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Subcellular localization of full-length human myeloid leukemia factor 1 (MLF1) is independent of 14-3-3 proteins

Cellular & Molecular Biology Letters volume 18, pages 137–148 (2013)Cite this article

Abstract

Myeloid leukemia factor 1 (MLF1) is associated with the development of leukemic diseases such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, information on the physiological function of MLF1 is limited and mostly derived from studies identifying MLF1 interaction partners like CSN3, MLF1IP, MADM, Manp and the 14-3-3 proteins. The 14-3-3-binding site surrounding S34 is one of the only known functional features of the MLF1 sequence, along with one nuclear export sequence (NES) and two nuclear localization sequences (NLS). It was recently shown that the subcellular localization of mouse MLF1 is dependent on 14-3-3 proteins. Based on these findings, we investigated whether the subcellular localization of human MLF1 was also directly 14-3-3-dependent. Live cell imaging with GFP-fused human MLF1 was used to study the effects of mutations and deletions on its subcellular localization. Surprisingly, we found that the subcellular localization of full-length human MLF1 is 14-3-3-independent, and is probably regulated by other as-yet-unknown proteins.

Abbreviations

AML:

acute myeloid leukemia

CMV:

cytomegalovirus

CSN3:

subunit 3 of the COP9 signalosome

DMEM:

Dulbecco’s modified Eagle’s medium

GFP:

green fluorescent protein

MADM:

MLF1 adaptor molecule

Manp:

MLF1-associated nuclear protein

MDS:

myelodysplastic syndrome

MLF1:

myeloid leukemia factor 1

MLF1IP:

MLF1-interacting protein

NES:

nuclear export sequence

NLS:

nuclear localization signal

NPM:

nucleophosmin

References

  1. Matsumoto, N., Yoneda-Kato, N., Iguchi, T., Kishimoto, Y., Kyo, T., Sawada, H., Tatsumi, E. and Fukuhara, S. Elevated MLF1 expression correlates with malignant progression from myelodysplastic syndrome. Leukemia 14 (2000) 1757–1765.

    Article  PubMed  CAS  Google Scholar 

  2. Sun, W., Zhang, K., Zhang, X., Lei, W., Xiao, T., Ma, J., Guo, S., Shao, S., Zhang, H., Liu, Y., Yuan, J., Hu, Z., Ma, Y., Feng, X., Hu, S., Zhou, J., Cheng, S. and Gao, Y. Identification of differentially expressed genes in human lung squamous cell carcinoma using suppression subtractive hybridization. Cancer Lett. 212 (2004) 83–93.

    Article  PubMed  CAS  Google Scholar 

  3. Chen, J., Guo, L., Peiffer, D.A., Zhou, L., Chan, O.T.M., Bibikova, M., Wickham-Garcia, E., Lu, S.-H., Zhan, Q., Wang-Rodriguez, J., Jiang, W. and Fan, J.B. Genomic profiling of 766 cancer-related genes in archived esophageal normal and carcinoma tissues. Int. J. Cancer 122 (2008) 2249–2254.

    Article  PubMed  CAS  Google Scholar 

  4. Winteringham, L.N., Kobelke, S., Williams, J.H., Ingley, E. and Klinken, S.P. Myeloid leukemia factor 1 inhibits erythropoietin-induced differentiation, cell cycle exit and p27Kip1 accumulation. Oncogene 23 (2004) 5105–5109.

    Article  PubMed  CAS  Google Scholar 

  5. Yoneda-Kato, N. and Kato, J.-Y. Shuttling imbalance of MLF1 results in p53 instability and increases susceptibility to oncogenic transformation. Mol. Cell Biol. 28 (2008) 422–434.

    Article  PubMed  CAS  Google Scholar 

  6. Bras, S., Martin-Lannerée, S., Gobert, V., Augé, B., Breig, O., Sanial, M., Yamaguchi, M., Haenlin, M., Plessis, A. and Waltzer, L. Myeloid Leukemia Factor is a conserved regulator of RUNX transcription factor activity involved in hematopoiesis. Proc. Natl. Acad. Sci. USA 109 (2012) 4986–4991.

    Article  PubMed  CAS  Google Scholar 

  7. Gobert, V., Haenlin, M. and Waltzer, L. Myeloid Leukemia Factor: A return ticket from human leukemia to fly hematopoiesis. Transcription 3 (2012) Epub ahead of print.

  8. Yoneda-Kato, N., Look, A.T., Kirstein, M.N., Valentine, M.B., Raimondi, S.C., Cohen, K.J., Carroll, A.J. and Morris, S.W. The t(3;5)(q25.1;q34) of myelodysplastic syndrome and acute myeloid leukemia produces a novel fusion gene, NPM-MLF1. Oncogene 12 (1996) 265–275.

    PubMed  CAS  Google Scholar 

  9. Olson, M.O., Wallace, M.O., Herrera, A.H., Marshall-Carlson, L. and Hunt, R.C. Preribosomal ribonucleoprotein particles are a major component of a nucleolar matrix fraction. Biochemistry 25 (1986) 484–491.

    Article  PubMed  CAS  Google Scholar 

  10. Falini, B., Bigerna, B., Pucciarini, A., Tiacci, E., Mecucci, C., Morris, S.W., Bolli, N., Rosati, R., Hanissian, S., Ma, Z., Sun, Y., Colombo, E., Arber, D.A., Pacini, R., La Starza, R., Verducci Galletti, B., Liso, A., Martelli, M.P., Diverio, D., Pelicci, P.G., Lo Coco, F. and Martelli, M.F. Aberrant subcellular expression of nucleophosmin and NPM-MLF1 fusion protein in acute myeloid leukaemia carrying t(3;5): a comparison with NPMc+ AML. Leukemia 20 (2006) 368–371.

    Article  PubMed  CAS  Google Scholar 

  11. Winteringham, L.N., Endersby, R., Kobelke, S., McCulloch, R.K., Williams, J.H., Stillitano, J., Cornwall, S.M., Ingley, E. and Klinken, S.P. Myeloid leukemia factor 1 associates with a novel heterogeneous nuclear ribonucleoprotein U-like molecule. J. Biol. Chem. 281 (2006) 38791–38800.

    Article  PubMed  CAS  Google Scholar 

  12. Yoneda-Kato, N., Tomoda, K., Umehara, M., Arata, Y. and Kato, J.-Y. Myeloid leukemia factor 1 regulates p53 by suppressing COP1 via COP9 signalosome subunit 3. EMBO J. 24 (2005) 1739–1749.

    Article  PubMed  CAS  Google Scholar 

  13. Hanissian, S.H., Akbar, U., Teng, B., Janjetovic, Z., Hoffmann, A., Hitzler, J.K., Iscove, N., Hamre, K., Du, X., Tong, Y., Mukatira, S., Robertson, J.H. and Morris, S.W. cDNA cloning and characterization of a novel gene encoding the MLF1-interacting protein MLF1IP. Oncogene 23 (2004) 3700–3707.

    Article  PubMed  CAS  Google Scholar 

  14. Hanissian, S.H., Teng, B., Akbar, U., Janjetovic, Z., Zhou, Q., Duntsch, C. and Robertson, J.H. Regulation of myeloid leukemia factor-1 interacting protein (MLF1IP) expression in glioblastoma. Brain Res. 1047 (2005) 56–64.

    Article  PubMed  CAS  Google Scholar 

  15. Lim, R., Winteringham, L.N., Williams, J.H., McCulloch, R.K., Ingley, E., Tiao, J.Y.H., Lalonde, J.-P., Tsai, S., Tilbrook, P.A., Sun, Y., Wu, X., Morris, S.W. and Klinken, S.P. MADM, a novel adaptor protein that mediates phosphorylation of the 14-3-3 binding site of myeloid leukemia factor 1. J. Biol. Chem. 277 (2002) 40997–41008.

    Article  PubMed  CAS  Google Scholar 

  16. Ohno, K., Takahashi, Y., Hirose, F., Inoue, Y.H., Taguchi, O., Nishida, Y., Matsukage, A. and Yamaguchi, M. Characterization of a Drosophila homologue of the human myelodysplasia/myeloid leukemia factor (MLF). Gene 260 (2000) 133–143.

    Article  PubMed  CAS  Google Scholar 

  17. Molzan, M., Weyand, M., Rose, R. and Ottmann, C. Structural insights of the MLF1/14-3-3 interaction. FEBS J. 279 (2012) 563–571.

    Article  PubMed  CAS  Google Scholar 

  18. Bridges, D. and Moorhead, G.B.G. 14-3-3 proteins: a number of functions for a numbered protein. Sci STKE 2005 (2005) 1–8.

    Article  Google Scholar 

  19. Yaffe, M.B., Rittinger, K., Volinia, S., Caron, P.R., Aitken, A., Leffers, H., Gamblin, S.J., Smerdon, S.J., Cantley, L.C. and Street, W. The structural basis for 14-3-3:phosphopeptide binding specificity. Cell 91 (1997) 961–971.

    Article  PubMed  CAS  Google Scholar 

  20. Johnson, C., Crowther, S., Stafford, M.J., Campbell, D.G., Toth, R. and MacKintosh, C. Bioinformatic and experimental survey of 14-3-3-binding sites. Biochem. J. 427 (2010) 69–78.

    Article  PubMed  CAS  Google Scholar 

  21. Morrison, D.K. The 14-3-3 proteins: integrators of diverse signaling cues that impact cell fate and cancer development. Trends Cell Biol. 19 (2009) 16–23.

    Article  PubMed  CAS  Google Scholar 

  22. Conklin, D.S., Galaktionov, K. and Beach, D. 14-3-3 Proteins associate with Cdc25 phosphatases. Proc. Natl. Acad. Sci. USA 92 (1995) 7892–7896.

    Article  PubMed  CAS  Google Scholar 

  23. Peng, C.-Y., Graves, P.R., Thoma, R.S., Wu, Z., Shaw, A.S. and Piwnica-Worms, H. Mitotic and G2 Checkpoint control: Regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science 277 (1997) 1501–1505.

    Article  PubMed  CAS  Google Scholar 

  24. Fantl, W.J., Muslin, A.J., Kikuchi, A., Martin, J.A., MacNicol, A.M., Gross, R.W. and Williams, L.T. Activation of Raf-1 by 14-3-3 proteins. Nature 371 (1994) 612–614.

    Article  PubMed  CAS  Google Scholar 

  25. Molzan, M., Schumacher, B., Ottmann, C., Baljuls, A., Polzien, L., Weyand, M., Thiel, P., Rose, R., Rose, M., Kuhenne, P., Kaiser, M., Rapp, U.R., Kuhlmann, J. and Ottmann, C. Impaired binding of 14-3-3 to C-RAF in Noonan syndrome suggests new approaches in diseases with increased Ras signaling. Mol. Cell Biol. 30 (2010) 4698–4711.

    Article  PubMed  CAS  Google Scholar 

  26. Vassilev, A., Kaneko, K.J., Shu, H., Zhao, Y. and Depamphilis, M.L. TEAD /TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm. Genes Dev. 15 (2001) 1229–1241.

    Article  PubMed  CAS  Google Scholar 

  27. Schumacher, B., Skwarczynska, M., Rose, R. and Ottmann, C. Structure of a 14-3-3ρ-YAP phosphopeptide complex at 1.15 A resolution. Acta Crystallogr. F 66 (2010) 978–984.

    Article  Google Scholar 

  28. Rajagopalan, S., Sade, R.S., Townsley, F.M. and Fersht, A.R. Mechanistic differences in the transcriptional activation of p53 by 14-3-3 isoforms. Nucleic Acids Res. 38 (2010) 893–906.

    Article  PubMed  CAS  Google Scholar 

  29. Schumacher, B., Mondry, J., Thiel, P., Weyand, M. and Ottmann, C. Structure of the p53 C-terminus bound to 14-3-3: implications for stabilization of the p53 tetramer. FEBS Lett. 584 (2010) 1443–1448.

    Article  PubMed  CAS  Google Scholar 

  30. Hermeking, H. The 14-3-3 cancer connection. Nat. Rev. Cancer 3 (2003) 931–943.

    Article  PubMed  CAS  Google Scholar 

  31. Fu, H., Coburn, J. and Collier, R.J. The eukaryotic host factor that activates exoenzyme S of Pseudomonas aeruginosa is a member of the 14-3-3 protein family. Proc. Natl. Acad. Sci. USA 90 (1993) 2320–2324.

    Article  PubMed  CAS  Google Scholar 

  32. Ottmann, C., Yasmin, L., Weyand, M., Veesenmeyer, J.L., Diaz, M.H., Palmer, R.H., Francis, M.S., Hauser, A.R., Wittinghofer, A. and Hallberg, B. Phosphorylation-independent interaction between 14-3-3 and exoenzyme S: from structure to pathogenesis. EMBO J. 26 (2007) 902–913.

    Article  PubMed  CAS  Google Scholar 

  33. Berg, D., Holzmann, C. and Riess, O. 14-3-3 Proteins in the nervous system. Nat. Rev. Neurosci. 4 (2003) 752–762.

    Article  PubMed  CAS  Google Scholar 

  34. Van Der Heide, L.P., Hoekman, M.F.M. and Smidt, M.P. The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation. Biochem. J. 380 (2004) 297–309.

    Article  Google Scholar 

  35. Kanai, F., Marignani, P.A., Sarbassova, D., Yagi, R., Hall, R.A., Donowitz, M., Hisaminato, A., Fujiwara, T., Ito, Y., Cantley, L.C. and Yaffe, M.B. TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins. EMBO J. 19 (2000) 6778–6791.

    Article  PubMed  CAS  Google Scholar 

  36. Aitken, A., Collinge, D.B., van Heusden, B.P.H., Isobe, T., Roseboom, P.H., Rosenfeld, G. and Soll, J. 14-3-3 proteins: a highly conserved, widespread family of eukaryotic proteins. Trends Biochem. Sci. 17 (1992) 498–501.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Chemical Genomics Centre of the Max-Planck-Society, Otto-Hahn-Strasse 15, 44227, Dortmund, Germany

    Manuela Molzan & Christian Ottmann

  2. Laboratory of Chemical Biology, Department of Biomedical Engineering, Technische Universiteit Eindhoven, Den Dolech 2, 5612 AZ, Eindhoven, The Netherlands

    Christian Ottmann

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  1. Manuela Molzan
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Correspondence to Christian Ottmann.

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Molzan, M., Ottmann, C. Subcellular localization of full-length human myeloid leukemia factor 1 (MLF1) is independent of 14-3-3 proteins. Cell Mol Biol Lett 18, 137–148 (2013). https://doi.org/10.2478/s11658-012-0044-1

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  • DOI: https://doi.org/10.2478/s11658-012-0044-1

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Cellular & Molecular Biology Letters

ISSN: 1689-1392

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