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BTK modulates p73 activity to induce apoptosis independently of p53.

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journal contribution
posted on 12.07.2019, 15:08 by M Rada, N Barlev, S Macip
Bruton's tyrosine kinase (BTK) is a key component of B cell receptor signalling. Because of this, BTK plays an important role in cell proliferation and survival in various B cell malignancies. However, in certain contexts, BTK can also have tumour suppressor functions. We have previously shown that BTK activates the p53 transcriptional activity by binding to and phosphorylating p53, as well as acting on MDM2 to reduce its inhibitory effects. This results in increased p53 functions, including enhanced cell death. Here, we report that BTK can also induce cell death and increase responses to DNA damage independently of p53. This is concomitant to the induction of p21, PUMA and MDM2, which are classic target genes of the p53 family of proteins. Our results show that these p53-independent effects of BTK are mediated through p73. Similar to what we observed in the p53 pathway, BTK can upregulate p73 after DNA damage and induce expression of its target genes, suggesting that BTK is a modulator of p73 functions and in the absence of p53. This effect allows BTK to have pro-apoptotic functions independently of its effects on the p53 pathway and thus play an important role in the DNA damage-related induction of apoptosis in the absence of p53. This provides a novel role of BTK in tumour suppression and contributes to the understanding of its complex pleiotropic functions.

Funding

Work in SM’s lab was supported by an MRC New Blood Fellowship, an Innovation Fellowship from the University of Leicester and the M.C. Andreu Memorial Fund. M.R. was supported by a Doctoral Studentship from the Kurdistan Regional Government (Iraq).

History

Citation

Cell Death Discovery, 2018, 5, p. 30

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Molecular & Cell Biology

Version

VoR (Version of Record)

Published in

Cell Death Discovery

Publisher

Springer Nature

issn

2058-7716

Acceptance date

06/08/2018

Copyright date

2018

Available date

12/07/2019

Notes

Supplementary data available form the publisher's website: https://doi.org/10.1038/s41420-018-0097-7

Language

en

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