Protein adduction causes non-mutational inhibition of p53 tumor suppressor
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
Affiliations
Ravindran Caspa Gokulan
Department of Surgery, University of Miami, Miami, FL, USA
Kodisundaram Paulrasu
Department of Surgery, University of Miami, Miami, FL, USA
Jamal Azfar
Department of Surgery, University of Miami, Miami, FL, USA
Wael El-Rifai
Department of Surgery, University of Miami, Miami, FL, USA
Jianwen Que
Department of Medicine, Columbia University Medical Center, New York, NY, USA
Olivier G. Boutaud
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Yuguang Ban
Department of Public Health Sciences, University of Miami, Miami, FL, USA
Zhen Gao
Department of Public Health Sciences, University of Miami, Miami, FL, USA
Monica Garcia Buitrago
Department of Pathology, University of Miami, Miami, FL, USA
Sergey I. Dikalov
Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA
Alexander I. Zaika
Department of Surgery, University of Miami, Miami, FL, USA; Department of Veterans Affairs, Miami VA Healthcare System, Miami, FL, USA; Corresponding author
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.
