title: Sequestration of connexin43 in the early endosomes: an early event of Leydig cell tumor progression.
abstract: Connexins form gap junction channels that allow intercellular communication between neighboring cells. Compelling evidence has revealed that Cx are tumor-suppressor genes and reduced Cx expression has been related with uncontrolled cell growth in tumors and transformed cells. In the present study, we addressed Cx transcriptional and posttranscriptional regulations during the earlier stage of testicular tumors confined to Leydig cells in a transgenic mice model. In situ hybridization indicated that connexin43 (Cx43) mRNA was highly expressed either at early tumorogenesis (3 m) characterized by intense proliferation of Leydig cells, or at advanced tumorogenesis (6-7 m) when tumor cells completely invaded the testis. In contrast, Cx43 protein analyzed by Western blotting or classic immunohistochemical analyses was present at the beginning of tumor progression, but was dramatically reduced as tumor advanced. Application of high-resolution deconvolution microscopy to testis sections demonstrates that cells that proliferate exhibited an aberrant cytoplasmic Cx43 localization, in contrast to the expected plasma membrane Cx43 localization in normal Leydig cells. Dual immunofluorescence labeling with specific markers of cellular compartments shows that cytoplasmic Cx43 signal was mainly sequestered within early endosomes. Altogether, this study provides the first evidence that impaired Cx43 trafficking in endosomes is an early event associated with uncontrolled cell proliferation that could serve as a neoplastic marker.
authors.affiliation: INSERM EMI 00-09, Université Paris V, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Segretain
authors.forename: Xavier
authors.initials: X
authors.lastname: Decrouy
authors.forename: Jim
authors.initials: J
authors.lastname: Dompierre
authors.forename: Denise
authors.initials: D
authors.lastname: Escalier
authors.forename: Nafis
authors.initials: N
authors.lastname: Rahman
authors.forename: Céline
authors.initials: C
authors.lastname: Fiorini
authors.forename: Baharia
authors.initials: B
authors.lastname: Mograbi
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Siffroi
authors.forename: Ilpo
authors.initials: I
authors.lastname: Huhtaniemi
authors.forename: Patrick
authors.initials: P
authors.lastname: Fenichel
authors.forename: Georges
authors.initials: G
authors.lastname: Pointis
mesh_terms: D000818:Animals; D002462:Cell Membrane; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D011992:Endosomes / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D017629:Gap Junctions / Q000648:ultrastructure; D015972:Gene Expression Regulation, Neoplastic; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D007265:Inhibins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007984:Leydig Cell Tumor / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D018031:Connexin 43; D012333:RNA, Messenger; C094377:inhibin-alpha subunit; D007265:Inhibins