Abstract
Akt/PKB is a serine/threonine kinase that promotes tumor cell growth by phosphorylating transcription factors and cell cycle proteins. There is particular interest in finding tumor-specific substrates for Akt to understand how this protein functions in cancer and to provide new avenues for therapeutic targeting. Our laboratory sought to identify novel Akt substrates that are expressed in breast cancer. In this study, we determined that activated Akt is positively correlated with the protein expression of the transcription/translation factor Y-box binding protein-1 (YB-1) in primary breast cancer by screening tumor tissue microarrays. We therefore questioned whether Akt and YB-1 might be functionally linked. Herein, we illustrate that activated Akt binds to and phosphorylates the YB-1 cold shock domain at Ser102. We then addressed the functional significance of disrupting Ser102 by mutating it to Ala102. Following the stable expression of Flag:YB-1 and Flag:YB-1 (Ala102) in MCF-7 cells, we observed that disruption of the Akt phosphorylation site on YB-1 suppressed tumor cell growth in soft agar and in monolayer. This correlated with an inhibition of nuclear translocation by the YB-1(Ala102) mutant. In conclusion, YB-1 is a new Akt substrate and disruption of this specific site inhibits tumor cell growth.
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Acknowledgements
We thank Dr Marty Cathcart for helping us with the Motif Scanner search engine. Dr Pepita Gimenez-Bonafe is gratefully recognized for creating the human YB-1 construct. We also thank Dr Brad McLean for helping us render the Akt-1 kinase structure using the RasMol program. M Chen is a visiting scholar in the Department of Pediatrics, University of British Columbia. SED and CKP are recipients of Investigatorship Awards from the BC Research Institute for Children's and Women's Health. This study was supported by the Canadian Breast Cancer Research Alliance through the National Cancer Institute of Canada-Streams of Excellence Program, the Johal Basic and Translational Research Program for Pediatric Oncology (SED and CJP), the Bertram Hoffmeister postdoctoral fellowship (BS), the BC Research Institute for Children's and Women's Health (SED and CJP), and the Canadian Institutes of Health Research (SED and CJP).
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Sutherland, B., Kucab, J., Wu, J. et al. Akt phosphorylates the Y-box binding protein 1 at Ser102 located in the cold shock domain and affects the anchorage-independent growth of breast cancer cells. Oncogene 24, 4281–4292 (2005). https://doi.org/10.1038/sj.onc.1208590
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DOI: https://doi.org/10.1038/sj.onc.1208590
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