein expression of the two isoforms in a variety of human tissues, peripheral blood mononuclear cells (PBMCs), and selected cell lines to investigate their regulation. Type I mRNA was expressed in most tissues with high expression in PBMCs and low expression in thymus. IMPDH type II transcript was also detected in most tissues with low expression in spleen and PBMCs. In PBMCs, induction of both type I and type II mRNAs was observed within 12
hr of mitogenic stimulation. Using type-selective IMPDH antibodies, an increase in the levels of type I and type II proteins was observed after mitogenic stimulation. The effect of two IMPDH inhibitors, MPA and VX-497, was investigated on the expression of type I and type II isoforms. VX-497 is an orally bioavailable, potent and reversible inhibitor of IMPDH, with broad applicability in many viral and immune system-mediated diseases. MPA and VX-497 inhibit both isoforms of IMPDH
in vitro. Prolonged treatment of lymphocytes with either VX-497 or MPA did not lead to an increase in type I or type II IMPDH protein levels. These results are discussed in the context of IMPDH being a target for immunosuppressive, anti-viral and anti-cancer therapy.</abstract><cop>New York, NY</cop><pub>Elsevier Inc</pub><pmid>14757177</pmid><doi>10.1016/j.bcp.2003.09.043</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0006-2952 |
| ispartof | Biochemical pharmacology, 2004-02, Vol.67 (4), p.767-776 |
| issn | 0006-2952 1873-2968 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_80128939 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Biological and medical sciences Carbamates - pharmacology Enzyme Inhibitors - pharmacology Gene regulation Humans Immune IMP Dehydrogenase - antagonists & inhibitors IMP Dehydrogenase - genetics IMP Dehydrogenase - metabolism IMPDH Isoenzymes - genetics Isoenzymes - metabolism Leukocytes, Mononuclear - drug effects Leukocytes, Mononuclear - enzymology Lymphocytes Lymphocytes - enzymology Medical sciences Mycophenolic acid Mycophenolic Acid - pharmacology Pharmacology. Drug treatments Phenylurea Compounds - pharmacology RNA, Messenger - metabolism Tumor Cells, Cultured VX-497 |
| title | Regulation of inosine monophosphate dehydrogenase type I and type II isoforms in human lymphocytes |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-18T22%3A04%3A28IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Regulation%20of%20inosine%20monophosphate%20dehydrogenase%20type%20I%20and%20type%20II%20isoforms%20in%20human%20lymphocytes&rft.jtitle=Biochemical%20pharmacology&rft.au=Jain,%20Jugnu&rft.date=2004-02-15&rft.volume=67&rft.issue=4&rft.spage=767&rft.epage=776&rft.pages=767-776&rft.issn=0006-2952&rft.eissn=1873-2968&rft.coden=BCPCA6&rft_id=info:doi/10.1016/j.bcp.2003.09.043&rft_dat=%3Cproquest_cross%3E80128939%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=80128939&rft_id=info:pmid/14757177&rft_els_id=S0006295203007962&rfr_iscdi=true |