Résumé
Les jonctions communicantes et leurs protéines constitutives, les connexines (Cxs), sont des constituants nécessaires à la cohésion tissulaire et reconnus comme suppresseurs de tumeurs. Le but de la présente revue est de faire le point sur l’organisation et le rôle des Cxs au sein du testicule et d’analyser leur expression en physiopathologie testiculaire. Organisées en structures hexamèriques formant un canal reliant directement les cytoplasmes des cellules adjacentes, les Cxs sont impliquées dans de nombreux processus physiologiques tels que la prolifération et la différenciation cellulaires. Le maintien d’une balance entre prolifération, différenciation et apoptose est un équilibre primordial évitant une prolifération cellulaire anarchique, risque de cancer. La spermatogenèse est un modèle sophistiqué de prolifération et de différenciation des cellules germinales dans lequel les Cxs jouent un rôle essentiel. Il est acquis qu’une altération de l’expression membranaire des Cxs est l’un des signes avant-coureurs de la cinétique tumorale germinale, et il a été suggéré que les toxiques environnementaux qui, dans leur grande majorité, affectent l’expression de ces protéines, puissent être impliqués dans le développement de cette pathologie. La recherche de molécules capables de freiner les effets délétères de toxiques carcinogènes sur les Cxs semble être à l’heure actuelle une voie intéressante ouvrant de nouvelles perspectives en santé humaine.
Abstract
Gap junctions and their constitutive proteins, connexins, are essential in cell homeostasis and are considered as tumour suppressors. The purpose of the present review is to discuss the role of connexins in the testis and their expression in testis physiopathology. Organized in an hexameric arrangement forming a channel that connects cytoplasms of adjacent cells, connexins are implicated in numerous physiological processes such as cell proliferation and differentiation. The balance between cell proliferation/differentiation/apoptosis is prerequisite for limiting anarchic cell proliferation, a major risk of cancer development. Spermatogenesis is a sophisticated model of germ cell proliferation and differentiation in which connexins play an essential role. It is well recognized that alteration of membranous expression of connexins is an early event of germ cell tumoral kinetics and it has been suggested that environmental toxicants such as non-genomic carcinogens, which in most cases impair connexin expression, could be associated with testis tumoral development. The identification of agents capable of regulating the deleterious effects of carcinogens on connexin expression could be today of interest for opening new therapeutic perspectives.
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Références
Bruzzone R, White TW, Paul DL (1996) Connections with connexins: the molecular basis of direct intercellular signaling. Eur J Biochem 238:1–27
Kumar NM, Gilula NB (1996) The gap junction communication channel. Cell 84:381–388
Willecke K, Eiberger J, Degen J, et al (2002) Structural and functional diversity of connexin genes in the mouse and human genome. Biol Chem 383:725–737
Zhang JT, Nicholson BJ (1994) The topological structure of connexin 26 and its distribution compared to connexin 32 in hepatic gap junctions. J Membr Biol 139:15–29
Oyamada M, Oyamada Y, Takamatsu T (2005) Regulation of connexin expression. Biochim Biophys Acta 1719:6–23
Lampe PD, Lau AF (2004) The effects of connexin phosphorylation on gap junctional communication. Int J Biochem Cell Biol 36:1171–1186
Chipman JK, Mally A, Edwards GO (2003) Disruption of gap junctions in toxicity and carcinogenicity. Toxicol Sci 71:146–153
Pointis G, Fiorini C, Gilleron J, et al (2007) Connexins as precocious markers and molecular targets for chemical and pharmacological agents in carcinogenesis. Curr Med Chem 14:2288–2303
Di WL, Common JE, Kelsell DP (2001) Connexin 26 expression and mutation analysis in epidermal disease. Cell Commun Adhes 8:415–418
Gros DB, Jongsma HJ (1996) Connexins in mammalian heart function. Bioessays 18:719–730
Risley MS (2000) Connexin gene expression in seminiferous tubules of the Sprague-Dawley rat. Biol Reprod 62:748–754
Reaume AG, De Sousa PA, Kulkarni S, et al (1995) Cardiac malformation in neonatal mice lacking connexin 43. Science 267:1831–1834
Plum A, Hallas G, Magin T, et al (2000). Unique and shared functions of different connexins in mice. Curr Biol 10:1083–1091
Pointis G, Segretain D (2005) Role of connexin-based gap junction channels in testis. Trends Endocrinol Metab 16:300–306
Brehm R, Zeiler M, Rüttinger C, et al (2007) A Sertoli cellspecific knockout of connexin 43 prevents initiation of spermatogenesis. Am J Pathol 171:19–31
Sridarhan S, Simon L, Meling DD, et al (2007) Proliferation of adult Sertoli cells following conditional knockout of the gap junctional protein GJA1 (connexin 43) in mice. Biol Reprod 76:804–812
Gilleron J, Carette D, Durand P, et al (2009) Connexin 43 a potential regulator of cell proliferation and apoptosis within the seminiferous epithelium. Int J Biochem Cell Biol 41:1381–1390
Carette D, Weider K, Gilleron J, et al (2010) Major involvement of connexin 43 in seminiferous epithelial junction dynamics and male fertility. Dev Biol 346:54–67
Gershon E, Plaks V, Dekel N (2008) Gap junctions in the ovary: expression, localization and function. Mol Cell Endocrinol 282:18–25
Batias C, Siffroi JP, Fénichel P, et al (2000) Connexin 43 gene expression and regulation in the rodent seminiferous epithelium. J Histochem Cytochem 48:793–805
Pointis G, Gilleron J, Carette D, Segretain D (2010) Physiological and physiopathological aspects of connexins and communicating gap junctions in spermatogenesis. Philos Trans R Soc Lond B Biol Sci 365:1607–1620
Gilleron J, Nebout M, Scarabelli L, et al (2006) A potential novel mechanism involving connexin 43 gap junction for control of Sertoli cell proliferation by thyroid hormones. J Cell Physiol 209:153–161
Trosko JE (2007) Gap junctional intercellular communication as a biological “Rosetta stone” in understanding, in a systems biological manner, stem cell behavior, mechanisms of epigenetic toxicology, chemoprevention and chemotherapy. J Membr Biol 218:93–100
Cronier L, Crespin S, Strale PO, et al (2009) Gap junctions and cancer: new functions for an old story. Antioxid Redox Signal 11:323–338
Defamie N, Berthaut I, Mograbi B, et al (2003) Impaired gap junction connexin 43 in Sertoli cells of patients with secretory azoospermia: a marker of undifferentiated Sertoli cells. Lab Invest 83:449–456
Brehm R, Marks A, Rey R, et al (2002) Altered expression of connexins 26 and 43 in Sertoli cells in seminiferous tubules infiltrated with carcinoma in situ or seminoma. J Pathol 197:647–653
Brehm R, Rüttinger C, Fischer P, et al (2006) Transition from preinvasive carcinoma in situ to seminoma is accompanied by a reduction of connexin 43 expression in Sertoli cells and germ cells. Neoplasia 8:499–509
Roger C, Mograbi B, Chevallier D, et al (2004) Disrupted traffic of connexin 43 in human testicular seminoma cells: overexpression of Cx43 induces membrane location and cell proliferation decrease. J Pathol 202:241–246
Segretain D, Decrouy X, Dompierre J, et al (2003) Sequestration of connexin 43 in the early endosomes: an early event of Leydig cell tumor progression. Mol Carcinog 38:179–187
Mauro V, Chevallier D, Gilleron J, et al (2008) Aberrant cytoplasmic accumulation of connexin 43 in human testicular seminoma. Open Biomarkers Journal 1:20–27
Okada K, Katagiri T, Tsunoda T, et al (2003) Analysis of geneexpression profiles in testicular seminomas using a genome-wide cDNA microarray. Int J Oncol 23:1615–1635
Gilleron J, Fiorini C, Carette D, et al (2008) Molecular reorganization of the connexin 43, zonula occludens-1 and c-Src complexes during gap junction plaque endocytosis in response to a non genomic carcinogen. J Cell Sci 121:4069–4078
Defamie N, Mograbi B, Roger C, et al (2001) Disruption of gap junctional intercellular communication by lindane is associated with aberrant localization of connexin 43 and zonula occludens-1 in 42GPA9 Sertoli cells. Carcinogenesis 22:1537–1542
Fiorini C, Tilloy-Ellul A, Chevalier S, et al (2004) Sertoli cell junctional proteins as early targets for different classes of reproductive toxicants. Reprod Toxicol 18:413–421
Mograbi B, Corcelle E, Defamie N, et al (2003) Aberrant connexin 43 endocytosis by the carcinogen lindane involves activation of the ERK/mitogen-activated protein kinase pathway. Carcinogenesis 24:1415–1423
Segretain D, Falk MM (2004) Regulation of connexin biosynthesis, assembly, gap junction formation, and removal. Biochim Biophys Acta 1662:3–21
Kandouz M, Batist G (2010) Gap junctions and connexins as therapeutic targets in cancer. Expert Opin Ther Targets 14:681–692
Bertram JS, Vine AL (2005) Cancer prevention by retinoids and carotenoids: independent action on a common target. Biochim Biophys Acta 1740:170–178
Takahashi H, Nomata K, Mori K, et al (2004) The preventive effect of green tea on the gap junction intercellular communication in renal epithelial cells treated with a renal carcinogen. Anticancer Res 24:3757–3762
Tramoni M, Gilleron J, Tahiri K, et al (2009) Contraceptive steroids from pharmaceutical waste perturbate junctional communication in Sertoli cells. Biochimie 91:1366–1375
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Segretain, D., Zeghimi, A., Carette, D. et al. Connexines testiculaires: marqueurs physiopathologiques et cibles potentielles aux toxiques environnementaux. Basic Clin. Androl. 21, 75–82 (2011). https://doi.org/10.1007/s12610-011-0123-6
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DOI: https://doi.org/10.1007/s12610-011-0123-6
Mots clés
- Communication jonctionnelle intercellulaire par gap
- Connexines
- Pathologies testiculaires
- Séminome
- Toxiques environnementaux