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SILAC-based phosphoproteomics reveals an inhibitory role of KSR1 in p53 transcriptional activity via modulation of DBC1

Background:We have previously identified kinase suppressor of ras-1 (KSR1) as a potential regulatory gene in breast cancer. KSR1, originally described as a novel protein kinase, has a role in activation of mitogen-activated protein kinases. Emerging evidence has shown that KSR1 may have dual functio...

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Main Authors: Zhang, H., Xu, Y., Filipovic, A., Lit, Lei Cheng, Koo, C.Y., Stebbing, J., Giamas, G.
Format: Article
Published: Springer Nature 2013
Subjects:
R Medicine
Online Access:http://eprints.um.edu.my/23075/
https://doi.org/10.1038/bjc.2013.628
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spelling my.um.eprints.230752019-11-20T03:09:23Z http://eprints.um.edu.my/23075/ SILAC-based phosphoproteomics reveals an inhibitory role of KSR1 in p53 transcriptional activity via modulation of DBC1 Zhang, H. Xu, Y. Filipovic, A. Lit, Lei Cheng Koo, C.Y. Stebbing, J. Giamas, G. R Medicine Background:We have previously identified kinase suppressor of ras-1 (KSR1) as a potential regulatory gene in breast cancer. KSR1, originally described as a novel protein kinase, has a role in activation of mitogen-activated protein kinases. Emerging evidence has shown that KSR1 may have dual functions as an active kinase as well as a scaffold facilitating multiprotein complex assembly. Although efforts have been made to study the role of KSR1 in certain tumour types, its involvement in breast cancer remains unknown.Methods:A quantitative mass spectrometry analysis using stable isotope labelling of amino acids in cell culture (SILAC) was implemented to identify KSR1-regulated phosphoproteins in breast cancer. In vitro luciferase assays, co-immunoprecipitation as well as western blotting experiments were performed to further study the function of KSR1 in breast cancer.Results:Of significance, proteomic analysis reveals that KSR1 overexpression decreases deleted in breast cancer-1 (DBC1) phosphorylation. Furthermore, we show that KSR1 decreases the transcriptional activity of p53 by reducing the phosphorylation of DBC1, which leads to a reduced interaction of DBC1 with sirtuin-1 (SIRT1); this in turn enables SIRT1 to deacetylate p53.Conclusion:Our findings integrate KSR1 into a network involving DBC1 and SIRT1, which results in the regulation of p53 acetylation and its transcriptional activity. © 2013 Cancer Research UK. All rights reserved. Springer Nature 2013 Article PeerReviewed Zhang, H. and Xu, Y. and Filipovic, A. and Lit, Lei Cheng and Koo, C.Y. and Stebbing, J. and Giamas, G. (2013) SILAC-based phosphoproteomics reveals an inhibitory role of KSR1 in p53 transcriptional activity via modulation of DBC1. British Journal of Cancer, 109 (10). pp. 2675-2684. ISSN 0007-0920 https://doi.org/10.1038/bjc.2013.628 doi:10.1038/bjc.2013.628
institution Universiti Malaya
building UM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Malaya
content_source UM Research Repository
url_provider http://eprints.um.edu.my/
topic R Medicine
spellingShingle R Medicine
Zhang, H.
Xu, Y.
Filipovic, A.
Lit, Lei Cheng
Koo, C.Y.
Stebbing, J.
Giamas, G.
SILAC-based phosphoproteomics reveals an inhibitory role of KSR1 in p53 transcriptional activity via modulation of DBC1
description Background:We have previously identified kinase suppressor of ras-1 (KSR1) as a potential regulatory gene in breast cancer. KSR1, originally described as a novel protein kinase, has a role in activation of mitogen-activated protein kinases. Emerging evidence has shown that KSR1 may have dual functions as an active kinase as well as a scaffold facilitating multiprotein complex assembly. Although efforts have been made to study the role of KSR1 in certain tumour types, its involvement in breast cancer remains unknown.Methods:A quantitative mass spectrometry analysis using stable isotope labelling of amino acids in cell culture (SILAC) was implemented to identify KSR1-regulated phosphoproteins in breast cancer. In vitro luciferase assays, co-immunoprecipitation as well as western blotting experiments were performed to further study the function of KSR1 in breast cancer.Results:Of significance, proteomic analysis reveals that KSR1 overexpression decreases deleted in breast cancer-1 (DBC1) phosphorylation. Furthermore, we show that KSR1 decreases the transcriptional activity of p53 by reducing the phosphorylation of DBC1, which leads to a reduced interaction of DBC1 with sirtuin-1 (SIRT1); this in turn enables SIRT1 to deacetylate p53.Conclusion:Our findings integrate KSR1 into a network involving DBC1 and SIRT1, which results in the regulation of p53 acetylation and its transcriptional activity. © 2013 Cancer Research UK. All rights reserved.
format Article
author Zhang, H.
Xu, Y.
Filipovic, A.
Lit, Lei Cheng
Koo, C.Y.
Stebbing, J.
Giamas, G.
author_facet Zhang, H.
Xu, Y.
Filipovic, A.
Lit, Lei Cheng
Koo, C.Y.
Stebbing, J.
Giamas, G.
author_sort Zhang, H.
title SILAC-based phosphoproteomics reveals an inhibitory role of KSR1 in p53 transcriptional activity via modulation of DBC1
title_short SILAC-based phosphoproteomics reveals an inhibitory role of KSR1 in p53 transcriptional activity via modulation of DBC1
title_full SILAC-based phosphoproteomics reveals an inhibitory role of KSR1 in p53 transcriptional activity via modulation of DBC1
title_fullStr SILAC-based phosphoproteomics reveals an inhibitory role of KSR1 in p53 transcriptional activity via modulation of DBC1
title_full_unstemmed SILAC-based phosphoproteomics reveals an inhibitory role of KSR1 in p53 transcriptional activity via modulation of DBC1
title_sort silac-based phosphoproteomics reveals an inhibitory role of ksr1 in p53 transcriptional activity via modulation of dbc1
publisher Springer Nature
publishDate 2013
url http://eprints.um.edu.my/23075/
https://doi.org/10.1038/bjc.2013.628
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score 13.211869

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