Connexin43 suppresses proliferation of osteosarcoma U2OS cells through post-transcriptional regulation of p27

Zhang, You Wei; Morita, Ikuo; Ikeda, Masa‐Aki; Wen, Ke; Murota, Sei‐itsu

doi:10.1038/sj.onc.1204563

Cited by 124 publications

(111 citation statements)

References 40 publications

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“…In agreement with this, Shao et al (2005) have shown that the downregulation of Cx43 in breast cancer cell lines increases the rate of cell proliferation. In addition, the role of Cx43 in the expression of some genes linked to growth regulation is well documented (for review, see Kardami et al, 2007), and the association between Cx43 and several proteins responsible for regulating the cell cycle is also well known (Koffler et al, 2000;Sin et al, 2007;Zhang et al, 2001Zhang et al, , 2003. Although most studies indicate that Cx43 behaves as a tumor suppressor protein (Huang et al, 1998;Metha et al, 1991;Naus, 2002;Su et al, 2000;Yamasaki et al, 1999;Zhu et al, 1991), there is also an important body of evidence suggesting that Cx43 would be required for cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Connexin43 is involved in the effect of endothelin‐1 on astrocyte proliferation and glucose uptake

Herrero-González

Valle-Casuso

Sánchez‐Alvarez

et al. 2008

Glia

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In previous studies, we showed that endothelin-1 increased astrocyte proliferation and glucose uptake. These effects were similar to those observed with other gap junction inhibitors, such as carbenoxolone (CBX). Because 24-h treatment with endothelin-1 or CBX downregulates the expression of connexin43, the main protein forming astrocytic gap junctions, which can also be involved in proliferation, in this study, we addressed the possible role of connexin43 in the effects of endothelin-1. To do so, connexin43 was silenced in astrocytes by siRNA. The knock down of connexin43 increased the rate of glucose uptake, characterized by the upregulation of GLUT-1 and type I hexokinase. Neither endothelin-1 nor CBX were able to further increase the rate of glucose uptake in connexin43-silenced astrocytes. In agreement, no effects of endothelin-1 and CBX on GLUT-1 and type I hexokinase were observed in connexin-43 silenced astrocytes or in astrocytes from connexin43 knock-out (KO) mice. Our previous studies suggested a close relationship between glucose uptake and astrocyte proliferation. Consistent with this, connexin43-silenced astrocytes exhibited an increase in Ki-67, a marker of proliferation. The effects of ET-1 on retinoblastoma phosphorylation on Ser780 and on the upregulation of cyclins D1 and D3 were affected by the levels of connexin43. In conclusion, our results indicate that connexin43 participates in the effects of endothelin-1 on glucose uptake and proliferation in astrocytes. Interestingly, although the rate of growth in connexin43 KO astrocytes has been reported to be reduced, we observed that an acute reduction in connexin43 by siRNA increased proliferation and glucose uptake. V V C

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Section: Discussionmentioning

confidence: 99%

Connexin43 is involved in the effect of endothelin‐1 on astrocyte proliferation and glucose uptake

Herrero-González

Valle-Casuso

Sánchez‐Alvarez

et al. 2008

Glia

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“…Recently, several papers have been published that lend evidence to a connexin function in cell cycle control through regulation of SKP2 ubiquitination processes that ultimately control p27 protein levels (Zhang et al, 2001(Zhang et al, , 2003. These studies implicate p27 as a mediator of GJICassociated tumor suppressor activity and suggest that GJIC may directly regulate cell cycle progression.…”

Section: Introductionmentioning

confidence: 99%

Deficiency in the gap junction protein Connexin32 alters p27Kip1 tumor suppression and MAPK activation in a tissue-specific manner

et al. 2005

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Connexin32 knockout mice (Cx32-KO) exhibit increased chemical-and radiation-induced liver and lung tumor formation with many lung tumors demonstrating decreased levels of the tumor suppressor p27 KIP1 . To determine if p27 deficiency alters Cx32-influenced tumorigenesis, we have generated a Cx32/p27 double-deficient mouse strain (DKO) and show here that exposure of these mice to X-ray radiation resulted in an increase or decrease in tumorigenesis depending on the tissue. Several tissues were highly sensitive to loss of p27 tumor suppressor function (intestine, adrenal, pituitary) resulting in an increased overall tumor burden in DKO mice compared to both wild-type (Po0.005) and Cx32-KO mice (P ¼ 0.066). However, additional deletion of p27 in a Cx32-KO background resulted in a statistically significant decrease in the liver tumor incidence suggesting that Cx32 and p27 pathways mechanistically interact. Immunohistochemical analysis revealed an increased percentage of Cx32-KO liver and lung tumors harboring active mitogen-activated protein kinase (Erk1, Erk2) pathways in contrast to lower percentages of activated wild-type (Po0.005) and DKO tumors (P ¼ 0.027). Increased MAPK activation in liver tumors did not correlate with Ha-ras codon-61 mutation status. This study demonstrates that tissues dependent on Cx32 tumor suppression, such as the liver and lung, exhibit altered tumorigenesis and tumor biology (MAPK pathway activation) related to p27 status.

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“…Cell Proliferation-Cell proliferation was estimated by counting the cell number as previously described (5).…”

Section: Construction Of the Cx43 Mutants-mentioning

confidence: 99%

“…Cx26, Cx32, and Cx43) have tumor-suppressing effects (3)(4)(5). Either the Cx-modulated GJs or the Cx protein itself contributed to the effects of tumor growth inhibition (4).…”

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confidence: 99%

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

Zhang

Kaneda

Morita

2003

Journal of Biological Chemistry

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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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Connexin43 suppresses proliferation of osteosarcoma U2OS cells through post-transcriptional regulation of p27

Cited by 124 publications

References 40 publications

Connexin43 is involved in the effect of endothelin‐1 on astrocyte proliferation and glucose uptake

Connexin43 is involved in the effect of endothelin‐1 on astrocyte proliferation and glucose uptake

Deficiency in the gap junction protein Connexin32 alters p27Kip1 tumor suppression and MAPK activation in a tissue-specific manner

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

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