TGFβ inhibition of Cdk4 synthesis is linked to cell cycle arrest
Transforming growth factor β1 (TGFβ1) causes G1 growth arrest and the accumulation of unphosphorylated retinoblastoma protein (Rb) in responsive cells. Cdk4 (cyclin-dependent kinase), a major catalytic subunit of the mammalian D-type G1 cyclins, can phosphorylate Rb in vitro, and at least one D-type...
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| Veröffentlicht in: | Cell 1993-09, Vol.74 (6), p.1009-1020 |
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| creator | Ewen, Mark E. Sluss, Hayla K. Whitehouse, Laura L. Livingston, David M. |
| description | Transforming growth factor β1 (TGFβ1) causes G1 growth arrest and the accumulation of unphosphorylated retinoblastoma protein (Rb) in responsive cells. Cdk4 (cyclin-dependent kinase), a major catalytic subunit of the mammalian D-type G1 cyclins, can phosphorylate Rb in vitro, and at least one D-type cyclin, D2, directs the phosphorylation of Rb in vivo. Here we show that TGFβ1 induces suppression of cdk4 synthesis in G1 in mink lung epithelial cells. Constitutive cdk4 synthesis in these cells led to TGFβ1 resistance. It also resulted in growth in low serum medium when these cells were released from contact inhibition. Cdk2 activity was also suppressed by TGFβ1 action, but its constitutive expression failed to override a TGFβ1-induced G1 block. Hence, the TGFβ1 block is primarily mediated by cdk4 modulation. Further evidence suggests that TGFβ1-induced down-modulation of cdk4 leads to inhibition of cdk2 activation and that both events might contribute to TGFβ1 growth suppression. |
| doi_str_mv | 10.1016/0092-8674(93)90723-4 |
| format | Article |
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Cdk4 (cyclin-dependent kinase), a major catalytic subunit of the mammalian D-type G1 cyclins, can phosphorylate Rb in vitro, and at least one D-type cyclin, D2, directs the phosphorylation of Rb in vivo. Here we show that TGFβ1 induces suppression of cdk4 synthesis in G1 in mink lung epithelial cells. Constitutive cdk4 synthesis in these cells led to TGFβ1 resistance. It also resulted in growth in low serum medium when these cells were released from contact inhibition. Cdk2 activity was also suppressed by TGFβ1 action, but its constitutive expression failed to override a TGFβ1-induced G1 block. Hence, the TGFβ1 block is primarily mediated by cdk4 modulation. Further evidence suggests that TGFβ1-induced down-modulation of cdk4 leads to inhibition of cdk2 activation and that both events might contribute to TGFβ1 growth suppression.</description><identifier>ISSN: 0092-8674</identifier><identifier>EISSN: 1097-4172</identifier><identifier>DOI: 10.1016/0092-8674(93)90723-4</identifier><identifier>PMID: 8402878</identifier><identifier>CODEN: CELLB5</identifier><language>eng</language><publisher>Cambridge, MA: Elsevier Inc</publisher><subject>Animals ; Biological and medical sciences ; CDC2-CDC28 Kinases ; Cell Cycle - drug effects ; Cell Cycle - physiology ; Cell Line ; Cell physiology ; Clone Cells ; Cyclin-Dependent Kinase 2 ; Cyclin-Dependent Kinase 4 ; Cyclin-Dependent Kinases ; Epithelium ; Fundamental and applied biological sciences. Psychology ; Lung ; Mink ; Molecular and cellular biology ; Peptide Mapping ; Phosphorylation ; Protamine Kinase - metabolism ; Protein Kinase Inhibitors ; Protein Kinases - biosynthesis ; Protein Kinases - metabolism ; Protein-Serine-Threonine Kinases ; Proto-Oncogene Proteins ; Recombinant Proteins - biosynthesis ; Recombinant Proteins - metabolism ; Responses to growth factors, tumor promotors, other factors ; Retinoblastoma Protein - metabolism ; Transfection ; Transforming Growth Factor beta - pharmacology</subject><ispartof>Cell, 1993-09, Vol.74 (6), p.1009-1020</ispartof><rights>1993</rights><rights>1993 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c417t-293367bd8c59724bcbc520b16cb36622fa830a382a4834388caf9db797f350263</citedby><cites>FETCH-LOGICAL-c417t-293367bd8c59724bcbc520b16cb36622fa830a382a4834388caf9db797f350263</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/0092-8674(93)90723-4$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3548,27922,27923,45993</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=4916440$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8402878$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ewen, Mark E.</creatorcontrib><creatorcontrib>Sluss, Hayla K.</creatorcontrib><creatorcontrib>Whitehouse, Laura L.</creatorcontrib><creatorcontrib>Livingston, David M.</creatorcontrib><title>TGFβ inhibition of Cdk4 synthesis is linked to cell cycle arrest</title><title>Cell</title><addtitle>Cell</addtitle><description>Transforming growth factor β1 (TGFβ1) causes G1 growth arrest and the accumulation of unphosphorylated retinoblastoma protein (Rb) in responsive cells. Cdk4 (cyclin-dependent kinase), a major catalytic subunit of the mammalian D-type G1 cyclins, can phosphorylate Rb in vitro, and at least one D-type cyclin, D2, directs the phosphorylation of Rb in vivo. Here we show that TGFβ1 induces suppression of cdk4 synthesis in G1 in mink lung epithelial cells. Constitutive cdk4 synthesis in these cells led to TGFβ1 resistance. It also resulted in growth in low serum medium when these cells were released from contact inhibition. Cdk2 activity was also suppressed by TGFβ1 action, but its constitutive expression failed to override a TGFβ1-induced G1 block. Hence, the TGFβ1 block is primarily mediated by cdk4 modulation. Further evidence suggests that TGFβ1-induced down-modulation of cdk4 leads to inhibition of cdk2 activation and that both events might contribute to TGFβ1 growth suppression.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>CDC2-CDC28 Kinases</subject><subject>Cell Cycle - drug effects</subject><subject>Cell Cycle - physiology</subject><subject>Cell Line</subject><subject>Cell physiology</subject><subject>Clone Cells</subject><subject>Cyclin-Dependent Kinase 2</subject><subject>Cyclin-Dependent Kinase 4</subject><subject>Cyclin-Dependent Kinases</subject><subject>Epithelium</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Lung</subject><subject>Mink</subject><subject>Molecular and cellular biology</subject><subject>Peptide Mapping</subject><subject>Phosphorylation</subject><subject>Protamine Kinase - metabolism</subject><subject>Protein Kinase Inhibitors</subject><subject>Protein Kinases - biosynthesis</subject><subject>Protein Kinases - metabolism</subject><subject>Protein-Serine-Threonine Kinases</subject><subject>Proto-Oncogene Proteins</subject><subject>Recombinant Proteins - biosynthesis</subject><subject>Recombinant Proteins - metabolism</subject><subject>Responses to growth factors, tumor promotors, other factors</subject><subject>Retinoblastoma Protein - metabolism</subject><subject>Transfection</subject><subject>Transforming Growth Factor beta - pharmacology</subject><issn>0092-8674</issn><issn>1097-4172</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1993</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkM1Kw0AQxxdRaq2-gcIeRPQQ3a_sx0UoxVah4KWel81mQ9emSd1Nhb6WD-IzmdjQo8LAHOY3M39-AFxidI8R5g8IKZJILtitoncKCUITdgSGGCmRMCzIMRgekFNwFuM7QkimaToAA8kQkUIOwXgxm35_QV8tfeYbX1ewLuAkXzEYd1WzdNFH2Fbpq5XLYVND68oS2p0tHTQhuNicg5PClNFd9H0E3qZPi8lzMn-dvUzG88S2YZqEKEq5yHJpUyUIy2xmU4IyzG1GOSekMJIiQyUxTFJGpbSmUHkmlChoiginI3Czv7sJ9ce2fazXPnZpTOXqbdQiVYoIlv4LYs4FJ4i1INuDNtQxBlfoTfBrE3YaI90p1p0_3fnTiupfxbpbu-rvb7O1yw9LvdN2ft3PTbSmLIKprI8HjCnMGUMt9rjHXCvt07ugo_Wusi73wdlG57X_O8cPNGuVoQ</recordid><startdate>19930924</startdate><enddate>19930924</enddate><creator>Ewen, Mark E.</creator><creator>Sluss, Hayla K.</creator><creator>Whitehouse, Laura L.</creator><creator>Livingston, David M.</creator><general>Elsevier Inc</general><general>Cell Press</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>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>19930924</creationdate><title>TGFβ inhibition of Cdk4 synthesis is linked to cell cycle arrest</title><author>Ewen, Mark E. ; Sluss, Hayla K. ; Whitehouse, Laura L. ; Livingston, David M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c417t-293367bd8c59724bcbc520b16cb36622fa830a382a4834388caf9db797f350263</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1993</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>CDC2-CDC28 Kinases</topic><topic>Cell Cycle - drug effects</topic><topic>Cell Cycle - physiology</topic><topic>Cell Line</topic><topic>Cell physiology</topic><topic>Clone Cells</topic><topic>Cyclin-Dependent Kinase 2</topic><topic>Cyclin-Dependent Kinase 4</topic><topic>Cyclin-Dependent Kinases</topic><topic>Epithelium</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Lung</topic><topic>Mink</topic><topic>Molecular and cellular biology</topic><topic>Peptide Mapping</topic><topic>Phosphorylation</topic><topic>Protamine Kinase - metabolism</topic><topic>Protein Kinase Inhibitors</topic><topic>Protein Kinases - biosynthesis</topic><topic>Protein Kinases - metabolism</topic><topic>Protein-Serine-Threonine Kinases</topic><topic>Proto-Oncogene Proteins</topic><topic>Recombinant Proteins - biosynthesis</topic><topic>Recombinant Proteins - metabolism</topic><topic>Responses to growth factors, tumor promotors, other factors</topic><topic>Retinoblastoma Protein - metabolism</topic><topic>Transfection</topic><topic>Transforming Growth Factor beta - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ewen, Mark E.</creatorcontrib><creatorcontrib>Sluss, Hayla K.</creatorcontrib><creatorcontrib>Whitehouse, Laura L.</creatorcontrib><creatorcontrib>Livingston, David M.</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>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ewen, Mark E.</au><au>Sluss, Hayla K.</au><au>Whitehouse, Laura L.</au><au>Livingston, David M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TGFβ inhibition of Cdk4 synthesis is linked to cell cycle arrest</atitle><jtitle>Cell</jtitle><addtitle>Cell</addtitle><date>1993-09-24</date><risdate>1993</risdate><volume>74</volume><issue>6</issue><spage>1009</spage><epage>1020</epage><pages>1009-1020</pages><issn>0092-8674</issn><eissn>1097-4172</eissn><coden>CELLB5</coden><abstract>Transforming growth factor β1 (TGFβ1) causes G1 growth arrest and the accumulation of unphosphorylated retinoblastoma protein (Rb) in responsive cells. Cdk4 (cyclin-dependent kinase), a major catalytic subunit of the mammalian D-type G1 cyclins, can phosphorylate Rb in vitro, and at least one D-type cyclin, D2, directs the phosphorylation of Rb in vivo. Here we show that TGFβ1 induces suppression of cdk4 synthesis in G1 in mink lung epithelial cells. Constitutive cdk4 synthesis in these cells led to TGFβ1 resistance. It also resulted in growth in low serum medium when these cells were released from contact inhibition. Cdk2 activity was also suppressed by TGFβ1 action, but its constitutive expression failed to override a TGFβ1-induced G1 block. Hence, the TGFβ1 block is primarily mediated by cdk4 modulation. Further evidence suggests that TGFβ1-induced down-modulation of cdk4 leads to inhibition of cdk2 activation and that both events might contribute to TGFβ1 growth suppression.</abstract><cop>Cambridge, MA</cop><pub>Elsevier Inc</pub><pmid>8402878</pmid><doi>10.1016/0092-8674(93)90723-4</doi><tpages>12</tpages></addata></record> |
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| subjects | Animals Biological and medical sciences CDC2-CDC28 Kinases Cell Cycle - drug effects Cell Cycle - physiology Cell Line Cell physiology Clone Cells Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinases Epithelium Fundamental and applied biological sciences. Psychology Lung Mink Molecular and cellular biology Peptide Mapping Phosphorylation Protamine Kinase - metabolism Protein Kinase Inhibitors Protein Kinases - biosynthesis Protein Kinases - metabolism Protein-Serine-Threonine Kinases Proto-Oncogene Proteins Recombinant Proteins - biosynthesis Recombinant Proteins - metabolism Responses to growth factors, tumor promotors, other factors Retinoblastoma Protein - metabolism Transfection Transforming Growth Factor beta - pharmacology |
| title | TGFβ inhibition of Cdk4 synthesis is linked to cell cycle arrest |
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