title: BTK Modulates p53 Activity to Enhance Apoptotic and Senescent Responses.
abstract: 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. Cancer Res; 76(18); 5405-14. ©2016 AACR.
authors.affiliation: Mechanisms of Cancer and Aging Laboratory, Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom. Cancer Research UK Leicester Centre, Leicester, United Kingdom. Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Althubiti
authors.affiliation: Mechanisms of Cancer and Aging Laboratory, Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom. Cancer Research UK Leicester Centre, Leicester, United Kingdom. Department of Biology, School of Science, Faculty of Science and Education Sciences, University of Sulaimani, Sulaimaniyah, Kurdistan Region, Iraq.
authors.forename: Miran
authors.initials: M
authors.lastname: Rada
authors.affiliation: Mechanisms of Cancer and Aging Laboratory, Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom. Cancer Research UK Leicester Centre, Leicester, United Kingdom.
authors.forename: Jesvin
authors.initials: J
authors.lastname: Samuel
authors.affiliation: Mechanisms of Cancer and Aging Laboratory, Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom. Cancer Research UK Leicester Centre, Leicester, United Kingdom.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Escorsa
authors.affiliation: Cancer Research UK Leicester Centre, Leicester, United Kingdom. Department of Cancer Studies, University of Leicester, Leicester, United Kingdom.
authors.forename: Hishyar
authors.initials: H
authors.lastname: Najeeb
authors.affiliation: Bioprocessing Technology Institute, A*STAR, Singapore.
authors.forename: Koon-Guan
authors.initials: KG
authors.lastname: Lee
authors.affiliation: Bioprocessing Technology Institute, A*STAR, Singapore.
authors.forename: Kong-Peng
authors.initials: KP
authors.lastname: Lam
authors.affiliation: Cancer Research UK Leicester Centre, Leicester, United Kingdom. Department of Cancer Studies, University of Leicester, Leicester, United Kingdom.
authors.forename: George D D
authors.initials: GD
authors.lastname: Jones
authors.affiliation: Institute of Cytology, RAS, Saint-Petersburg, Russia.
authors.forename: Nickolai A
authors.initials: NA
authors.lastname: Barlev
authors.affiliation: Mechanisms of Cancer and Aging Laboratory, Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom. Cancer Research UK Leicester Centre, Leicester, United Kingdom. sm460@le.ac.uk.
authors.forename: Salvador
authors.initials: S
authors.lastname: Macip
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology; D016922:Cellular Senescence / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D020552:Comet Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000401:mortality / Q000473:pathology; D008175:Lung Neoplasms / Q000401:mortality / Q000473:pathology; D008297:Male; D009369:Neoplasms / Q000401:mortality / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human