title: Connexin Controls Cell-Cycle Exit and Cell Differentiation by Directly Promoting Cytosolic Localization and Degradation of E3 Ligase Skp2.
abstract: Connexins and connexin channels play important roles in cell growth/differentiation and tumorigenesis. Here, we identified a relationship between a connexin molecule and a critical cell-cycle regulator. Our data show that connexin (Cx) 50 regulated lens cell-cycle progression and differentiation by modulating expression of cyclin-dependent kinase inhibitor p27/p57 and E3 ubiquitin ligase Skp2. Cx50 directly interacted with and retained Skp2 in the cytosol by masking the nuclear targeting domain of Skp2, and this effect was supported by an increased nuclear localization of Skp2, disruption of Skp2 interaction with importin-7, and decreased levels of p27/p57 in mouse lenses lacking Cx50. As a result, Cx50 increased auto-ubiquitination and subsequent degradation of Skp2. A mutation (V362E) on the C terminus of Cx50 disrupted the interaction between Cx50 and Skp2 and completely abolished such effects. Therefore, this study identifies a role for connexins in regulating cell-cycle modulators and, consequently, cell growth and differentiation.
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors.forename: Sumin
authors.initials: S
authors.lastname: Gu
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors.forename: X Sean
authors.initials: XS
authors.lastname: Yu
authors.affiliation: Department of Physiology and Biophysics, State University of New York, Stony Brook, NY 11794-8661, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: White
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Banks
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA. Electronic address: jiangj@uthscsa.edu.
authors.forename: Jean X
authors.initials: JX
authors.lastname: Jiang
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002642:Chick Embryo; D002645:Chickens; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D007908:Lens, Crystalline / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D059748:Proteolysis; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000099264:Connexin 50
chemical_list: D017630:Connexins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D044786:S-Phase Kinase-Associated Proteins; D000099264:Connexin 50