Abstract
Cell-Penetrating Peptides (CPPs) are small peptides internalized by live cells, gaining access to their cytoplasm and intracellular organelles (i.e., mitochondria, nucleus) and are used as pharmacological tools. This is indeed a very important issue, fully justifying the efforts of several groups to better understand the mechanisms of peptide transduction and to verify if and how this strategy can be translated into therapeutic improvements. However, the discovery of peptide transduction is a consequence of that of a novel signaling mechanism based on the intercellular transfer of homeoprotein transcription factors. Indeed, the first and probably most popular CPPs (Tat and Penetratin) correspond to domains that drive TAT (HIV) and homeoprotein transcription factors into the cells. These findings have fostered several studies on transduction and allowed the design of “nonnatural” CPPs. As useful as they are, these lines of research have, in general, neglected the fact that protein transduction is a signaling mechanism, in its own right, with important physiological functions. In this chapter, I describe some of these functions and propose that this class of signaling molecules, in particular homeoproteins, may also be used as therapeutic agents.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Frankel AD, Bredt DS, Pabo CO. Tat protein from human immunodeficiency virus forms a metal-linked dimer. Science 1988;240:70–3.
Prochiantz A, Joliot A. Can transcription factors function as cell-cell signalling molecules? Nat Rev Mol Cell Biol 2003;4:814–9.
Lucas WJ, Bouche-Pillon S, Jackson DP, et al. Selective trafficking of KNOTTED1 homeodomain protein and its mRNA through plasmodesmata. Science 1995;270:1980–3.
Tassetto M, Maizel A, Osorio J, Joliot A. Plant and animal homeodomains use convergent mechanisms for intercellular transfer. EMBO Rep 2005;6:885–90.
Joliot A, Prochiantz A. Transduction peptides: from technology to physiology. Nat Cell Biol 2004;6:189–96.
Cai C, Masumiya H, Weisleder N, et al. MG53 nucleates assembly of cell membrane repair machinery. Nat Cell Biol 2009;11:56–64.
Simeone A. Positioning the isthmic organizer where Otx2 and Gbx2 meet. Trends Genet 2000;16:237–40.
Briscoe J, Pierani A, Jessell TM, Ericson J. A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube. Cell 2000;101:435–45.
Callaerts P, Halder G, Gehring WJ. PAX-6 in development and evolution. Annu Rev Neurosci 1997;20:483–532.
Quiring R, Walldorf U, Kloter U, Gehring WJ. Homology of the eyeless gene of Drosophila to the Small eye gene in mice and Aniridia in humans. Science 1994;265:785–9.
Halder G, Callaerts P, Gehring WJ. Induction of ectopic eyes by targeted expression of the eyeless gene in Drosophila. Science 1995;267:1788–92.
Chow RL, Altmann CR, Lang RA, Hemmati-Brivanlou A. Pax6 induces ectopic eyes in a vertebrate. Development 1999;126:4213–22.
Brunet I, Di Nardo AA, Sonnier L, Beurdeley M, Prochiantz A. The topological role of homeoproteins in the developing central nervous system. Trends Neurosci 2007;30:260–7.
Holcman D, Kasatkin V, Prochiantz A. Modeling homeoprotein intercellular transfer unveils a parsimonious mechanism for gradient and boundary formation in early brain development. J Theor Biol 2007;249:503–17.
Lesaffre B, Joliot A, Prochiantz A, Volovitch M. Direct non-cell autonomous Pax6 activity regulates eye development in the zebrafish. Neural Dev 2007;2:2.
Sperry RW. Chemoaffinity in the orderly growth of nerve fiber patterns and connections. Proc Natl Acad Sci USA 1963;50:703–10.
Flanagan JG, Vanderhaeghen P. The ephrins and Eph receptors in neural development. Annu Rev Neurosci 1998;21:309–45.
Flanagan JG. Neural map specification by gradients. Curr Opin Neurobiol 2006;16:59–66.
McLaughlin T, O’Leary DD. Molecular gradients and development of retinotopic maps. Annu Rev Neurosci 2005;28:327–55.
Brunet I, Weinl C, Piper M, et al. The transcription factor Engrailed-2 guides retinal axons. Nature 2005;438:94–8.
Wizenmann A, Brunet I, Lam JSY, et al. Extracellular Engrailed participates in the topographic guidance of retinal axons in vivo. Neuron 2009;64(3):355–66.
Sugiyama S, Di Nardo AA, Aizawa S, et al. Experience-dependent transfer of Otx2 homeoprotein into the visual cortex activates postnatal plasticity. Cell 2008;134:508–20.
Kennedy DP, Courchesne E. The intrinsic functional organization of the brain is altered in autism. Neuroimage 2008;39:1877–85.
Harrison PJ. Schizophrenia susceptibility genes and neurodevelopment. Biol Psychiatry 2007;61:1119–20.
Walsh CA, Morrow EM, Rubenstein JL. Autism and brain development. Cell 2008;135:396–400.
Simon HH, Thuret S, Alberi L. Midbrain dopaminergic neurons: control of their cell fate by the engrailed transcription factors. Cell Tissue Res 2004;318:53–61.
Sonnier L, Le Pen G, Hartmann A, et al. Progressive loss of dopaminergic neurons in the ventral midbrain of adult mice heterozygote for Engrailed1. J Neurosci 2007;27:1063–71.
Acknowledgments
This work was supported by Centre national de la Recherche Scientifique, Ecole normale supérieure and Collège de France. I want to thank Elizabeth Di Lullo for her useful comments and careful rereading of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2011 Springer Science+Business Media, LLC
About this protocol
Cite this protocol
Prochiantz, A. (2011). Homeoprotein Intercellular Transfer, the Hidden Face of Cell-Penetrating Peptides. In: Langel, Ü. (eds) Cell-Penetrating Peptides. Methods in Molecular Biology, vol 683. Humana Press. https://doi.org/10.1007/978-1-60761-919-2_18
Download citation
DOI: https://doi.org/10.1007/978-1-60761-919-2_18
Published:
Publisher Name: Humana Press
Print ISBN: 978-1-60761-918-5
Online ISBN: 978-1-60761-919-2
eBook Packages: Springer Protocols