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Open AccessArticle

Human TRIB2 Oscillates during the Cell Cycle and Promotes Ubiquitination and Degradation of CDC25C

1
Paul O’Gorman Leukemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 0ZD, UK
2
School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
3
Stem Cell and Leukaemia Proteomics Laboratory, University of Manchester, Manchester M20 3LJ, UK
4
Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK
5
Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK
6
Paediatric and Adolescent Oncology, Royal Manchester Children’s and Christie Hospital, University of Manchester, Manchester M13 9WL, UK
*
Author to whom correspondence should be addressed.
Academic Editors: William Chi-shing Cho and Sanjay K. Srivastava
Int. J. Mol. Sci. 2016, 17(9), 1378; https://doi.org/10.3390/ijms17091378
Received: 23 June 2016 / Revised: 4 August 2016 / Accepted: 18 August 2016 / Published: 23 August 2016
(This article belongs to the Collection Advances in Molecular Oncology)
Tribbles homolog 2 (TRIB2) is a member of the mammalian Tribbles family of serine/threonine pseudokinases (TRIB1-3). Studies of TRIB2 indicate that many of the molecular interactions between the single Drosophila Tribbles (Trbl) protein and interacting partners are evolutionary conserved. In this study, we examined the relationship between TRIB2 and cell division cycle 25 (CDC25) family of dual-specificity protein phosphatases (mammalian homologues of Drosophila String), which are key physiological cell cycle regulators. Using co-immunoprecipitation we demonstrate that TRIB2 interacts with CDC25B and CDC25C selectively. Forced overexpression of TRIB2 caused a marked decrease in total CDC25C protein levels. Following inhibition of the proteasome, CDC25C was stabilized in the nuclear compartment. This implicates TRIB2 as a regulator of nuclear CDC25C turnover. In complementary ubiquitination assays, we show that TRIB2-mediated degradation of CDC25C is associated with lysine-48-linked CDC25C polyubiquitination driven by the TRIB2 kinase-like domain. A cell cycle associated role for TRIB2 is further supported by the cell cycle regulated expression of TRIB2 protein levels. Our findings reveal mitotic CDC25C as a new target of TRIB2 that is degraded via the ubiquitin proteasome system. Inappropriate CDC25C regulation could mechanistically underlie TRIB2 mediated regulation of cellular proliferation in neoplastic cells. View Full-Text
Keywords: TRIB2; pseudokinase; CDC25B; CDC25C; dual-specificity phosphatase; ubiquitin proteasome; degradation; cell cycle TRIB2; pseudokinase; CDC25B; CDC25C; dual-specificity phosphatase; ubiquitin proteasome; degradation; cell cycle
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MDPI and ACS Style

Liang, K.L.; Paredes, R.; Carmody, R.; Eyers, P.A.; Meyer, S.; McCarthy, T.V.; Keeshan, K. Human TRIB2 Oscillates during the Cell Cycle and Promotes Ubiquitination and Degradation of CDC25C. Int. J. Mol. Sci. 2016, 17, 1378.

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