Interaction of DBC1 with polyoma small T antigen promotes its degradation and negatively regulates tumorigenesis |
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Authors: | Zarka Sarwar Nusrat Nabi Sameer Ahmed Bhat Syed Qaaifah Gillani Irfana Reshi Misbah Un Nisa Guillaume Adelmant Jarrod A Marto Shaida Andrabi |
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Institution: | 1.Department of Biochemistry, University of Kashmir, Srinagar, India;2.Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA |
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Abstract: | Deleted in Breast Cancer 1 (DBC1) is an important metabolic sensor. Previous studies have implicated DBC1 in various cellular functions, notably cell proliferation, apoptosis, histone modification, and adipogenesis. However, current reports about the role of DBC1 in tumorigenesis are controversial and designate DBC1 alternatively as a tumor suppressor or a tumor promoter. In the present study, we report that polyoma small T antigen (PyST) associates with DBC1 in mammalian cells, and this interaction leads to the posttranslational downregulation of DBC1 protein levels. When coexpressed, DBC1 overcomes PyST-induced mitotic arrest and promotes the exit of cells from mitosis. Using both transient and stable modes of PyST expression, we also show that cellular DBC1 is subjected to degradation by LKB1, a tumor suppressor and cellular energy sensor kinase, in an AMP kinase-independent manner. Moreover, LKB1 negatively regulates the phosphorylation as well as activity of the prosurvival kinase AKT1 through DBC1 and its downstream pseudokinase substrate, Tribbles 3 (TRB3). Using both transient transfection and stable cell line approaches as well as soft agar assay, we demonstrate that DBC1 has oncogenic potential. In conclusion, our study provides insight into a novel signaling axis that connects LKB1, DBC1, TRB3, and AKT1. We propose that the LKB1–DBC1–AKT1 signaling paradigm may have an important role in the regulation of cell cycle and apoptosis and consequently tumorigenesis. |
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Keywords: | DBC1 CCAR2 KIAA 1967 small T antigen AKT LKB1 mitosis apoptosis tumor cell biology tumor virus |
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