BTK blocks the inhibitory effects of MDM2 on p53 activity.pdf (2.9 MB)
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BTK blocks the inhibitory effects of MDM2 on p53 activity

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journal contribution
posted on 08.02.2018, 11:41 by Miran Rada, Mohammad Althubiti, Akang E. Ekpenyong-Akiba, Koon-Guan Lee, Kong Peng Lam, Olga Fedorova, Nickolai A. Barlev, Salvador Macip
p53 is a tumour suppressor that is activated in response to various types of stress. It is regulated by a complex pattern of over 50 different post-translational modifications, including ubiquitination by the E3 ligase MDM2, which leads to its proteasomal degradation. We have previously reported that expression of Bruton's Tyrosine Kinase (BTK) induces phosphorylation of p53 at the N-terminus, including Serine 15, and increases its protein levels and activity. The mechanisms involved in this process are not completely understood. Here, we show that BTK also increases MDM2 and is necessary for MDM2 upregulation after DNA damage, consistent with what we have shown for other p53 target genes. Moreover, we found that BTK binds to MDM2 on its PH domain and induces its phosphorylation. This suggested a negative regulation of MDM2 functions by BTK, supported by the fact BTK expression rescued the inhibitory effects of MDM2 on p53 transcriptional activity. Indeed, we observed that BTK mediated the loss of the ubiquitination activity of MDM2, a process that was dependent on the phosphorylation functions of BTK. Our data together shows that the kinase activity of BTK plays an important role in disrupting the MDM2-p53 negative feedback loop by acting at different levels, including binding to and inactivation of MDM2. This study provides a potential mechanism to explain how BTK modulates p53 functions.

Funding

Work in SM’s lab was supported by an MRC New Blood Fellowship and an Innovation Fellowship from the University of Leicester and the M.C. Andreu Memorial Fund. MR was supported by a Doctoral Studentship from the Kurdistan Regional Government (Iraq). MA was supported by a Saudi Government Doctoral Scholarship. NB and OF acknowledges funding from RSCF (grant 14-15-00816).

History

Citation

Oncotarget, 2017, 8 (63), pp. 106639-106647

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Old Departments Pre 01 Aug 2015/Department of Biochemistry (Pre 01 Aug 2015)

Version

VoR (Version of Record)

Published in

Oncotarget

Publisher

Impact Journals

eissn

1949-2553

Acceptance date

30/10/2017

Copyright date

2017

Available date

08/02/2018

Publisher version

http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=22543&path[]=71260

Language

en

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