A Proline-Rich Motif in p53 is Required for Transactivation-Independent Growth Arrest as Induced by Gas1
The involvement of p53 in regulating diverse cellular processes dictates that it must respond to multiple signaling mechanisms, thus coordinating the response to various ``stress conditions.'' Genotoxic stress has served as a paradigm to dissect the transactivation-dependent branch of the...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 1997-04, Vol.94 (9), p.4675-4680 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Ruaro, Elisabetta M. Collavin, Licio Del Sal, Giannino Haffner, Rebecca Oren, Moshe Levine, Arnold J. Schneider, Claudio |
| description | The involvement of p53 in regulating diverse cellular processes dictates that it must respond to multiple signaling mechanisms, thus coordinating the response to various ``stress conditions.'' Genotoxic stress has served as a paradigm to dissect the transactivation-dependent branch of the pathway by which p53 can induce growth arrest. Alternate mechanisms have been invoked to explain transactivation-independent effects of p53, especially in the context of apoptosis. We have identified a p53-dependent pathway initiated by the gas1 product, a plasma membrane protein highly expressed during G0, which activates a transactivation-independent p53 growth arrest function. Through a detailed deletional analysis and site-specific mutagenesis of p53 we show that the Gas1-dependent signal transduction relies on a proline-rich region (amino acids 63-85) of murine p53. In vivo competition experiments using combinations of such mutants implicate this functional domain of p53 as a docking site in the transmission of antiproliferative signals. |
| doi_str_mv | 10.1073/pnas.94.9.4675 |
| format | Article |
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Genotoxic stress has served as a paradigm to dissect the transactivation-dependent branch of the pathway by which p53 can induce growth arrest. Alternate mechanisms have been invoked to explain transactivation-independent effects of p53, especially in the context of apoptosis. We have identified a p53-dependent pathway initiated by the gas1 product, a plasma membrane protein highly expressed during G0, which activates a transactivation-independent p53 growth arrest function. Through a detailed deletional analysis and site-specific mutagenesis of p53 we show that the Gas1-dependent signal transduction relies on a proline-rich region (amino acids 63-85) of murine p53. 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Genotoxic stress has served as a paradigm to dissect the transactivation-dependent branch of the pathway by which p53 can induce growth arrest. Alternate mechanisms have been invoked to explain transactivation-independent effects of p53, especially in the context of apoptosis. We have identified a p53-dependent pathway initiated by the gas1 product, a plasma membrane protein highly expressed during G0, which activates a transactivation-independent p53 growth arrest function. Through a detailed deletional analysis and site-specific mutagenesis of p53 we show that the Gas1-dependent signal transduction relies on a proline-rich region (amino acids 63-85) of murine p53. In vivo competition experiments using combinations of such mutants implicate this functional domain of p53 as a docking site in the transmission of antiproliferative signals.</description><subject>Amino Acid Sequence</subject><subject>Amino acids</subject><subject>Animals</subject><subject>Binding Sites</subject><subject>Biological Sciences</subject><subject>Cell cycle</subject><subject>Cell Cycle - physiology</subject><subject>Cell Cycle Proteins</subject><subject>Cell growth</subject><subject>Cell membranes</subject><subject>Cellular biology</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA Mutational Analysis</subject><subject>Fibroblasts</subject><subject>GPI-Linked Proteins</subject><subject>Mathematical functions</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Models, Biological</subject><subject>Molecular Sequence Data</subject><subject>Mutagenesis, Site-Directed</subject><subject>Plasma</subject><subject>Proline</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Signal Transduction</subject><subject>Transactivation</subject><subject>Transcriptional Activation</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkcFrHCEYxaU0pNu01x4KBcmht5noquMIvSyh3QYSUkJ6FkedrsusTtRJm_--LrtZNqUXPbzf-3jf9wD4gFGNEScXo1epFrQWNW04ewVmGAlcNVSg12CG0JxXLZ3TN-BtSmuEkGAtOgWnAmOKGJqB1QL-iGFw3lZ3Tq_gTciuh87DkRHoEryzD5OL1sA-RHgflU9KZ_eosgu-uvLGjrY8PsNlDL_zCi5itClDlWARJ12M3RNcqoTfgZNeDcm-3_9n4Oe3r_eX36vr2-XV5eK60gyTXGkuhGr73hjRMtM1GuPezjUVwnLeYkM0a1pGtSatabBpiMYEGd53naZco4acgS-7uePUbazRJVtUgxyj26j4JINy8qXi3Ur-Co9yjnhLiv3z3h7Dw1RWkRuXtB0G5W2YksRMNA2jbQHP_wHXYYq-rFYmlUyEcl6gegfpGFKKtj_kwEhu65Pb-qSgUshtfcXw6Tj9Ad_3dRRv6zuoz37ZT8OQ7Z98NOi_YNE_7vR1yiEeAFqugMlfljW3mA</recordid><startdate>19970429</startdate><enddate>19970429</enddate><creator>Ruaro, Elisabetta M.</creator><creator>Collavin, Licio</creator><creator>Del Sal, Giannino</creator><creator>Haffner, Rebecca</creator><creator>Oren, Moshe</creator><creator>Levine, Arnold J.</creator><creator>Schneider, Claudio</creator><general>National Academy of Sciences of the United States of America</general><general>National Acad Sciences</general><general>National Academy of Sciences</general><general>The National Academy of Sciences of the USA</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>19970429</creationdate><title>A Proline-Rich Motif in p53 is Required for Transactivation-Independent Growth Arrest as Induced by Gas1</title><author>Ruaro, Elisabetta M. ; 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| ispartof | Proceedings of the National Academy of Sciences - PNAS, 1997-04, Vol.94 (9), p.4675-4680 |
| issn | 0027-8424 1091-6490 |
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| source | MEDLINE; Jstor Complete Legacy; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Amino Acid Sequence Amino acids Animals Binding Sites Biological Sciences Cell cycle Cell Cycle - physiology Cell Cycle Proteins Cell growth Cell membranes Cellular biology DNA DNA damage DNA Mutational Analysis Fibroblasts GPI-Linked Proteins Mathematical functions Membrane Proteins - metabolism Mice Mice, Inbred BALB C Models, Biological Molecular Sequence Data Mutagenesis, Site-Directed Plasma Proline Protein Binding Proteins Signal Transduction Transactivation Transcriptional Activation Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism |
| title | A Proline-Rich Motif in p53 is Required for Transactivation-Independent Growth Arrest as Induced by Gas1 |
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