The cell-cell channel in the control of growth

Loewenstein, Werner R.; Rose, Birgit

doi:10.1016/s1043-4682(10)80008-x

Cited by 243 publications

(131 citation statements)

References 115 publications

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“…Therefore, the mechanisms by which Cxs inhibit tumor growth were originally proposed to be through the diffusion of putative growth inhibitory factors via the Cx-modulated GJs (10). However, increasing evidence suggests that the GJ-independent roles are also involved in the Cx-induced growth inhibition (5,6,(11)(12)(13)(14).…”

Section: Discussionmentioning

confidence: 99%

The Gap Junction-independent Tumor-suppressing Effect of Connexin 43

Zhang

Kaneda

Morita

2003

Journal of Biological Chemistry

168

128

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The gap junction gene connexin 43 (Cx43) showed tumor-suppressing effects on various tumor cell lines. We have previously demonstrated that Cx43 inhibited expression of S phase kinase-associated protein 2 (Skp2), the human F-box protein that regulates the ubiquitination of p27. Cx43 did not alter the mRNA level of SKP2, but it promoted the degradation of the Skp2 proteins (Zhang, Y. W., Nakayama, K., Nakayama K. I., and Morita, I. (2003) Cancer Res. 63, 1623-1630). In this study, we showed that the specific gap junction inhibitor 18 ␤-glycyrrhetinic acid did not influence the inhibitory effect of Cx43 on Skp2 expression. Further, the deletion mutation analyses demonstrated that the C-terminal domain of Cx43 that did not form gap junctions was sufficient to inhibit expression of Skp2, whereas the N-terminal domain that formed the gap junctions did not show such an effect. Like the full-length Cx43, the Cterminal domain also increased the protein instability of Skp2, whereas the N terminus did not. Moreover, the C-terminal domain was as effective as the full-length Cx43 in inhibiting cell proliferation; however, the Nterminal domain did not show any inhibitory effect on cell proliferation. Therefore, these data revealed a gap junction-independent pathway for Cx43 to inhibit tumor growth by suppressing the Skp2 expression.

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Section: Discussionmentioning

confidence: 99%

The Gap Junction-independent Tumor-suppressing Effect of Connexin 43

Zhang

Kaneda

Morita

2003

Journal of Biological Chemistry

168

128

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“…Regulation of tumor (Loewenstein and Rose, 1992;Yamasaki et al, 1995;Krutovskikh and Yamasaki, 1997;Li and Herlyn, 2000;Omori et al, 2001) and stem cell (Trosko et al, 2000;Burnside and Collas, 2002;Tazuke et al, 2002;Gilboa et al, 2003;Cai et al, 2004;Wong et al, 2004) …”

Section: Gap Junctional Signalingmentioning

confidence: 99%

Mathematical model of morphogen electrophoresis through gap junctions

Esser

Smith

Weaver

et al. 2006

Developmental Dynamics

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Gap junctional communication is important for embryonic morphogenesis. However, the factors regulating the spatial properties of small molecule signal flows through gap junctions remain poorly understood. Recent data on gap junctions, ion transporters, and serotonin during left-right patterning suggest a specific model: the net unidirectional transfer of small molecules through long-range gap junctional paths driven by an electrophoretic mechanism. However, this concept has only been discussed qualitatively, and it is not known whether such a mechanism can actually establish a gradient within physiological constraints. We review the existing functional data and develop a mathematical model of the flow of serotonin through the early Xenopus embryo under an electrophoretic force generated by ion pumps. Through computer simulation of this process using realistic parameters, we explored quantitatively the dynamics of morphogen movement through gap junctions, confirming the plausibility of the proposed electrophoretic mechanism, which generates a considerable gradient in the available time frame. The model made several testable predictions and revealed properties of robustness, cellular gradients of serotonin, and the dependence of the gradient on several developmental constants. This work quantitatively supports the plausibility of electrophoretic control of morphogen movement through gap junctions during early left-right patterning. This conceptual framework for modeling gap junctional signaling-an epigenetic patterning mechanism of wide relevance in biological regulation-suggests numerous experimental approaches in other patterning systems.

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“…Furthermore, cell-cell communication via gap junctions is hypothesized to have a significant role in endocrine cell growth, differentiation and hormone response (Murray & Fletcher 1984, Loewenstein & Rose 1992, Meda 1996, Munari-Silem 1996, Oyoyo et al 1997, Yamasaki et al 1999. Gap junctions have been shown to provide channels between adjoining cells (Loewenstein 1981).…”

Section: Introductionmentioning

confidence: 99%

Bimodal inhibition of connexin 43 gap junctions decreases ACTH-induced steroidogenesis and increases bovine adrenal cell population growth

Shah

Murray

2001

Journal of Endocrinology

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In order to elucidate the role of gap junctions in adrenal cell responses, we measured the effect of inhibiting gap junctions with 18-glycerrhetinic acid (GA; a potent inhibitor of cell-cell communication) and connexin antisense transfection on cell proliferation and adrenocorticotropin (ACTH)-stimulated steroidogenesis. In these experiments we utilized a bovine adrenocortical cell (SBAC) population, which responds to ACTH treatment with a dose-dependent increase in steroid production, an increase in connexin 43 ( 1 -Cx43) gap junction protein concentrations, and a decrease in cell population growth. SBAC cell populations treated with GA had increased growth rates, decreased ACTH-stimulated steroidogenesis, but no reduction in 1 -Cx43 gap junction protein contents. In contrast, when SBAC cells were transfected with 1 -Cx43 antisense cDNA, gap junction protein concentration was dramatically reduced as expected, unlike the GA-treated cell populations. Cell populations transfected with 1 -Cx43-antisense also exhibited increased growth rates and a decreased steroidogenic response to ACTH treatment as compared with control or vector-only transfected cell populations. The decreased responsiveness and increased number of cells in the population after gap junction function was decreased by either GA treatment or antisense transfection, suggests that gap junctions may be necessary factors in ACTH-stimulated responsiveness and growth control in the adrenal gland.

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The cell-cell channel in the control of growth

Cited by 243 publications

References 115 publications

The Gap Junction-independent Tumor-suppressing Effect of Connexin 43

The Gap Junction-independent Tumor-suppressing Effect of Connexin 43

Mathematical model of morphogen electrophoresis through gap junctions

Bimodal inhibition of connexin 43 gap junctions decreases ACTH-induced steroidogenesis and increases bovine adrenal cell population growth

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