Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10895531 | Biochimica et Biophysica Acta (BBA) - Reviews on Cancer | 2016 | 14 Pages |
Abstract
The connexins constitute a family of integral membrane proteins that form intercellular channels, enabling adjacent cells to directly exchange ions and small molecules. The connexin channels assemble into distinct plasma membrane domains known as gap junctions. Intercellular communication via gap junctions has an important role in regulating cell growth and differentiation, as well as in maintaining tissue homeostasis. Connexin43 (Cx43), the most ubiquitously expressed connexin isoform in human tissues, has been shown to act as a tumor suppressor and is frequently downregulated during cancer development. Cx43 has a short half-life, and modulation of the Cx43 turnover rate represents an important mechanism by which the level of gap junctional intercellular communication is regulated under basal conditions. Moreover, many growth factors, oncogenes, and tumor promoters are potent inducers of Cx43 endocytosis and endolysosomal degradation, resulting in loss of gap junctions. Emerging evidence indicates that the ubiquitin system has a major role in these processes. Recent studies have shown that ubiquitination is also involved in the autophagy-mediated degradation of Cx43 in a process mediated by the proto-oncogenic E3 ubiquitin ligase NEDD4. Moreover, ubiquitination of connexins has been implicated in modulating the level of intercellular communication via gap junctions in response to oxidative stress. This review article provides an overview of our current understanding of the role of the ubiquitin system in the regulation of connexins and discusses how the malfunction of these processes may contribute to the loss of intercellular communication via gap junctions during carcinogenesis.
Keywords
IP3epidermal growth factor receptor substrate 15TGF-βTSG101SMURF2Nedd4HECTESCRTEPS15ZO-1SCFPKCIGF-1Inositol trisphosphate12-O-tetradecanoylphorbol-13-acetateHRSSUMOERADEGFtPAcAMPLC-MS/MSMAPKSmall interfering RNAsiRNAAdenosine TriphosphateATPCyclic adenosine monophosphateIntercellular communicationsmall ubiquitin-related modifierSDS-PAGESodium dodecyl sulfate polyacrylamide gel electrophoresisAMshinsulin-like growth factor-1transforming growth factor-βendoplasmic reticulum-associated degradationEMTRingCancerHepatocyte growth factor-regulated tyrosine kinase substrateepidermal growth factorgap junctionphosphatase and tensin homologendosomal sorting complex required for transportZonula occludens-1Protein kinase Cmitogen-activated protein kinasePtenreally interesting new geneliquid chromatography tandem mass spectrometryconnexinEpithelial-mesenchymal transitionUbiquitin
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Authors
Edward Leithe,