Disease relevance of Gjb2

• No hyperproliferation or hyperplasia was observed, suggesting that Cx26 does not function as a tumor suppressor [1].
• In papillomas, no clear reduction of the two connexins was observed; however, Cx26 and Cx43 were frequently co-localized in the same gap junction plaques, whereas the two kinds of Cxs were differentially expressed in normal and surrounding non-tumorous epidermis [2].
• Squamous cell carcinomas at invasive sites showed clear reduction of Cx26 and Cx43 [2].
• The channel properties responsible for producing the rectifying current observed for Cx26/Cx32 heterotypic gap junction channels were determined in transfected mouse neuroblastoma 2A (N2A) cells [3].
• This suggests that, during the acute-phase response, the second hepatic Cx26 protein may compensate in part for the downregulation of the Cx32 protein [4].

High impact information on Gjb2

• We provide support for this approach and report the identification of mutations in the gene (Gjb2) encoding connexin 26, using archives established from the UK ENU mutagenesis program [5].
• Here we study a pedigree containing cases of autosomal dominant deafness and have identified a mutation in the gene encoding the gap-junction protein connexin 26 (Cx26) that segregates with the profound deafness in the family [6].
• The same antibodies bound connexin 26, gene mutations of which lead to congenital inner-ear deafness [7].
• We generated mice in which extra copies of the Cx26 gene were transgenically expressed from a modified bacterial artificial chromosome in a Cx30(-/-) background [8].
• In the absence of the Cx30 gene, Cx26 expressed from extra alleles completely restored hearing sensitivity and prevented hair cell death in deaf Cx30(-/-) mice [8].

Chemical compound and disease context of Gjb2

• Induction of an acute phase response in connexin-32-deficient mice by intraperitoneal injection of lipopolysaccharide increased dye coupling by 33%, probably due to upregulation of connexin-26-containing gap junction channels [9].
• In this study, we have examined the dominant-negative effects of mutant (prepared by site-directed mutagenesis) Cx43 constructs in C6 glioma cells, and of mutant Cx26 constructs in HeLa cells, on tumorigenicity [10].
• One of these, denoted metastasis inhibitor-18 (MI-18), inhibited the GJIC formed by Cx26 as well as oleamide but unlike oleamide, which is a non-selective inhibitor of connexin, it did not inhibit the GJIC formed by Cx43 [11].
• To investigate the efficacy of the bystander effect in HSVtk/GCV gene therapy, the Cx 26 gene was introduced into UM-UC-3 and UM-UC-14 bladder cancer cell lines by an adenovirus poly-L-lysine conjugate using a multigenic expression plasmid that expressed both the HSVtk and Cx 26 genes [12].

Biological context of Gjb2

• In contrast, loss of Cx26 in mammary epithelium before puberty resulted in abrogated lobulo-alveolar development and increased cell death during pregnancy, which was accompanied by impaired lactation [1].
• Loss of connexin 26 in mammary epithelium during early but not during late pregnancy results in unscheduled apoptosis and impaired development [1].
• Cx26 is considered a tumor suppressor gene and Cx26-null mammary tissue was evaluated after five pregnancies [1].
• The treatment with urethane was associated with the downregulation of Cx26, 32 and 46 expressions, and with the upregulation of Cx43 expression in lung tissue [13].
• Cx32 gene transcription was greatly reduced in all Mist1KO exocrine cells, while Cx26 gene expression remained unaffected [14].

Anatomical context of Gjb2

• Presence of Cx26 in astrocyte cultures was indicated by RT-PCR and by Western blot analysis, although we were unable to resolve whether it was contributed by contaminating cells; Cx30 mRNA was detected by Northern blot in long term (2 weeks) but not fresh cultures of astrocytes [15].
• Loss of Cx26 in mammary epithelium during the later part of pregnancy did not adversely interfere with functional mammary development [1].
• Expression of gap junction proteins connexin 26 and 43 is modulated during differentiation of keratinocytes in newborn mouse epidermis [16].
• In squamous cell carcinomas metastasized into lymph nodes, Cx26 was expressed, but few carcinoma cells expressed Cx43 [2].
• Mice with loxP-flanked Cx26 coding DNA were crossed with mice expressing the Cre recombinase exclusively in hepatocytes [17].

Associations of Gjb2 with chemical compounds

• In rodents, gene knock out in mice have vastly improved our understanding of the role of Cx genes in mouse placental development: Cx26 in transplacental uptake of glucose, Cx31 in the proliferative process of trophoblastic cells and Cx45 in placental vascularisation [18].
• Microinjection of connexin-30 cRNA into Xenopus oocytes induced formation of functional gap junction channels that gated somewhat asymmetrically in response to transjunctional voltage and at significantly lower voltage (Vo = +38 and -46 mV) than the closely homologous connexin-26 channels (Vo = 89 mV) [19].
• Lastly, by combining bromodeoxyuridine and connexin immunohistochemistry on acutely dissociated neocortical cells, we show that the percentage of cycling cells immunoreactive to connexin 26 and connexin 43 changes through the cell cycle [20].
• Homomeric Cx26 and heteromeric channels with high Cx26/Cx32 stoichiometry are also inhibited by taurine, an osmolyte playing a key role in milk protein synthesis [21].
• Most remarkably, heteromeric Cx26-Cx32 channels are selectively permeability to adenosine 3',5' cyclic phosphate (cAMP), guanosine 3',5' cyclic phosphate (cGMP), and inositol 1,4,5-triphosphate (IP(3)), whereas homomeric channels are not [21].

Regulatory relationships of Gjb2

• Previously, we found increased formation of chemically induced liver tumours but no increase in spontaneous development of preneoplastic hepatic foci in mice that lacked Cx32 and expressed decreased amounts of Cx26 [17].
• Cx26 immunofluorescence and a beta-gal reporter under regulatory control of the Cx36 promoter did not colocalize with a horizontal cell marker, indicating that these genes are not expressed by horizontal cells [22].
• In addition, FA strongly induced metallothionein 1 expression and inhibited connexin 26 expression in skin but did not affect expression of these genes in tumors [23].

Other interactions of Gjb2

• The expression of Cx26 and Cx32 is induced during pregnancy and lactation, respectively, thus suggesting unique roles for them in the functional development of the gland [1].
• Microscopy was used to further examine the distribution of Cx26 and Cx36 [22].
• Although the absence of gap junction channels led to altered expression of adhesion-related proteins like E-cadherin and actin, microarray analyses of total liver transcripts yielded only few differences between Cx26-deficient and double deficient livers compared to control samples [17].
• Perturbation in connexin 43 and connexin 26 gap-junction expression in mouse skin hyperplasia and neoplasia [24].
• For the study of astrocytes lacking Cx45 and Cx26 in vitro, which deficiencies are embryonic lethal, conditionally deficient astrocyte cultures are essential [25].

Analytical, diagnostic and therapeutic context of Gjb2

• Additionally, Cx26, -31, -32 and -40 mRNAs were detected in retina by RT-PCR but none of the corresponding proteins were found [26].
• The Western blot analysis confirmed that both Cx26 and Cx43 proteins were reduced in squamous cell carcinomas compared with papillomas [2].
• No Cx26 protein was detected in retina by using Cx26 antibodies for immunoblot analyses or confocal microscopy [27].
• Analysis of gap junction hemichannels (connexons) isolated from lactating mammary gland plasma membranes by a rate-density centrifugation procedure, followed by immunoprecipitation and by size-exclusion chromatography, showed that Cx26 and Cx32 were organized as homomeric and heteromeric connexons [28].
• The absence of Cx26 mRNA in these cells could also be confirmed by reverse transcription-polymerase chain reaction and in situ hybridization [29].

References