Cooperation of bcl -2 and myc in the neoplastic transformation of normal rat liver epithelial cells is related to the down-regulation of gap junction-mediated intercellular communication

Deocampo, Nestor D.; Wilson, Melinda R.; Trosko, James E.

doi:10.1093/carcin/21.8.1501

Cited by 12 publications

(6 citation statements)

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“…Cell-cell communication assay. We used the scrape-loading dye transfer (SLDT) technique (23,24) to assess GJIC activity. Briefly, cells were grown in normal or high-glucose medium to confluency and rinsed three times with PBS containing 0.01% Ca 2ϩ and 0.01% Mg 2ϩ (Ca 2ϩ ,Mg 2ϩ -PBS).…”

Section: Methodsmentioning

confidence: 99%

Downregulation of Connexin 43 Expression by High Glucose Reduces Gap Junction Activity in Microvascular Endothelial Cells

et al. 2002

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Impairment of retinal vascular homeostasis is associated with the development and progression of diabetic retinopathy involving gap junction intercellular communication (GJIC) activity. The principal gap junction protein of intercellular communication, connexin, was investigated to determine the effects of high glucose concentrations on the expression of endothelial-specific connexins (Cx37, Cx40, and Cx43), connexin phosphorylation pattern, and GJIC activity. Rat microvascular endothelial (RME) cells grown in high (30 mmol/l)-glucose medium for 9 days had reduced Cx43 expression: Cx43 mRNA (68 ؎ 13% of control; P ‫؍‬ 0.019, n ‫؍‬ 5) and protein (55.6 ؎ 16% of control; P ‫؍‬ 0.003, n ‫؍‬ 5) levels were reduced; however, Cx37 and Cx40 expression was not affected. Using alkaline phosphatase and Western blot analyses, we identified three forms of Cx43: a nonphosphorylated form (P0) and two phosphorylated forms (P1 and P2). Expression of all three forms was decreased in cells grown in high-glucose medium: PO, 73 ؎ 15% of control (P ‫؍‬ 0.04); P1, 57 ؎ 16% of control (P ‫؍‬ 0.01); and P2, 42 ؎ 22% of control (P ‫؍‬ 0.006). Using immunofluorescence microscopy, we observed Cx43 localization at specific sites of contact (plaques) between adjacent cells. In cells grown in highglucose medium, we observed reduced plaque counts (63 ؎ 6% of control; P ‫؍‬ 0.009) and decreased intensity of Cx43 immunofluorescence compared with cells grown in normal medium. Furthermore, using scrape load dye transfer (SLDT) technique, we found that these cells exhibited reduced GJIC activity (60% of control; P ‫؍‬ 0.01, n ‫؍‬ 5). The reduction in GJIC activity correlated with the decreased Cx43 protein levels (r ‫؍‬ 0.9). These results indicate that high glucose concentrations inhibited GJIC activity by reducing Cx43 synthesis in RME cells. Impaired intercellular communication may contribute to breakdown of homeostatic balance in diabetic microangiopathy. Diabetes 51:1565-1571, 2002

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Section: Methodsmentioning

confidence: 99%

Downregulation of Connexin 43 Expression by High Glucose Reduces Gap Junction Activity in Microvascular Endothelial Cells

et al. 2002

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“…MYC cooperates with many other oncogenic events to initiate tumorigenesis (Murray et al 1983;Compere et al 1989;DeoCampo et al 2000;Welm et al 2005;Clegg et al 2011). Many oncogenes were first discovered as cooperating events in screens of MYC-induced tumor formation (Jonkers and Berns 1996;Mikkers et al 2002;Mikkers and Berns 2003;Kool and Berns 2009;Mendrysa et al 2010).…”

Section: Myc Cooperates To Induce Tumorigenesismentioning

confidence: 99%

MYC Activation Is a Hallmark of Cancer Initiation and Maintenance

Gabay

Felsher

2014

Cold Spring Harbor Perspectives in Medicine

643

572

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The MYC proto-oncogene has been implicated in the pathogenesis of most types of human tumors. MYC activation alone in many normal cells is restrained from causing tumorigenesis through multiple genetic and epigenetically controlled checkpoint mechanisms, including proliferative arrest, apoptosis, and cellular senescence. When pathologically activated in a permissive epigenetic and/or genetic context, MYC bypasses these mechanisms, enforcing many of the "hallmark" features of cancer, including relentless tumor growth associated with DNA replication and transcription, cellular proliferation and growth, protein synthesis, and altered cellular metabolism. MYC mandates tumor cell fate, by inducing stemness and blocking cellular senescence and differentiation. Additionally, MYC orchestrates changes in the tumor microenvironment, including the activation of angiogenesis and suppression of the host immune response. Provocatively, brief or even partial suppression of MYC back to its physiological levels of activation can result in the restoration of intrinsic checkpoint mechanisms, resulting in acute and sustained tumor regression, associated with tumor cells undergoing proliferative arrest, differentiation, senescence, and apoptosis, as well as remodeling of the tumor microenvironment, recruitment of an immune response, and shutdown of angiogenesis. Hence, tumors appear to be "addicted" to MYC because of both tumor cellintrinsic, cell-autonomous and host-dependent, immune cell-dependent mechanisms. Both the trajectory and persistence of many human cancers require sustained MYC activation. Multiscale mathematical modeling may be useful to predict when tumors will be addicted to MYC. MYC is a hallmark molecular feature of both the initiation and maintenance of tumorigenesis.

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“…Several studies have shown that gap junctional communication is decreased in carcinogenesis (14). While the reason for this loss of intercellular communication has not been completely elucidated, it has been suggested that the loss of apoptotic control from adjacent cells may be essential for tumor development (15). Furthermore, the loss of cell-cell interactions between adjacent cells may be necessary for the clonal expansion of tumors.…”

Section: Introductionmentioning

confidence: 99%

Decreased gap junctional intercellular communication in hexachlorobenzene-induced gender-specific hepatic tumor formation in the rat

Plante

Charbonneau²,

Cyr

2002

Carcinogenesis

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Hexachlorobenzene (HCB), an epigenetic carcinogen, HCB induces the formation of liver tumors in female rats, whereas only a small percentage of males are responsive. Intercellular communication via gap junctions is decreased in carcinogenesis. Gap junctions are composed of proteins termed connexins (Cxs). The objectives of this study were (i) to determine if HCB-induced tumor development is associated with a loss of gap junctional communication; (ii) to assess if HCB causes a gender-specific decrease in the expression of Cx32 and Cx26; and (iii) to establish if these effects result from gender differences in the constitutive expression of these Cxs. Rats were given HCB by gavage for five consecutive days. In the first experiment, control and HCB-treated female rats were sampled on day 100. Intercellular communication was significantly decreased in HCB-treated females compared to controls. To investigate if changes in Cx levels occur prior to day 100, experiments done using male and female rats sampled on day 50. Hepatic mRNA levels for Cx26 and Cx32 were significantly lower only in HCB-treated females as compared to controls. Cx26 mRNA levels were 3-fold higher and Cx32 mRNA levels were 8-fold lower in females compared with males. In a third experiment, ovariectomy abolished any differences between male and female controls for both Cxs, while estradiol had a partial role in the regulation of Cx32. This suggests that the sexual dimorphism in hepatic Cx levels is determined by the ovarian hormones. However, the HCB-induced decrease in Cx32 and Cx26 mRNA levels was maintained in ovariectomized rats, suggesting that the HCB effects are not mediated via an ovary-dependent pathway. Overall results show that HCB exposure induces gender-specific long-term alterations in intercellular gap junctional communication in female rat liver. This effect appears to be a critical mechanism of HCB-induced liver carcinogenesis and tumor promotion.

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Cooperation of bcl -2 and myc in the neoplastic transformation of normal rat liver epithelial cells is related to the down-regulation of gap junction-mediated intercellular communication

Cited by 12 publications

References 50 publications

Downregulation of Connexin 43 Expression by High Glucose Reduces Gap Junction Activity in Microvascular Endothelial Cells

Downregulation of Connexin 43 Expression by High Glucose Reduces Gap Junction Activity in Microvascular Endothelial Cells

MYC Activation Is a Hallmark of Cancer Initiation and Maintenance

Decreased gap junctional intercellular communication in hexachlorobenzene-induced gender-specific hepatic tumor formation in the rat

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