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BTK modulates p53 activity to enhance apoptotic and senescent responses

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journal contribution
posted on 11.10.2016, 14:47 by Mohammad Althubiti, Miran Rada, Jesvin Samuel, Josep M. Escorsa, Hishyar Najeeb, Koon-Guan Lee, Kong-Peng Lam, George D. D. Jones, Nickolai Barlev, Salvador Macip
p53 is a tumor suppressor that prevents the emergence of transformed cells by inducing apoptosis or senescence, among other responses. Its functions are regulated tightly by posttranslational modifications. Here we show that Bruton's tyrosine kinase (BTK) is a novel modulator of p53. We found that BTK is induced in response to DNA damage and p53 activation. BTK induction leads to p53 phosphorylation, which constitutes a positive feedback loop that increases p53 protein levels and enhances the transactivation of its target genes in response to stress. Inhibiting BTK reduced both p53-dependent senescence and apoptosis. Further, BTK expression also upregulated DNA damage signals and apoptosis. We conclude that despite being involved in oncogenic signals in blood malignancies, BTK has antineoplastic properties in other contexts, such as the enhancement of p53's tumor suppressor responses. Along with evidence that BTK expression correlates with good prognosis in some epithelial tumors, our findings may encourage a reevaluation of the clinical uses of BTK inhibitors in cancer therapy.

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Citation

Cancer Research, 2016, 76 (18), pp. 5405-5414

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Old Departments Pre 01 Aug 2015/Department of Biochemistry (Pre 01 Aug 2015)

Version

AM (Accepted Manuscript)

Published in

Cancer Research

Publisher

American Association for Cancer Research

issn

0008-5472

eissn

1538-7445

Acceptance date

28/06/2016

Copyright date

2016

Available date

11/10/2016

Publisher version

http://cancerres.aacrjournals.org/content/76/18/5405

Language

en

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