Rapid ATM-Dependent Phosphorylation of MDM2 Precedes p53 Accumulation in Response to DNA Damage
The p53 tumor-suppressor protein, a key regulator of cellular responses to genotoxic stress, is stabilized and activated after DNA damage. This process is associated with posttranslational modifications of p53, some of which are mediated by the ATM protein kinase. However, these modifications alone...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 1999-12, Vol.96 (26), p.14973-14977 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Khosravi, Rami Maya, Ruth Gottlieb, Tanya Oren, Moshe Shiloh, Yosef Shkedy, Dganit |
| description | The p53 tumor-suppressor protein, a key regulator of cellular responses to genotoxic stress, is stabilized and activated after DNA damage. This process is associated with posttranslational modifications of p53, some of which are mediated by the ATM protein kinase. However, these modifications alone may not account in full for p53 stabilization. p53's stability and activity are negatively regulated by the oncoprotein MDM2, whose gene is activated by p53. Conceivably, p53 function may be modulated by modifications of MDM2 as well. We show here that after treatment of cells with ionizing radiation or a radiomimetic chemical, but not UV radiation, MDM2 is phosphorylated rapidly in an ATM-dependent manner. This phosphorylation is independent of p53 and the DNA-dependent protein kinase. Furthermore, MDM2 is directly phosphorylated by ATM in vitro. These findings suggest that in response to DNA strand breaks, ATM may promote p53 activity and stability by mediating simultaneous phosphorylation of both partners of the p53-MDM2 autoregulatory feedback loop. |
| doi_str_mv | 10.1073/pnas.96.26.14973 |
| format | Article |
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This process is associated with posttranslational modifications of p53, some of which are mediated by the ATM protein kinase. However, these modifications alone may not account in full for p53 stabilization. p53's stability and activity are negatively regulated by the oncoprotein MDM2, whose gene is activated by p53. Conceivably, p53 function may be modulated by modifications of MDM2 as well. We show here that after treatment of cells with ionizing radiation or a radiomimetic chemical, but not UV radiation, MDM2 is phosphorylated rapidly in an ATM-dependent manner. This phosphorylation is independent of p53 and the DNA-dependent protein kinase. Furthermore, MDM2 is directly phosphorylated by ATM in vitro. 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These findings suggest that in response to DNA strand breaks, ATM may promote p53 activity and stability by mediating simultaneous phosphorylation of both partners of the p53-MDM2 autoregulatory feedback loop.</description><subject>Alkaline Phosphatase - metabolism</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Apoptosis</subject><subject>Ataxia Telangiectasia Mutated Proteins</subject><subject>ATM protein</subject><subject>Biological Sciences</subject><subject>Cell Cycle</subject><subject>Cell Cycle Proteins</subject><subject>Cell lines</subject><subject>Cellular biology</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA Damage - physiology</subject><subject>DNA Repair</subject><subject>DNA-Activated Protein Kinase</subject><subject>DNA-Binding Proteins</subject><subject>Feedback</subject><subject>Humans</subject><subject>Infrared radiation</subject><subject>Ionizing radiation</subject><subject>MDM2 protein</subject><subject>Mice</subject><subject>Nuclear Proteins</subject><subject>Phosphatases</subject><subject>Phosphorylation</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-mdm2</subject><subject>Radiation damage</subject><subject>Radiation, Ionizing</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumor Suppressor Proteins</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUtv1DAUhS0EokNhj4QEFgvEJoNfsWOJzajDS-pAVZW15bFvOhklcWonqP339TADtCxgdWWd79yHD0LPKZlTovi7obdpruWcyTkVWvEHaEaJpoUUmjxEM0KYKirBxBF6ktKWEKLLijxGR5RISjljM2TO7dB4vLhYFUsYoPfQj_hsE9KwCfGmtWMTehxqvFquGD6L4MBDwkPJ8cK5qZsORNPjc0hD6BPgMeDl1wVe2s5ewlP0qLZtgmeHeoy-f_xwcfK5OP326cvJ4rRwpaZjISQjNm_NnSa-ElysqWdeEqiVg9pZD9StS5Z1L0vQtRSe0xqEtiK_yoofo_f7vsO07sC7fEa0rRli09l4Y4JtzH2lbzbmMvwwTKhSZfubgz2GqwnSaLomOWhb20OYkpGaK1Up-l-QKsF4VZIMvv4L3IYp9vkPDCOUayH5DiJ7yMWQUoT698KUmF3CZpew0dIwaX4mnC0v7x56x7CPNAOvDsDO-ku-3-LtvwlTT207wvWY0Rd7dJvGEP8MY5Rqym8BHdbDaA</recordid><startdate>19991221</startdate><enddate>19991221</enddate><creator>Khosravi, Rami</creator><creator>Maya, Ruth</creator><creator>Gottlieb, Tanya</creator><creator>Oren, Moshe</creator><creator>Shiloh, Yosef</creator><creator>Shkedy, Dganit</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</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>19991221</creationdate><title>Rapid ATM-Dependent Phosphorylation of MDM2 Precedes p53 Accumulation in Response to DNA Damage</title><author>Khosravi, Rami ; 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This process is associated with posttranslational modifications of p53, some of which are mediated by the ATM protein kinase. However, these modifications alone may not account in full for p53 stabilization. p53's stability and activity are negatively regulated by the oncoprotein MDM2, whose gene is activated by p53. Conceivably, p53 function may be modulated by modifications of MDM2 as well. We show here that after treatment of cells with ionizing radiation or a radiomimetic chemical, but not UV radiation, MDM2 is phosphorylated rapidly in an ATM-dependent manner. This phosphorylation is independent of p53 and the DNA-dependent protein kinase. Furthermore, MDM2 is directly phosphorylated by ATM in vitro. These findings suggest that in response to DNA strand breaks, ATM may promote p53 activity and stability by mediating simultaneous phosphorylation of both partners of the p53-MDM2 autoregulatory feedback loop.</abstract><cop>United States</cop><pub>National Academy of Sciences of the United States of America</pub><pmid>10611322</pmid><doi>10.1073/pnas.96.26.14973</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Proceedings of the National Academy of Sciences - PNAS, 1999-12, Vol.96 (26), p.14973-14977 |
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| subjects | Alkaline Phosphatase - metabolism Animals Antibodies Apoptosis Ataxia Telangiectasia Mutated Proteins ATM protein Biological Sciences Cell Cycle Cell Cycle Proteins Cell lines Cellular biology Deoxyribonucleic acid DNA DNA damage DNA Damage - physiology DNA Repair DNA-Activated Protein Kinase DNA-Binding Proteins Feedback Humans Infrared radiation Ionizing radiation MDM2 protein Mice Nuclear Proteins Phosphatases Phosphorylation Protein-Serine-Threonine Kinases - metabolism Proteins Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-mdm2 Radiation damage Radiation, Ionizing Tumor Suppressor Protein p53 - metabolism Tumor Suppressor Proteins |
| title | Rapid ATM-Dependent Phosphorylation of MDM2 Precedes p53 Accumulation in Response to DNA Damage |
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