Endogenous and exogenous modulation of gap junctional intercellular communication: Toxicological and pharmacological implications

Trosko, James E.; Madhukar, Burra V.; Chang, Chia Cheng

doi:10.1016/0024-3205(93)90606-4

Cited by 115 publications

(76 citation statements)

References 105 publications

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“…Thus it is possible to speculate that Cx43 expression allows GJIC formation, which in turn elevates p27 levels dependent on increased, or extant, cAMP levels. The often-referenced observation that cAMP elevation increased GJIC and Cx expression (Trosko et al, 1993;Mehta et al, 1996) places it upstream of these entities; however, the present study showed that Cx expression might also elevate the cAMP levels through unidenti®ed mechanisms.…”

Section: Discussioncontrasting

confidence: 69%

“…It is able to up-regulate both GJIC and Cx expression (Trosko et al, 1993;Mehta et al, 1996). Furthermore, cAMP can be transmitted between cells through the GJ channels.…”

Section: Camp Was Involved In the Cx43-induced Up-regulation Of P27mentioning

confidence: 99%

“…Tumor promoting chemicals (Fitzgerald and Yamasaki, 1990) and oncogenes (like src, ras, raf, fms) (Martin et al, 1991) inhibit the level of GJIC, whereas anti-tumor agents (such as retinoids, cAMP) up-regulate GJIC (Trosko et al, 1993). Most, if not all, tumor cells are usually associated with decreased or diminished expression and function of Cxs (Yamasaki and Naus, 1996).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussioncontrasting

confidence: 69%

“…It is able to up-regulate both GJIC and Cx expression (Trosko et al, 1993;Mehta et al, 1996). Furthermore, cAMP can be transmitted between cells through the GJ channels.…”

Section: Camp Was Involved In the Cx43-induced Up-regulation Of P27mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2001

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“…2,3) In addition, many cancer cells have a decreased number of gap junctions and loss of GJIC has been correlated with the degree of malignancy of tumors. [4][5][6][7] Recently, at least 12 cDNAs for connexin gap junction proteins in mammals have been cloned. 8) Of these, connexins 26, 32 and 43 are the best characterized, and their transfection into cell lines causes growth retardation or suppression of tumorigenicity.…”

mentioning

confidence: 99%

Enhanced Tumorigenicity of Rat Bladder Squamous Cell Carcinoma Cells after Abrogation of Gap Junctional Intercellular Communication

Asamoto¹,

Toriyama‐Baba²,

Krutovskikh³

et al. 1998

Japanese Journal of Cancer Research

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We previously demonstrated a clear tendency for actively communicating rat bladder carcinoma cell lines with elevated expression of connexin 43 mRNA to possess strong tumorigenicity. In the present study, immunohistochemical analysis established that normal bladder epithelium did not express connexin 43 protein, but bladder carcinomas often expressed the protein, particularly on the membranes of cells within areas of squamous cell differentiation. To investigate the role of connexin 43 overexpression in rat bladder carcinoma cells, an anti-sense connexin 43 expression vector was transfected into BC31 cells having a high communication capacity. In the resultant transfectants, there was little or no communication capacity and connexin 43 expression. The growth rate in vitro was not changed compared to that of cells treated with the vector alone (without the anti-sense sequence), but tumorigenicity in nude mice was dramatically enhanced. The results indicate that connexin 43 overexpression in rat bladder carcinogenesis is related to squamous cell differentiation, and the protein can have tumor suppressor characteristics, as in other organs. Key words: Gap junction -Connexin 43 -Bladder -Tumor -RatDirect transfer of nutrients, ions, nucleotides and other regulatory molecules between adjacent mammalian cells can occur through gap junctions, such gap junctional intercellular communication (GJIC) being important for regulation of cell proliferation, embryogenesis and differentiation.1) Certain nongenotoxic carcinogens inhibit GJIC and this inhibition may be involved in the clonal expansion of initiated cells by releasing them from the suppressive control exerted by surrounding normal cells.2, 3) In addition, many cancer cells have a decreased number of gap junctions and loss of GJIC has been correlated with the degree of malignancy of tumors. 4-7)Recently, at least 12 cDNAs for connexin gap junction proteins in mammals have been cloned. 8) Of these, connexins 26, 32 and 43 are the best characterized, and their transfection into cell lines causes growth retardation or suppression of tumorigenicity. [9][10][11][12] Rat bladder carcinogenesis has been well studied and several rat bladder cell lines are available. We previously showed that there is a tendency for these with greater communication capacity to have greater connexin 43 and connexin 26 mRNA expression and tumorigenicity.13) Furthermore, while connexin 43 mRNA expression was found to be barely detectable in normal bladder tissue, we showed it to be abundant in rat bladder carcinomas. 13)Since these observations for rat bladder carcinomas do not fit with the reported observations for gap junctions and carcinogenesis in other organs, we conducted the following experiments.First, connexin 43 protein localization in normal and cancerous bladder tissue was investigated in order to confirm the results obtained for mRNA levels. In a preliminary study, we found that connexin 26 protein was not expressed in the cell lines despite abundant connexin 26 mRNA expression. We ...

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“…PCBs are embryotoxic in mink, neurotoxic during development in animals, and can alter uterine progesterone and progesten receptors (17,19). Although some bioassay data on rodents suggest that many of these pesticides and chemicals, such as the PCBs and PBBs, are carcinogens, in vitro and in vivo initiation-promotion bioassays suggest that most of these chemicals are acting as tumor promoters via nongenotoxic or epigenetic mechanisms (20 Because carcinogenesis is a multistep, multimechanism process, consisting of the operational steps of initiation, promotion, and progression (35), and because both genotoxic and epigenetic mechanisms play a role in this complex process, it is important to consider these concepts in the design and interpretation of both animal bioassays and epidemiological studies of cancer. One of the facts related to the concern that these chemicals be assessed for their carcinogenic potential on human breast tissue is that data showing that most of these chemicals (DDT, PCB, PBB, dieldrin, etc.)…”

mentioning

confidence: 99%

Inhibition of gap junctional intercellular communication in normal human breast epithelial cells after treatment with pesticides, PCBs, and PBBs, alone or in mixtures.

Kang

Wilson²,

Hayashi³

et al. 1996

Environ Health Perspect

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Chemical pollutants in the Great Lakes have found their way through the food chain into humans because of their environmental persistence and lipophilicity. Some epidemiological studies have claimed an association between metabolites of 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane (DDT), polychlorinated biphenyls (PCBs), and polybrominated biphenyls (PBBs) and breast cancer, but others have reported no such association. We examined various halogenated hydrocarbons for their capacity to inhibit gap junctional intercellular communication (GJIC) in normal human breast epithelial cells (HBEC) when given as single compounds or as mixtures. The scrape-loading/dye transfer and fluorescent redistribution after photobleaching techniques were used to measure GJIC; immunostaining and Western and Northern analyses were performed on connexin 43 (Cx43) gap junction protein and message to determine how halogenated hydrocarbons might affect GJIC. DDT, dieldrin, and toxaphene inhibited GJIC in a dose-responsive manner after 90 min treatments. Dieldrin suppressed GJIC within 30 min with no recovery after 24 hr. Inhibition of GJIC by DDT and toxaphene was partially restored after 12 hr and fully restored after 24 hr. Several PCB and PBB congeners inhibited GJIC in a dose-responsive and time-dependent manner, but GJIC was almost restored to control values 24 hr after exposure. The highest concentrations of the individual chemicals that did not inhibit GJIC was determined, and mixtures containing two of these chemicals were tested for their ability to inhibit GJIC. Significant inhibition of GJIC was observed when cells were treated with a mixture of DDT and 2,4,5-hexachlorobiphenyl (2,4,5-HCB), dieldrin and 2,4,5-HCB, or dieldrin and 2,4,5-hexabromobiphenyl (2,4,5-HBB). These results indicate that halogenated hydrocarbons, alone or in specific combinations, can alter GJIC at the post-translational level. These results are consistent with the hypothesis that DDT, dieldrin, toxaphene, 2,3,4-HCB, 2,4,5-HCB, and 2,4,5-HBB could have tumor-promoting potential in human breast tissue. Images Figure 1. A Figure 1. B Figure 1. C Figure 1. D Figure 1. E Figure 1. F Figure 2. A Figure 2. B Figure 2. C Figure 2. D Figure 2. E Figure 2. F Figure 3. Figure 4. A Figure 4. B Figure 4. C Figure 4. D Figure 4. E Figure 4. F Figure 4. G Figure 4. H Figure 5. A Figure 5. B Figure 5. C Figure 6. Figure 6.

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Endogenous and exogenous modulation of gap junctional intercellular communication: Toxicological and pharmacological implications

Cited by 115 publications

References 105 publications

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

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

Enhanced Tumorigenicity of Rat Bladder Squamous Cell Carcinoma Cells after Abrogation of Gap Junctional Intercellular Communication

Inhibition of gap junctional intercellular communication in normal human breast epithelial cells after treatment with pesticides, PCBs, and PBBs, alone or in mixtures.

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