Acetylation Is Crucial for p53-Mediated Ferroptosis and Tumor Suppression
Although previous studies indicate that loss of p53-mediated cell cycle arrest, apoptosis, and senescence does not completely abrogate its tumor suppression function, it is unclear how the remaining activities of p53 are regulated. Here, we have identified an acetylation site at lysine K98 in mouse...
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Elsevier
2016-10-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112471631244X |
| _version_ | 1818284160009109504 |
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| author | Shang-Jui Wang Dawei Li Yang Ou Le Jiang Yue Chen Yingming Zhao Wei Gu |
| author_facet | Shang-Jui Wang Dawei Li Yang Ou Le Jiang Yue Chen Yingming Zhao Wei Gu |
| author_sort | Shang-Jui Wang |
| collection | DOAJ |
| description | Although previous studies indicate that loss of p53-mediated cell cycle arrest, apoptosis, and senescence does not completely abrogate its tumor suppression function, it is unclear how the remaining activities of p53 are regulated. Here, we have identified an acetylation site at lysine K98 in mouse p53 (or K101 for human p53). Whereas the loss of K98 acetylation (p53K98R) alone has very modest effects on p53-mediated transactivation, simultaneous mutations at all four acetylation sites (p534KR: K98R+ 3KR[K117R+K161R+K162R]) completely abolish its ability to regulate metabolic targets, such as TIGAR and SLC7A11. Notably, in contrast to p533KR, p534KR is severely defective in suppressing tumor growth in mouse xenograft models. Moreover, p534KR is still capable of inducing the p53-Mdm2 feedback loop, but p53-dependent ferroptotic responses are markedly abrogated. Together, these data indicate the critical role of p53 acetylation in ferroptotic responses and its remaining tumor suppression activity. |
| first_indexed | 2024-12-13T00:48:23Z |
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| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-13T00:48:23Z |
| publishDate | 2016-10-01 |
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| series | Cell Reports |
| spelling | doaj.art-0379811ac2074b098a1fcbcf27b579ff2022-12-22T00:04:59ZengElsevierCell Reports2211-12472016-10-0117236637310.1016/j.celrep.2016.09.022Acetylation Is Crucial for p53-Mediated Ferroptosis and Tumor SuppressionShang-Jui Wang0Dawei Li1Yang Ou2Le Jiang3Yue Chen4Yingming Zhao5Wei Gu6Institute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, 1130 Nicholas Avenue, New York, NY 10032, USAInstitute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, 1130 Nicholas Avenue, New York, NY 10032, USAInstitute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, 1130 Nicholas Avenue, New York, NY 10032, USAInstitute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, 1130 Nicholas Avenue, New York, NY 10032, USABen May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USABen May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USAInstitute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, 1130 Nicholas Avenue, New York, NY 10032, USAAlthough previous studies indicate that loss of p53-mediated cell cycle arrest, apoptosis, and senescence does not completely abrogate its tumor suppression function, it is unclear how the remaining activities of p53 are regulated. Here, we have identified an acetylation site at lysine K98 in mouse p53 (or K101 for human p53). Whereas the loss of K98 acetylation (p53K98R) alone has very modest effects on p53-mediated transactivation, simultaneous mutations at all four acetylation sites (p534KR: K98R+ 3KR[K117R+K161R+K162R]) completely abolish its ability to regulate metabolic targets, such as TIGAR and SLC7A11. Notably, in contrast to p533KR, p534KR is severely defective in suppressing tumor growth in mouse xenograft models. Moreover, p534KR is still capable of inducing the p53-Mdm2 feedback loop, but p53-dependent ferroptotic responses are markedly abrogated. Together, these data indicate the critical role of p53 acetylation in ferroptotic responses and its remaining tumor suppression activity.http://www.sciencedirect.com/science/article/pii/S221112471631244Xp53acetylationdeacetylationferroptosismetabolic regulationtranscriptionSLC7A11tumor suppression |
| spellingShingle | Shang-Jui Wang Dawei Li Yang Ou Le Jiang Yue Chen Yingming Zhao Wei Gu Acetylation Is Crucial for p53-Mediated Ferroptosis and Tumor Suppression Cell Reports p53 acetylation deacetylation ferroptosis metabolic regulation transcription SLC7A11 tumor suppression |
| title | Acetylation Is Crucial for p53-Mediated Ferroptosis and Tumor Suppression |
| title_full | Acetylation Is Crucial for p53-Mediated Ferroptosis and Tumor Suppression |
| title_fullStr | Acetylation Is Crucial for p53-Mediated Ferroptosis and Tumor Suppression |
| title_full_unstemmed | Acetylation Is Crucial for p53-Mediated Ferroptosis and Tumor Suppression |
| title_short | Acetylation Is Crucial for p53-Mediated Ferroptosis and Tumor Suppression |
| title_sort | acetylation is crucial for p53 mediated ferroptosis and tumor suppression |
| topic | p53 acetylation deacetylation ferroptosis metabolic regulation transcription SLC7A11 tumor suppression |
| url | http://www.sciencedirect.com/science/article/pii/S221112471631244X |
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