Protein adduction causes non-mutational inhibition of p53 tumor suppressor
Summary: p53 is a key tumor suppressor that is frequently mutated in human tumors. In this study, we investigated how p53 is regulated in precancerous lesions prior to mutations in the p53 gene. Analyzing esophageal cells in conditions of genotoxic stress that promotes development of esophageal aden...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723000359 |
| _version_ | 1797944080245719040 |
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| author | Ravindran Caspa Gokulan Kodisundaram Paulrasu Jamal Azfar Wael El-Rifai Jianwen Que Olivier G. Boutaud Yuguang Ban Zhen Gao Monica Garcia Buitrago Sergey I. Dikalov Alexander I. Zaika |
| author_facet | Ravindran Caspa Gokulan Kodisundaram Paulrasu Jamal Azfar Wael El-Rifai Jianwen Que Olivier G. Boutaud Yuguang Ban Zhen Gao Monica Garcia Buitrago Sergey I. Dikalov Alexander I. Zaika |
| author_sort | Ravindran Caspa Gokulan |
| collection | DOAJ |
| description | Summary: p53 is a key tumor suppressor that is frequently mutated in human tumors. In this study, we investigated how p53 is regulated in precancerous lesions prior to mutations in the p53 gene. Analyzing esophageal cells in conditions of genotoxic stress that promotes development of esophageal adenocarcinoma, we find that p53 protein is adducted with reactive isolevuglandins (isoLGs), products of lipid peroxidation. Modification of p53 protein with isoLGs diminishes its acetylation and binding to the promoters of p53 target genes causing modulation of p53-dependent transcription. It also leads to accumulation of adducted p53 protein in intracellular amyloid-like aggregates that can be inhibited by isoLG scavenger 2-HOBA in vitro and in vivo. Taken together, our studies reveal a posttranslational modification of p53 protein that causes molecular aggregation of p53 protein and its non-mutational inactivation in conditions of DNA damage that may play an important role in human tumorigenesis. |
| first_indexed | 2024-04-10T20:33:58Z |
| format | Article |
| id | doaj.art-7ea2dcfd51124855ae7d8e7d14fbf15f |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-10T20:33:58Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-7ea2dcfd51124855ae7d8e7d14fbf15f2023-01-25T04:15:02ZengElsevierCell Reports2211-12472023-01-01421112024Protein adduction causes non-mutational inhibition of p53 tumor suppressorRavindran Caspa Gokulan0Kodisundaram Paulrasu1Jamal Azfar2Wael El-Rifai3Jianwen Que4Olivier G. Boutaud5Yuguang Ban6Zhen Gao7Monica Garcia Buitrago8Sergey I. Dikalov9Alexander I. Zaika10Department of Surgery, University of Miami, Miami, FL, USADepartment of Surgery, University of Miami, Miami, FL, USADepartment of Surgery, University of Miami, Miami, FL, USADepartment of Surgery, University of Miami, Miami, FL, USADepartment of Medicine, Columbia University Medical Center, New York, NY, USADepartment of Medicine, Vanderbilt University Medical Center, Nashville, TN, USADepartment of Public Health Sciences, University of Miami, Miami, FL, USADepartment of Public Health Sciences, University of Miami, Miami, FL, USADepartment of Pathology, University of Miami, Miami, FL, USADepartment of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USADepartment of Surgery, University of Miami, Miami, FL, USA; Department of Veterans Affairs, Miami VA Healthcare System, Miami, FL, USA; Corresponding authorSummary: p53 is a key tumor suppressor that is frequently mutated in human tumors. In this study, we investigated how p53 is regulated in precancerous lesions prior to mutations in the p53 gene. Analyzing esophageal cells in conditions of genotoxic stress that promotes development of esophageal adenocarcinoma, we find that p53 protein is adducted with reactive isolevuglandins (isoLGs), products of lipid peroxidation. Modification of p53 protein with isoLGs diminishes its acetylation and binding to the promoters of p53 target genes causing modulation of p53-dependent transcription. It also leads to accumulation of adducted p53 protein in intracellular amyloid-like aggregates that can be inhibited by isoLG scavenger 2-HOBA in vitro and in vivo. Taken together, our studies reveal a posttranslational modification of p53 protein that causes molecular aggregation of p53 protein and its non-mutational inactivation in conditions of DNA damage that may play an important role in human tumorigenesis.http://www.sciencedirect.com/science/article/pii/S2211124723000359CP: Cancer |
| spellingShingle | Ravindran Caspa Gokulan Kodisundaram Paulrasu Jamal Azfar Wael El-Rifai Jianwen Que Olivier G. Boutaud Yuguang Ban Zhen Gao Monica Garcia Buitrago Sergey I. Dikalov Alexander I. Zaika Protein adduction causes non-mutational inhibition of p53 tumor suppressor Cell Reports CP: Cancer |
| title | Protein adduction causes non-mutational inhibition of p53 tumor suppressor |
| title_full | Protein adduction causes non-mutational inhibition of p53 tumor suppressor |
| title_fullStr | Protein adduction causes non-mutational inhibition of p53 tumor suppressor |
| title_full_unstemmed | Protein adduction causes non-mutational inhibition of p53 tumor suppressor |
| title_short | Protein adduction causes non-mutational inhibition of p53 tumor suppressor |
| title_sort | protein adduction causes non mutational inhibition of p53 tumor suppressor |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723000359 |
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