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Can transcription factors function as cell–cell signalling molecules?

Nature Reviews Molecular Cell Biology volume 4, pages 814–819 (2003)Cite this article

Abstract

Recent data support the view that transcription factors — in particular, homeoproteins — can be transferred from cell to cell and have direct non-cell-autonomous (and therefore paracrine) activities. This intercellular transfer, based on atypical internalization and secretion, has important biotechnological consequences. But the real excitement stems from the physiological and developmental implications of this mode of signal transduction.

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Figure 1: Functional domains for homeoprotein intercellular transfer.
Figure 2: Intercellular transfer of Engrailed homeoprotein.
Figure 3: Hypothetical signalling with homeoproteins.
Figure 4: A model for homeoproteins as infectious proteins.

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References

  1. Ensoli, B. et al. Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation. J. Virol. 67, 277–287 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Prochiantz, A. Messenger proteins: homeoproteins, TAT and others. Curr. Opin. Cell Biol. 12, 400–406 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Joliot, A. et al. Identification of a signal sequence necessary for the unconventional secretion of Engrailed homeoprotein. Curr. Biol. 8, 856–863 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. Simon, H. H., Saueressig, H., Wurst, W., Goulding, M. D. & O'Leary, D. D. Fate of midbrain dopaminergic neurons controlled by the engrailed genes. J. Neurosci. 21, 3126–3134 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lucas, W. J. et al. Selective trafficking of KNOTTED1 homeodomain protein and its mRNA through plasmodesmata. Science 270, 1980–1983 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Lee, J. Y. et al. Selective trafficking of non-cell-autonomous proteins mediated by NtNCAPP1. Science 299, 392–396 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Kragler, F., Monzer, J., Xoconostle-Cazares, B. & Lucas, W. J. Peptide antagonists of the plasmodesmal macromolecular trafficking pathway. EMBO J. 19, 2856–2868 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Joliot, A., Pernelle, C., Deagostini-Bazin, H. & Prochiantz, A. Antennapedia homeobox peptide regulates neural morphogenesis. Proc. Natl Acad. Sci. USA 88, 1864–1868 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Derossi, D., Joliot, A. H., Chassaing, G. & Prochiantz, A. The third helix of Antennapedia homeodomain translocates through biological membranes. J. Biol. Chem. 269, 10444–10450 (1994).

    CAS  PubMed  Google Scholar 

  10. Lundberg, M. & Johansson, M. Positively charged DNA-binding proteins cause apparent cell membrane translocation. Biochem. Biophys. Res. Commun. 291, 367–371 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Thoren, P. E., Persson, D., Karlsson, M. & Norden, B. The antennapedia peptide penetratin translocates across lipid bilayers — the first direct observation. FEBS Lett. 482, 265–268 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Derossi, D. et al. Cell internalization of the third helix of the Antennapedia homeodomain is receptor-independent. J. Biol. Chem. 271, 18188–18193 (1996).

    Article  CAS  PubMed  Google Scholar 

  13. Berlose, J. P., Convert, O., Derossi, D., Brunissen, A. & Chassaing, G. Conformational and associative behaviours of the third helix of Antennapedia homeodomain in membrane-mimetic environments. Eur. J. Biochem. 242, 372–386 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Chatelin, L., Volovitch, M., Joliot, A. H., Perez, F. & Prochiantz, A. Transcription factor Hoxa-5 is taken up by cells in culture and conveyed to their nuclei. Mech. Dev. 55, 111–117 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Le Roux, I., Joliot, A. H., Bloch-Gallego, E., Prochiantz, A. & Volovitch, M. Neurotrophic activity of the Antennapedia homeodomain depends on its specific DNA-binding properties. Proc. Natl Acad. Sci. USA 90, 9120–9124 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Maizel, A., Bensaude, O., Prochiantz, A. & Joliot, A. A short region of its homeodomain is necessary for Engrailed nuclear export and secretion. Development 126, 3183–3190 (1999).

    CAS  PubMed  Google Scholar 

  17. Joliot, A. et al. Association of engrailed homeoproteins with vesicles presenting caveolae-like properties. Development 124, 1865–1875 (1997).

    CAS  PubMed  Google Scholar 

  18. Thery, C. et al. Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles. J. Immunol. 166, 7309–7318 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Hamon, Y. et al. Interleukin-1β secretion is impaired by inhibitors of the Atp binding cassette transporter, ABC1. Blood 90, 2911–2915 (1997).

    CAS  PubMed  Google Scholar 

  20. Gupta, S., Aggarwal, S. & Nakamura, S. A possible role of multidrug resistance-associated protein (MRP) in basic fibroblast growth factor secretion by AIDS-associated Kaposi's sarcoma cells: a survival molecule? J. Clin. Immunol. 18, 256–263 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Kim, N. et al. Proteins released by Helicobacter pylori in vitro. J. Bacteriol. 184, 6155–6162 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ishiwatari, Y. et al. Thioredoxin H is one of the major proteins in rice phloem sap. Planta 195, 456–463 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Rubartelli, A., Bajetto, A., Allavena, G., Wollman, E. & Sitia, R. Secretion of thioredoxin by normal and neoplastic cells through a leaderless secretory pathway. J. Biol. Chem. 267, 24161–24164 (1992).

    CAS  PubMed  Google Scholar 

  24. Davidson, P. J. et al. Shuttling of galectin-3 between the nucleus and cytoplasm. Glycobiology 12, 329–337 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Dono, R. & Zeller, R. Cell-type-specific nuclear translocation of fibroblast growth factor-2 isoforms during chicken kidney and limb morphogenesis. Dev. Biol. 163, 316–330 (1994).

    Article  CAS  PubMed  Google Scholar 

  26. Stachowiak, M. K. et al. Regulation of bFGF gene expression and subcellular distribution of bFGF protein in adrenal medullary cells. J. Cell Biol. 127, 203–223 (1994).

    Article  CAS  PubMed  Google Scholar 

  27. Hirota, K. et al. AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1. Proc. Natl Acad. Sci. USA 94, 3633–3638 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cao, Y. & Pettersson, R. Release and subcellular localization of acidic fibroblast growth factor expressed to high levels in HeLa cells. Growth Factors 8, 277–290 (1993).

    Article  CAS  PubMed  Google Scholar 

  29. Gardella, S. et al. The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Rep. 3, 995–1001 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Eberhard, D. A., Karns, L. R., VandenBerg, S. R. & Creutz, C. E. Control of the nuclear–cytoplasmic partitioning of annexin II by a nuclear export signal and by p11 binding. J. Cell Sci. 114, 3155–3166 (2001).

    CAS  PubMed  Google Scholar 

  31. Sahaf, B. & Rosen, A. Secretion of 10-kDa and 12-kDa thioredoxin species from blood monocytes and transformed leukocytes. Antioxid. Redox Signal. 2, 717–726 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Gong, H. C. et al. The NH2 terminus of galectin-3 governs cellular compartmentalization and functions in cancer cells. Cancer Res. 59, 6239–6245 (1999).

    CAS  PubMed  Google Scholar 

  33. Maizel, A. et al. Engrailed homeoprotein secretion is a regulated process. Development 129, 3545–3553 (2002).

    CAS  PubMed  Google Scholar 

  34. Vecchi, M. et al. Nucleocytoplasmic shuttling of endocytic proteins. J. Cell Biol. 153, 1511–1517 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mahanty, S. K., Wang, Y., Farley, F. W. & Elion, E. A. Nuclear shuttling of yeast scaffold Ste5 is required for its recruitment to the plasma membrane and activation of the mating MAPK cascade. Cell 98, 501–512 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Chatterjee, T. K. & Fisher, R. A. Cytoplasmic, nuclear, and Golgi localization of RGS proteins. Evidence for N-terminal and RGS domain sequences as intracellular targeting motifs. J. Biol. Chem. 275, 24013–24021 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Smart, E. J., Ying, Y. S. & Anderson, R. G. Hormonal regulation of caveolae internalization. J. Cell Biol. 131, 929–938 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Goutte, C. & Johnson, A. D. Yeast a1 and α2 homeodomain proteins form a DNA-binding activity with properties distinct from those of either protein. J. Mol. Biol. 233, 359–371 (1993).

    Article  CAS  PubMed  Google Scholar 

  39. Gillissen, B. et al. A two-component regulatory system for self/non-self recognition in Ustilago maydis. Cell 68, 647–657 (1992).

    Article  CAS  PubMed  Google Scholar 

  40. Van den Ackerveken, G., Marois, E. & Bonas, U. Recognition of the bacterial avirulence protein AvrBs3 occurs inside the host plant cell. Cell 87, 1307–1316 (1996).

    Article  CAS  PubMed  Google Scholar 

  41. Dumas, F., Duckely, M., Pelczar, P., Van Gelder, P. & Hohn, B. An Agrobacterium VirE2 channel for transferred-DNA transport into plant cells. Proc. Natl Acad. Sci. USA 98, 485–490 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Desvoyes, B., Faure-Rabasse, S., Chen, M. H., Park, J. W. & Scholthof, H. B. A novel plant homeodomain protein interacts in a functionally relevant manner with a virus movement protein. Plant Physiol. 129, 1521–1532 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Thomas, C. A., Dobkin, J. & Weinberger, O. K. TAT-mediated transcellular activation of HIV-1 long terminal repeat directed gene expression by HIV-1-infected peripheral blood mononuclear cells. J. Immunol. 153, 3831–3839 (1994).

    CAS  PubMed  Google Scholar 

  44. Bailly, K., Soulet, F., Leroy, D., Amalric, F. & Bouche, G. Uncoupling of cell proliferation and differentiation activities of basic fibroblast growth factor. FASEB J. 14, 333–344 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Wiedlocha, A., Falnes, P., Madshus, H., Sandvig, K. & Olsnes, S. Dual mode of signal transduction by externally added acidic fibroblast growth factor. Cell 76, 1039–1051 (1994).

    Article  CAS  PubMed  Google Scholar 

  46. Rivera-Pomar, R., Niessing, D., Schmidt, O. U., Gehring, W. J. & Jäckle, H. RNA binding and translational suppression by bicoid. Nature 379, 746–749 (1996).

    Article  CAS  PubMed  Google Scholar 

  47. Dubnau, J. & Struhl, G. RNA recognition and translational regulation by a homeodomain protein Nature 379, 694–699 (1996).

    Article  CAS  PubMed  Google Scholar 

  48. Niessing, D. et al. Homeodomain position 54 specifies transcriptional versus translational control by Bicoid. Mol. Cell 5, 395–401 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Niessing, D., Blanke, S. & Jäckle, H. Bicoid associates with the 5′-cap-bound complex of caudal mRNA and represses translation. Genes Dev. 16, 2576–2582 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Topisirovic, I. et al. The proline-rich homeodomain protein, PRH, is a tissue-specific inhibitor of eIF4E-dependent cyclin D1 mRNA transport and growth. EMBO J. 22, 689–703 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Marie, B., Cruz-Orengo, L. & Blagburn, J. M. Persistent engrailed expression is required to determine sensory axon trajectory, branching, and target choice. J. Neurosci. 22, 832–841 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bloch-Gallego, E. et al. Antennapedia homeobox peptide enhances growth and branching of embryonic chicken motoneurons in vitro. J. Cell Biol. 120, 485–492 (1993).

    Article  CAS  PubMed  Google Scholar 

  53. Simeone, A. & Acampora, D. The role of Otx2 in organizing the anterior patterning in mouse. Int. J. Dev. Biol. 45, 337–345 (2001).

    CAS  PubMed  Google Scholar 

  54. Ruiz i Altaba, A. Planar and vertical signals in the induction and patterning of the Xenopus nervous system. Development 116, 67–80 (1992).

    PubMed  Google Scholar 

  55. Li, J. Y. & Joyner, A. L. Otx2 and Gbx2 are required for refinement and not induction of mid-hindbrain gene expression. Development 128, 4979–4991 (2001).

    CAS  PubMed  Google Scholar 

  56. Bishop, K. M., Rubenstein, J. L. & O'Leary, D. D. Distinct actions of Emx1, Emx2, and Pax6 in regulating the specification of areas in the developing neocortex. J. Neurosci. 22, 7627–7638 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Toresson, H., Potter, S. S. & Campbell, K. Genetic control of dorsal-ventral identity in the telencephalon: opposing roles for Pax6 and Gsh2. Development 127, 4361–4371 (2000).

    CAS  PubMed  Google Scholar 

  58. Matsunaga, E., Araki, I. & Nakamura, H. Pax6 defines the di-mesencephalic boundary by repressing En1 and Pax2. Development 127, 2357–2365 (2000).

    CAS  PubMed  Google Scholar 

  59. Turing, A. M. The chemical basis of morphogenesis. Bull. Math. Biol. 1990, 153–197 (1953).

    Google Scholar 

  60. Briata, P. et al. EMX1 homeoprotein is expressed in cell nuclei of the developing cerebal cortex and in the axons of the olfactory sensory neurons. Mech. Dev. 57, 169–180 (1996).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank the members of our groups for many helpful discussions and C. Goridis for his critical reading of the manuscript. Many of the experiments discussed in this article were supported by the Centre National de la Recherche Scientifique and the Ecole Normale Supérieure, and by grants from the Association Française de lutte contre les Myopathies, the Human Frontier Research Program and the European Economic Community.

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  1. Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8542, Ecole Normale Supérieure, 46 rue d'Ulm, Paris, 75230 Cedex 05, France

    Alain Prochiantz & Alain Joliot

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DATABASES

FlyBase

Antennapedia

Engrailed

LocusLink

eIF4E

FGF1

FGF2

Gbx2

Gsh2

IL-1

IL-1β

HMGB1

Otx2

Pax6

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Prochiantz, A., Joliot, A. Can transcription factors function as cell–cell signalling molecules?. Nat Rev Mol Cell Biol 4, 814–819 (2003). https://doi.org/10.1038/nrm1227

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