Haploinsufficient tumor suppressor Tip60 negatively regulates oncogenic Aurora B kinase
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The Aurora kinases represent a group of serine/threonine kinases which are crucial regulators of mitosis. Dysregulated Aurora kinase B (AurkB) expression, stemming from genomic amplification, increased gene transcription or overexpression of its allosteric activators, is capable of initiating and sustaining malignant phenotypes. Although AurkB level in cells is well-orchestrated, studies that relate to its stability or activity, independent of mitosis, are lacking. We report that AurkB undergoes acetylation in vitro by lysine acetyltransferases (KATs) belonging to different families, namely by p300 and Tip60. The haploinsufficient tumor suppressor Tip60 acetylates two highly conserved lysine residues within the kinase domain of AurkB which not only impinges the protein stability but also its kinase activity. These results signify a probable outcome on the increase in “overall activity” of AurkB upon Tip60 downregulation, as observed under cancerous conditions. The present work, therefore, uncovers an important functional interplay between AurkB and Tip60, frailty of which may be an initial event in carcinogenesis.
KeywordsAurkB acetylation kinase activity stability Tip60
aurora kinase B
HIV-1 Tat interacting protein, 60 kDa
The authors thank Prof. Didier Trouche (LBCMCP, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France) for 2N3T empty vector and 2N3T-Tip60 plasmids and Dr. Amit Dutt (Integrated Cancer Genomics Lab, ACTREC, Mumbai, India) for sharing MDA-MB-231 and MCF7 breast cancer cells. AB is a recipient of Senior Research Fellowship from the Council of Scientific and Industrial Research (CSIR), Government of India; SS and VJR were supported by Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR). This study was supported in part by JNCASR and Sir JC Bose National Fellowship, Department of Science and Technology, India, to TKK. This work was also supported by Indo-Japan bilateral joint research program by Department of Science and Technology, India, and Japan Society for the Promotion of Science (JSPS), Japan. Studies at Tohoku University was supported in part by grants-in-aid from JSPS (17K07278 and 25670156).
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