Caspase-2-Mediated Cleavage of Mdm2 Creates a p53-Induced Positive Feedback Loop
Caspase-2 is an evolutionarily conserved caspase, yet its biological function and cleavage targets are poorly understood. Caspase-2 is activated by the p53 target gene product PIDD (also known as LRDD) in a complex called the Caspase-2-PIDDosome. We show that PIDD expression promotes growth arrest a...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2015
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| Online Access: | http://hdl.handle.net/1721.1/95804 https://orcid.org/0000-0001-5785-8911 |
| _version_ | 1826200786836652032 |
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| author | Oliver, Trudy Meylan, Etienne Chang, Gregory P. Xue, Wen Burke, James R. Humpton, Timothy J. Hubbard, Diana D. Bhutkar, Arjun (AJ) Jacks, Tyler E. |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Oliver, Trudy Meylan, Etienne Chang, Gregory P. Xue, Wen Burke, James R. Humpton, Timothy J. Hubbard, Diana D. Bhutkar, Arjun (AJ) Jacks, Tyler E. |
| author_sort | Oliver, Trudy |
| collection | MIT |
| description | Caspase-2 is an evolutionarily conserved caspase, yet its biological function and cleavage targets are poorly understood. Caspase-2 is activated by the p53 target gene product PIDD (also known as LRDD) in a complex called the Caspase-2-PIDDosome. We show that PIDD expression promotes growth arrest and chemotherapy resistance by a mechanism that depends on Caspase-2 and wild-type p53. PIDD-induced Caspase-2 directly cleaves the E3 ubiquitin ligase Mdm2 at Asp 367, leading to loss of the C-terminal RING domain responsible for p53 ubiquitination. As a consequence, N-terminally truncated Mdm2 binds p53 and promotes its stability. Upon DNA damage, p53 induction of the Caspase-2-PIDDosome creates a positive feedback loop that inhibits Mdm2 and reinforces p53 stability and activity, contributing to cell survival and drug resistance. These data establish Mdm2 as a cleavage target of Caspase-2 and provide insight into a mechanism of Mdm2 inhibition that impacts p53 dynamics upon genotoxic stress. |
| first_indexed | 2024-09-23T11:41:44Z |
| format | Article |
| id | mit-1721.1/95804 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:41:44Z |
| publishDate | 2015 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/958042022-10-01T05:19:35Z Caspase-2-Mediated Cleavage of Mdm2 Creates a p53-Induced Positive Feedback Loop Oliver, Trudy Meylan, Etienne Chang, Gregory P. Xue, Wen Burke, James R. Humpton, Timothy J. Hubbard, Diana D. Bhutkar, Arjun (AJ) Jacks, Tyler E. Koch Institute for Integrative Cancer Research at MIT Bhutkar, Arjun (AJ) Jacks, Tyler E. Oliver, Trudy Meylan, Etienne Chang, Gregory P. Xue, Wen Burke, James R. Humpton, Timothy J. Caspase-2 is an evolutionarily conserved caspase, yet its biological function and cleavage targets are poorly understood. Caspase-2 is activated by the p53 target gene product PIDD (also known as LRDD) in a complex called the Caspase-2-PIDDosome. We show that PIDD expression promotes growth arrest and chemotherapy resistance by a mechanism that depends on Caspase-2 and wild-type p53. PIDD-induced Caspase-2 directly cleaves the E3 ubiquitin ligase Mdm2 at Asp 367, leading to loss of the C-terminal RING domain responsible for p53 ubiquitination. As a consequence, N-terminally truncated Mdm2 binds p53 and promotes its stability. Upon DNA damage, p53 induction of the Caspase-2-PIDDosome creates a positive feedback loop that inhibits Mdm2 and reinforces p53 stability and activity, contributing to cell survival and drug resistance. These data establish Mdm2 as a cleavage target of Caspase-2 and provide insight into a mechanism of Mdm2 inhibition that impacts p53 dynamics upon genotoxic stress. Virginia and D.K. Ludwig Fund for Cancer Research (Postdoctoral Fellowship) Human Frontier Science Program (Strasbourg, France) (Fellowship) National Cancer Institute (U.S.) (Cancer Center Support (Core) Grant P30-CA14051) 2015-03-04T17:31:57Z 2015-03-04T17:31:57Z 2011-07 2011-05 Article http://purl.org/eprint/type/JournalArticle 10972765 1097-4164 http://hdl.handle.net/1721.1/95804 Oliver, Trudy G., Etienne Meylan, Gregory P. Chang, Wen Xue, James R. Burke, Timothy J. Humpton, Diana Hubbard, Arjun Bhutkar, and Tyler Jacks. “Caspase-2-Mediated Cleavage of Mdm2 Creates a P53-Induced Positive Feedback Loop.” Molecular Cell 43, no. 1 (July 2011): 57–71. © 2011 Elsevier Inc. https://orcid.org/0000-0001-5785-8911 en_US http://dx.doi.org/10.1016/j.molcel.2011.06.012 Molecular Cell Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Elsevier Elsevier |
| spellingShingle | Oliver, Trudy Meylan, Etienne Chang, Gregory P. Xue, Wen Burke, James R. Humpton, Timothy J. Hubbard, Diana D. Bhutkar, Arjun (AJ) Jacks, Tyler E. Caspase-2-Mediated Cleavage of Mdm2 Creates a p53-Induced Positive Feedback Loop |
| title | Caspase-2-Mediated Cleavage of Mdm2 Creates a p53-Induced Positive Feedback Loop |
| title_full | Caspase-2-Mediated Cleavage of Mdm2 Creates a p53-Induced Positive Feedback Loop |
| title_fullStr | Caspase-2-Mediated Cleavage of Mdm2 Creates a p53-Induced Positive Feedback Loop |
| title_full_unstemmed | Caspase-2-Mediated Cleavage of Mdm2 Creates a p53-Induced Positive Feedback Loop |
| title_short | Caspase-2-Mediated Cleavage of Mdm2 Creates a p53-Induced Positive Feedback Loop |
| title_sort | caspase 2 mediated cleavage of mdm2 creates a p53 induced positive feedback loop |
| url | http://hdl.handle.net/1721.1/95804 https://orcid.org/0000-0001-5785-8911 |
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