Role of the Cytoplasmic Loop Domain of Cx43 in Its Intracellular Localization and Function: Possible Interaction with Cadherin

Nambara, Chika; Kawasaki, Yumi; Yamasaki, Hiroshi

doi:10.1007/s00232-007-9032-1

Cited by 20 publications

(16 citation statements)

References 30 publications

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“…The findings suggested that the expression of cell junction-related proteins such as connexin and par-3 were down-regulated in the tumor tissues and there existed a positive relationship between such expression and the distal margin of resection. Yano and Nambara et al reported the similar findings by tumor cells culture in vitro [10,11] . These findings evidenced that connexin was closely associated with tumorigenesis and tumor differentiation.…”

Section: Discussionsupporting

confidence: 76%

Expressions of connexin and par-3 in the distal margin of rectal cancer after ultra-low anterior resection

Zhang

Liu

et al. 2009

J. Huazhong Univ. Sci. Technol. [Med. Sci.]

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This study examined the expression of connexin and protease-activated receptor 3 (par-3) in the distal resection margin of rectal cancer and the correlation of the expression of the two proteins with tumor relapse. A total of 40 patients with rectal cancer underwent ultra-low anterior resection with curved cutter stapler. The pathological specimens were divided into 3 groups in terms of sampling sites: tumor group, 2.0-cm group (in which the tissues were harvested 2.0 cm distal to the tumor tissues), 3.0-cm group (in which the tissues were taken 3.0 cm away from the tumor tissues). All the samples were pathologically observed and then measured for the expression of connexin and par-3 by employing immunohistochemistry and Western blotting. The operations in this series went uneventfully. No anastomotic stoma bleeding, stenosis and death occurred postoperatively. Histopathologically, in the tumor group, epithelial cells lost normal pattern of arrangement and polarity, and were loosely connected and even detached. In the 3.0-cm group, the epithelia had normal appearance, obvious cell polarity and essentially intact cell junction. Immunohistochemistry and Western blotting indicated that the 3.0-cm group had the strongest expression of connexin and par-3, and the expression in the 2.0-cm group and the tumor group was relatively weak. There existed significant difference in the expression of the two proteins among the three groups (P<0.05 for all). It was concluded that the down-regulated connexin and par-3 in the distal margin of rectal cancer tissues may indicate the progression of the disease and high likelihood of recurrence and metastasis. Although no tumor cells were found in the sections of the 2.0-cm group, the decreased expression of connexin and par-3 may suggest the development of anaplasia and the increased odds of tumor relapse. Therefore, we are led to speculate that tumor resection only including 2.0 cm of unaffected rectum could not completely avoid the distant metastasis and local relapse.

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Section: Discussionsupporting

confidence: 76%

Expressions of connexin and par-3 in the distal margin of rectal cancer after ultra-low anterior resection

Zhang

Liu

et al. 2009

J. Huazhong Univ. Sci. Technol. [Med. Sci.]

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“…31 In nonproliferative DR, cadherin-5 expression in the retina is reduced, 32 which may compromise interactions between cadherin and the cytoplasmic loop domain of Cx43. 33 Such altered interactions could compromise barrier characteristics in the retinal vessels. Additionally, because blood-retinal barrier (BRB) breakdown in diabetes involves the decreased expression of tight junction protein ZO-1, 34 which can alter Cx43 function 35 through interaction with the COOH-terminal of Cx43, 36 it is possible that in diabetes, BRB breakdown involves both tight junctions and gap junctions.…”

Section: Discussionmentioning

confidence: 99%

Reduced Connexin 43 Expression and Its Effect on the Development of Vascular Lesions in Retinas of Diabetic Mice

Bobbie

Roy

Trudeau

et al. 2010

Invest. Ophthalmol. Vis. Sci.

100

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PURPOSE. To examine whether diabetes-induced connexin 43 downregulation promotes retinal vascular lesions characteristic of diabetic retinopathy (DR). METHODS. Two animal models, streptozotocin-induced diabetic mice and Cx43 heterozygous knockout (Cx43(+/-)) mice, were studied to directly assess whether diabetes reduces the expression of retinal Cx43, which, in turn, contributes to retinal vascular cell loss by apoptosis. Retinal Cx43 protein levels were assessed in nondiabetic control mice, diabetic mice, and Cx43(+/-) mice by Western blot analysis, and Cx43 localization and distribution in the retinal vascular cells were studied by immunostaining of retinal trypsin digests (RTDs). In parallel, RTDs were stained with hematoxylin and periodic acid Schiff to determine pericyte loss (PL) and acellular capillaries (AC), and TUNEL assays were performed to determine retinal vascular cell apoptosis. RESULTS. Western blot analysis indicated significant reductions in retinal Cx43 protein levels in diabetic mice and Cx43(+/-) mice compared with those of nondiabetic mice. Similarly, a significant reduction in Cx43 immunostaining was observed in the retinal capillaries of diabetic mice and Cx43(+/-) mice compared with those of control mice. Both diabetic and age-matched Cx43(+/-) mice exhibited increased amount of PL, AC, and TUNEL-positive cells compared with control mice. CONCLUSIONS. Diabetes-induced inhibition of Cx43 expression contributes to vascular cell apoptosis in retinas of diabetic mice. This suggests that reduced Cx43 expression plays a critical role in the development of AC and PL associated with DR.

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“…In addition to tubulin binding (Dai et al, 2007;Giepmans et al, 2001a;Giepmans et al, 2001b;Guo et al, 2003;Johnson et al, 2002;Shaw et al, 2007;Thomas et al, 2001), Cx43 has also been shown to bind ZO-1 (Barker et al, 2002;Giepmans and Moolenaar, 1998), which might explain the redistribution of ZO-1 to the cytoplasm in Cx43 KO epicardial cells. In some cell types, Cx43 is observed to traffic and colocalize with cadherins (Li et al, 2008;Nambara et al, 2007;Wei et al, 2005;Xu et al, 2001).…”

Section: Research Articlementioning

confidence: 99%

Connexin 43 regulates epicardial cell polarity and migration in coronary vascular development

et al. 2009

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Connexin 43 knockout (Cx43 KO) mice exhibit conotruncal malformations and coronary artery defects. We observed epicardial blisters in the Cx43 KO hearts that suggest defects in epicardial epithelial-mesenchymal transformation (EMT), a process that generates coronary vascular progenitors. Analysis using a three-dimensional collagen gel invasion assay showed that Cx43 KO epicardial cells are less invasive and that, unlike wild-type epicardial cells, they fail to organize into thin vessel-like projections. Examination of Cx43 KO hearts using Wt1 as an epicardial marker revealed a disorganized pattern of epicardial cell infiltration. Time-lapse imaging and motion analysis using epicardial explants showed a defect in directional cell migration. This was associated with changes in the actin/tubulin cytoskeleton. A defect in cell polarity was indicated by a failure of the microtubule-organizing center to align with the direction of cell migration. Forced expression of Cx43 constructs in epicardial explants showed the Cx43 tubulin-binding domain is required for Cx43 modulation of cell polarity and cell motility. Pecam staining revealed early defects in remodeling of the primitive coronary vascular plexuses in the Cx43 KO heart. Together, these findings suggest an early defect in coronary vascular development arising from a global perturbation of the cytoarchitecture of the cell. Consistent with this, we found aberrant myocardialization of the outflow tract, a process also known to be EMT dependent. Together, these findings suggest cardiac defects in the Cx43 KO mice arise from the disruption of cell polarity, a process that may be dependent on Cx43-tubulin interactions.

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Role of the Cytoplasmic Loop Domain of Cx43 in Its Intracellular Localization and Function: Possible Interaction with Cadherin

Cited by 20 publications

References 30 publications

Expressions of connexin and par-3 in the distal margin of rectal cancer after ultra-low anterior resection

Expressions of connexin and par-3 in the distal margin of rectal cancer after ultra-low anterior resection

Reduced Connexin 43 Expression and Its Effect on the Development of Vascular Lesions in Retinas of Diabetic Mice

Connexin 43 regulates epicardial cell polarity and migration in coronary vascular development

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