Dominant-negative abrogation of connexin-mediated cell growth control by mutant connexin genes

Duflot-Dancer, Agnès; Mesnil, Marc; Yamasaki, Hiroshi

doi:10.1038/sj.onc.1201393

Cited by 74 publications

(43 citation statements)

References 17 publications

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“…However, in this study we did not find that inhibition of GJIC by the inhibitor negates the enhanced effect of BBI on cisplatin-induced cytotoxicity in H28 cells (data not shown), indicating that BBI-mediated restoration of GJIC does not affect cisiplatin-induced cytotoxicity. Apart from the GJIC-dependent effect of Cx, other data showed that Cx affects cellular homeostatic balance independently of GJIC, and that this GJ-independent effect plays an important role in regulating abnormal growth of cancer cells (5,20). Moreover, we demonstrated that the Cx32 gene acts as a tumor suppressor gene against renal cancer cells in a GJIC-independent mechanism (21).…”

Section: Discussionmentioning

confidence: 78%

Bowman-Birk protease inhibitor from soybeans enhances cisplatin-induced cytotoxicity in human mesothelioma cells

Kashiwagi

Virgona

Yamada

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Malignant mesothelioma (MM) is an aggressive cancer with no effective treatment options. Enforced expression of the gap junction (GJ) component connexin 43 (Cx43) increases the sensitivity of MM cells to cisplatin. BowmanBirk protease inhibitor (BBI) induces the restoration of Cx43 in several types of tumor cells. In this study, we examined the capability of BBI to enhance the cytotoxic effect of cisplatin in MM cells via the induction of Cx43. Human MM H28 cells were used. Cell viability was evaluated by a WST-1 assay and proteasomal activity was determined by fluorometric analysis. Protein and mRNA levels were determined by immunoblot analysis and real-time RT-PCR, respectively. GJ function mediated by Cx43 was evaluated using the scrapeloading method. BBI effectively inhibited H28 cell growth in a dose-dependent manner (200-400 µg/ml). In parallel with the growth inhibition, Cx43 levels (mRNA and protein) and GJ function were elevated by BBI treatment. Knockdown of BBI-induced Cx43 by an antisense nucleotide treatment almost cancelled the growth inhibition. BBI enhanced cisplatin-induced cytotoxicity in H28 cells, and down-regulation of Cx43 by the antisense nucleotide treatment abrogated the enhancing effect of BBI. The induction of Cx43 by BBI contributed to Src inactivation and subsequent induction of Bax. Furthermore, an Src inhibitor (SU6656) also enhanced cisplatin-induced cytotoxicity in H28 cells. These results suggest that BBI improves the cytotoxic efficacy of cisplatin in H28 cells via the inhibition of Src signaling.

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Section: Discussionmentioning

confidence: 78%

Bowman-Birk protease inhibitor from soybeans enhances cisplatin-induced cytotoxicity in human mesothelioma cells

Kashiwagi

Virgona

Yamada

et al. 2011

Experimental and Therapeutic Medicine

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“…Previously we demonstrated that several Cx mutants are strong dominant negative inhibitors of GJIC in dierent cell lines (Du¯ot-Dancer et al, 1997;Krutovskikh et al, 1998Krutovskikh et al, , 2000. Speci®cally, we found that Cx43 lacking seven residues from the internal loop at positions 130 ± 136, eectively abrogated GJIC in BC31 cells (Krutovskikh et al, 1998) by occluding the channels of established gap junctions in the lateral plasma membrane of cells.…”

Section: Inhibition Of Intrinsic Gjic In Bc31 Cells By Dominant-negatmentioning

confidence: 99%

“…± by dominant negative mutant of Cx43 As we described previously (Du¯ot-Dancer et al, 1997, Krutovskikh et al, 1998, several mutations of Cx proteins have been characterized as dominant negative because on being coexpressed with wild type Cx these communication-defective Cx mutants are able to interfere with the functional normal Cx protein and deactivate its function. One such Cx43 mutant with a strong dominant negative property has seven residues deleted from its cytoplasmic loop at positions 130 ± 136 (Krutovskikh et al, 1998).…”

Section: Inhibition Of Gjicmentioning

confidence: 99%

Gap junction intercellular communication propagates cell death in cancerous cells

2002

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“…One is linked to the Cx-mediated GJIC function, in which putative growth inhibitory factors are assumed to di use through the GJ channels and then induce the growth inhibition (Loewenstein, 1979;Mehta et al, 1986;Cornil et al, 1991;Martin et al, 1991;Zhu et al, 1992). The other suggests that the Cx proteins themselves may show some GJIC-independent biological roles in inhibiting the tumor cell growth (Bradshaw et al, 1993;Chen et al, 1995;Du¯ot-Dancer et al, 1997;Statuto et al, 1997;Omori and Yamasaki, 1998;Krutovskikh et al, 2000). However, the precise mechanisms remain unclear.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2001

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Many lines of evidence indicate that connexin genes expressing gap junction (GJ) proteins inhibit tumor cell proliferation. However, the precise molecular mechanisms remain unclear. In this study, we show that overexpression of connexin43 (Cx43) suppressed proliferation of human osteosarcoma U2OS cells through inhibition of the cell cycle transition from G1 to S phase. This inhibition was attributed to a signi®cant accumulation of the hypophosphorylated retinoblastoma (Rb) protein, which was causally related to decreases in the kinase activities of cyclin-dependent kinases (CDKs) 2 and 4. Enforced Cx43 expression markedly increased the level of the CDK inhibitor p27. This increase resulted from an increased synthesis and a reduced degradation of the p27 proteins, but not in¯uence of the p27 mRNA. Moreover, we show that the Cx43-modulated GJ function was the main contributor to the elevation in p27 levels, in which cAMP was involved. These data suggest that Cx43 appears to inhibit proliferation of U2OS cells by increasing the levels of p27 proteins via post-transcriptional regulatory mechanisms. Oncogene (2001) 20, 4138 ± 4149.

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Dominant-negative abrogation of connexin-mediated cell growth control by mutant connexin genes

Cited by 74 publications

References 17 publications

Bowman-Birk protease inhibitor from soybeans enhances cisplatin-induced cytotoxicity in human mesothelioma cells

Bowman-Birk protease inhibitor from soybeans enhances cisplatin-induced cytotoxicity in human mesothelioma cells

Gap junction intercellular communication propagates cell death in cancerous cells

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

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