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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 volume 24, pages 4281–4292 (2005)Cite this article

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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References

  • Altiok S, Batt D, Altiok N, Papautsky A, Downward J, Roberts TM and Avraham H . (1999). J. Biol. Chem., 274, 32274–32278.

  • Bader AG, Felts KA, Jiang N, Chang HW and Vogt PK . (2003). Proc. Natl. Acad. Sci. USA, 100, 12384–12389.

  • Bargou RC, Jurchott K, Wagener C, Bergmann S, Metzner S, Bommert K, Mapara MY, Winzer KJ, Dietel M, Dorken B and Royer HD . (1997). Nat. Med., 3, 447–450.

  • Brazil DP and Hemmings BA . (2001). Trends Biochem. Sci., 26, 657–664.

  • Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J and Greenberg ME . (1999). Cell, 96, 857–868.

  • Delcommenne M, Tan C, Gray V, Rue L, Woodgett JR and Dedhar S . (1998). Proc. Natl. Acad. Sci. USA, 95, 11211–11216.

  • Du K and Montminy M . (1998). J. Biol. Chem., 273, 32377–32379.

  • Dunn SE, Ehrlich M, Sharp NJH, Reiss K, Solomon G, Hawkins R, Baserga R and Barrett JC . (1998). Cancer Res., 58, 3353–3361.

  • Dunn SE, Torres JV and Barrett JC . (2001). Cancer Res., 61, 1367–1374.

  • Feng J, Park J, Cron P, Hess D and Hemmings BA . (2004). J. Biol. Chem., 279, 41189–41196.

  • Gimenez-Bonafe P, Fedoruk MN, Whitmore TG, Akbari M, Ralph JL, Gleave ME and Nelson CC . (2004). Prostate, 59, 337–349.

  • Grant CE and Deeley RG . (1993). Mol. Cell. Biol., 13, 4186–4196.

  • Higashi K, Inagaki Y, Fujimori K, Nakao A, Kaneko H and Nakatsuka I . (2003). J. Biol. Chem., 278, 43470–43479.

  • Hill MM and Hemmings BA . (2002). Pharmacol. Ther., 93, 243–251.

  • Janz M, Harbeck N, Dettmar P, Berger U, Schmidt A, Jurchott K, Schmitt M and Royer HD . (2002). Int. J. Cancer, 97, 278–282.

  • Jurchott K, Bergmann S, Stein U, Walther W, Janz M, Manni I, Paiggo G, Fietze E, Dietel M and Royer HD . (2003). J. Biol. Chem., 278, 27988–27996.

  • Kamura T, Yahata H, Amada S, Ogawa S, Sonoda T, Kobayashi H, Mitsumoto M, Kohno K, Kuwano M and Nakano H . (1999). Cancer, 85, 2450–2454.

  • Kloks CPAM, Spronk CAEM, Lasonder E, Hoffmann A, Wuister GW, Grzesiek S and Hilbers CW . (2002). J. Mol. Biol., 316, 317–326.

  • Knuefermann C, Lu YY, Liu B, Jin W, Liang K, Wu L, Schmidt M, Mills GB, Mendelsohn J and Fan Z . (2003). Oncogene, 22, 3205–3212.

  • Koike K, Uchiumi T, Toh S, Wada M, Kohno K and Kuwano M . (1997). FEBS Lett., 417, 390–394.

  • Kops GJPL, de Ruiter ND, De Vries-Smits AMM, Powell DR, Bos JL and Burgering BMT . (1999). Nature, 398, 630–634.

  • Lasham A, Moloney S, Hale T, Homer C, Zhang Y, Murison JG, Braithwaite AW and Watson J . (2003). J. Biol. Chem., 278, 35516–35523.

  • Makretsov N, Huntsman D, Nielsen T, Yorida E, Peacock M, Cheang M, Dunn SE, Hayes M, van de Rijn M, Bajdik CD and Gilks B . (2004). Clin. Cancer Res., 10, 6143–6151.

  • Nicholson KM and Anderson NG . (2002). Cell. Signal., 14, 381–395.

  • Obata T, Yaffe MB, Leparc GG, Piro ET, Maegawa H, Kashiwagi A, Kikkawa R and Cantley LC . (2000). J. Biol. Chem., 275, 36108–36115.

  • Oda Y, Ohishi Y, Saito T, Hinoshita E, Uchiumi T, Kinukawa N, Iwamoto Y, Kohno K, Kuwano M and Tsuneyoshi M . (2003). J. Pathol., 199, 251–258.

  • Oda Y, Sakamoto A, Shinohara N, Ohga T, Uchiumi T, Kohno K, Tsuneyoshi M, Kuwano M and Iwamoto Y . (1998). Clin. Cancer Res., 4, 2273–2277.

  • Oh JS, Buchel P, Martin K, Kucab JE, Oshimura T, Bennett L, Barrett JC, DiAugustine RP, Afshsari C and Dunn SE . (2002). Neoplasia, 4, 204–217.

  • Okamoto T, Izumi H, Imamura T, Takano H, Ise T, Uchiumi T, Kuwano M and Kohno K . (2000). Oncogene, 19, 6194–6202.

  • Persad S, Attwell S, Gray V, Delcommenne M, Troussard A, Sanghera J, Walsh MP and Dedhar S . (2001). J. Biol. Chem., 276, 27462–27469.

  • Rubinstein DB, Stortchevoi A, Bossalis M, Ashfaq R and Guillaume T . (2002). Cancer Res., 62, 4985–4991.

  • Shibao K, Takano H, Nakayama Y, Okazaki K, Nagata N, Izumi H, Uchiumi T, Kuwano M, Kohn K and Itoh H . (1999). Int. J. Cancer, 83, 732–737.

  • Shin I, Yakes FM, Rojo F, Shin N, Bakin AV, Baselga J and Arteaga CL . (2002). Nat. Med., 8, 1145–1152.

  • Stenina OI, Poptic EJ and DiCorleto PE . (2000). J. Clin. Invest., 106, 579–587.

  • Swamynathan SK, Varma BR, Weber KT and Guntaka RV . (2002). Biochem. Biophy. Res. Commun., 296, 451–457.

  • Troussard AA, Mawji NM, Ong C, Mui A, St Arnaud R and Dedhar S . (2003). J. Biol. Chem., 278, 22374–22378.

  • van Weeren PC, de Bruyn KM, de Vries-Smits AM, van Lint J and Burgering BM . (1998). J. Biol. Chem., 273, 13150–13156.

  • Yahata H, Kobayashi H, Kamura T, Amada S, Hirakawa T, Kohno K, Kuwano M and Nakano H . (2002). J. Cancer Res. Clin. Oncol., 128, 621–626.

  • Zhou BP, Liao Y, Xia W, Spohn B, Lee MH and Hung MC . (2001). Nat. Cell Biol., 3, E71–3.

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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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Authors and Affiliations

  1. Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA

    Brent W Sutherland

  2. Laboratory for Oncogenomic Research, Department of Pediatrics, British Columbia Research Institute for Children's and Women's Health, Vancouver, British Columbia, Canada

    Jill Kucab, Joyce Wu, Cathy Lee & Sandra E Dunn

  3. Genetic Pathology Evaluation Center, Vancouver Hospital and Health Sciences Center and BC Cancer Agency, Vancouver, British Columbia, Canada

    Maggie C U Cheang, Erika Yorida, Dmitry Turbin, David Huntsman & C Blake-Gilks

  4. British Columbia Cancer Agency, Vancouver, British Columbia, Canada

    Shoukat Dedhar

  5. Prostate Center at Vancouver General Hospital, Jack Bell Research Laboratories, Vancouver, British Columbia, Canada

    Colleen Nelson

  6. Division of Experimental Medicine, Department of Medicine and Department of Oncology, McGill University, Montreal, Quebec, Canada

    Michael Pollak

  7. Institute for Cellular Therapeutics, Louisville, KY, USA

    H Leighton Grimes

  8. Department of Medicine, Indiana University, Bloomington, IN, USA

    Kathy Miller

  9. Department of Pathology, Indiana University, Bloomington, IN, USA

    Sunil Badve

  10. Institute of Molecular and Cell Biology, Singapore

    Min Chen

  11. Cell Phosphosignaling Laboratory, Department of Pediatrics, British Columbia Research Institute for Children's and Women's Health, Vancouver, British Columbia, Canada

    Min Chen & Catherine J Pallen

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  1. Brent W Sutherland
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Correspondence to Sandra E Dunn.

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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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