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Evaluation of the role of p53 tumor suppressor post-translational modifications and TTC5 cofactor in lung cancer

Alhebshi, Hasen; Tian, Kun; Patnaik, Lipsita; Taylor, Rebecca; Bezecny, Pavel; Hall, Callum; Muller, Patricia AJ; Safari, Nazila; Menendez Creamer, Delta Patricia; Demonacos, Constantinos; Mutti, Luciano; Bittar, Mohamad Nidal; Krstic-Demonacos, Marija

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Authors

Hasen Alhebshi

Kun Tian

Lipsita Patnaik

Rebecca Taylor

Pavel Bezecny

Callum Hall

Nazila Safari

Delta Patricia Menendez Creamer

Constantinos Demonacos

Luciano Mutti

Mohamad Nidal Bittar

Marija Krstic-Demonacos



Abstract

Mutations in the p53 tumor suppressor are found in over 50% of cancers. p53 function is controlled through posttranslational modifications and cofactor interactions. In this study, we investigated the posttranslationally modified p53, including p53 acetylated at lysine 382 (K382), p53 phosphorylated at serine 46 (S46), and the p53 cofactor TTC5/STRAP (Tetratricopeptide repeat domain 5/ Stress-responsive activator of p300-TTC5) proteins in lung cancer. Immunohistochemical (IHC) analysis of lung cancer tissues from 250 patients was carried out and the results were correlated with clinicopathological features. Significant associations between total or modified p53 with a higher grade of the tumour and shorter overall survival (OS) probability were detected, suggesting that mutant and/or modified p53 acts as an oncoprotein in these patients. Acetylated at K382 p53 was predominantly nuclear in some samples and cytoplasmic in others. The localization of the K382 acetylated p53 was significantly associated with the gender and grade of the disease. The TTC5 protein levels were significantly associated with the grade, tumor size, and node involvement in a complex manner. SIRT1 expression was evaluated in 50 lung cancer patients and significant positive correlation was found with p53 S46 intensity, whereas negative TTC5 staining was associated with SIRT1 expression. Furthermore, p53 protein levels showed positive association with poor OS, whereas TTC5 protein levels showed positive association with better OS outcome. Overall, our results indicate that an analysis of p53 modified versions together with TTC5 expression, upon testing on a larger sample size of patients, could serve as useful prognostic factors or drug targets for lung cancer treatment.

Citation

Alhebshi, H., Tian, K., Patnaik, L., Taylor, R., Bezecny, P., Hall, C., …Krstic-Demonacos, M. (2021). Evaluation of the role of p53 tumor suppressor post-translational modifications and TTC5 cofactor in lung cancer. International Journal of Molecular Sciences, 22(24), Article 13198. https://doi.org/10.3390/ijms222413198

Journal Article Type Article
Acceptance Date Dec 2, 2021
Online Publication Date Dec 7, 2021
Publication Date Dec 2, 2021
Deposit Date Dec 16, 2021
Publicly Available Date Dec 16, 2021
Journal International Journal of Molecular Sciences
Print ISSN 1661-6596
Electronic ISSN 1422-0067
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 22
Issue 24
Article Number 13198
DOI https://doi.org/10.3390/ijms222413198
Public URL https://durham-repository.worktribe.com/output/1222014

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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/

Copyright Statement
© 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).





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