Ablation of gap junctional communication in hepatocytes of transgenic mice does not lead to disrupted cellular homeostasis or increased spontaneous tumourigenesis

Ott, Thomas; Jokwitz, Melanie; Lenhard, Diana C.; Romualdi, Alessandro; Dombrowski, Frank; Ittrich, Carina; Schwarz, Michael; Willecke, Klaus

doi:10.1016/j.ejcb.2006.03.004

Cited by 17 publications

(10 citation statements)

References 34 publications

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“…22 Contradictory to the paradigm that GJIC facilitates apoptosis are a number of investigations showing that GJs may impede the occurrence of cell death (Figure 2). [103][104][105][106][107][108][109][110][111][112][113][114][115][116] In line with this notion are a number of reports describing induction of apoptosis by chemical GJIC inhibitors 107,108,[117][118][119] as well as by Cx mimetic peptides, 120 which are peptides identical to a short Cx sequence that act as GJ blockers. 121 Healthy cells may indeed provide their dying neighbors with rescue signals 3 or cells in danger may dilute toxic substances toward healthy neighbors through GJs.…”

Section: Connexin-based Gap Junction Channels and Cell Deathmentioning

confidence: 63%

Connexin-related signaling in cell death: to live or let die?

et al. 2009

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Section: Connexin-based Gap Junction Channels and Cell Deathmentioning

confidence: 63%

Connexin-related signaling in cell death: to live or let die?

et al. 2009

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“…Also, previous studies showed that developing bile ducts expressed Cx43 and nascent hepatocytes expressed Cx32 (Zhang and Thorgeirsson 1994;Bode et al 2002). Dexamethasone/DMSO treatment has been shown to modulate the expression of connexin family members in the GAP junctions of hepatocytes and bile duct cells (Kojima et al 1995(Kojima et al , 1997Yoshizawa et al 1997), presumably affecting liver differentiation by controlling the exchange of small molecules, although Cx knockout studies did not show any acute effect on the maintenance or function of adult liver parenchymal cells (Ott et al 2006;Teixeira et al 2007). A fuller understanding of the regulators of hepatocyte/cholangiocyte differentiation, and, in particular, the mechanisms guiding the self-assembly of cholangiocytes into defined ducts, may come from the ongoing proteomic and genomic studies of our pig liver cell culture system.…”

Section: Discussionmentioning

confidence: 94%

Culture of porcine hepatocytes or bile duct epithelial cells by inductive serum-free media

Caperna

Blomberg

Garrett

et al. 2011

In Vitro Cell.Dev.Biol.-Animal

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A serum-free, feeder cell-dependent, selective culture system for the long-term culture of porcine hepatocytes or cholangiocytes was developed. Liver cells were isolated from 1-wk-old pigs or young adult pigs (25 and 63 kg live weight) and were placed in primary culture on feeder cell layers of mitotically blocked mouse fibroblasts. In serum-free medium containing 1% DMSO and 1 μM dexamethasone, confluent monolayers of hepatocytes formed and could be maintained for several wk. Light and electron microscopic analysis showed hepatocytes with in vivo-like morphology, and many hepatocytes were sandwiched between the feeder cells. When isolated liver cells were cultured in medium without dexamethasone but with 0.5% DMSO, monolayers of cholangioctyes formed that subsequently self-organized into networks of multicellular ductal structures, and whose cells had monocilia projecting into the lumen of the duct. Gamma-glutamyl transpeptidase (GGT) was expressed by the cholangiocytes at their apical membranes, i.e., at the inner surface of the ducts. Cellular GGT activity increased concomitantly with the development of ductal structures. Cytochrome P-450 was determined in microsomes following addition of metyrapone to the cultures. In vivo-like levels of P-450s were found in hepatocyte monolayers while levels of P-450 were markedly reduced in cholangiocyte monolayers. Serum protein secretion in conditioned media was analyzed by Western blot and indicated that albumin, transferrin, and haptoglobin levels were maintained in hepatocytes while albumin and haptoglobin declined over time in cholangiocytes. Quantitative RT-PCR analysis showed that serum protein mRNA levels were significantly elevated in the hepatocytes monolayers in comparison to the bile ductule-containing monolayers. Further, mRNAs specific to cholangiocyte differentiation and function were significantly elevated in bile ductule monolayers in comparison to hepatocyte monolayers. The results demonstrate an in vitro model for the study of either porcine hepatocytes or cholangiocytes with in vivo-like morphology and function.

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“…Although it is generally accepted that Cx proteins are involved in carcinogenesis, it remains controversial as to exactly how they relate to cancer development and even whether they inhibit or promote cancer development (Moennikes et al 2000(Moennikes et al , 2003Hokaiwado et al 2005;Ott et al 2006;Conklin et al 2007;Li et al 2007). These apparently conXicting hypotheses may be attributed to the fact that the function of Cx proteins during carcinogenesis depend on the activity of functional gap junctions or on the localization of Cxs relative to the membrane or cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

“…However, ablation of the Cx32 gene in mice inhibits phenobarbital-mediated promotion of hepatocarcinoma (Moennikes et al 2000), and hepatocyte-speciWc targeting of Cx26 gene shows no increase in the incidence of spontaneous hepatic cancer in Cx26-and even in double Cx26/ Cx32-deWcient mice (Ott et al 2006). Hepatocellular damage by liver-toxic substances is also suppressed by ablation of the Cx32 gene (Asamoto et al 2004).…”

Section: Introductionmentioning

confidence: 96%

Hepatic gap junctions in the hepatocarcinogen-resistant DRH rat

Gotow

Shiozaki

Higashi

et al. 2008

Histochem Cell Biol

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Although the gap junction or connexin (Cx) is considered to be a tumor-suppressor, it is also required for tumor promotion. Therefore, we examined hepatic gap junctions in hepatocarcinogen-resistant (DRH) rats. Specifically, we investigated gap junction structure and Cx32 expression during normal conditions and in response to a hepatocarcinogen, 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB). On a basal diet without 3'-MeDAB, hepatic gap junctions and Cx32 protein expression were greater in DRH rats than in control Donryu rats, as evidenced by morphometry, immunohistochemistry and immunoblotting. On a diet containing 3'-MeDAB, gap junctions and expressed Cx32 were increased significantly in Donryu rats, but not in DRH rats. In this condition, Donryu rats lost weight but DRH rats increased relative liver weight. After 3'-MeDAB treatment, cathepsin D expression in hepatocytes was significantly increased only in Donryu rats, indicating that DRH rats were less susceptible to 3'-MeDAB. The abundance of mitogen-activated protein kinase, some constituent of which might be associated with the degree of Cx protein phosphorylation, was reduced to a greater extent in Donryu than in DRH rats after 3'-MeDAB treatment. The resistance of DRH rats to carcinogenesis may be due partially to their stabilized gap junctions, which could coordinate metabolic coupling to evade 3'-MeDAB toxicity.

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Ablation of gap junctional communication in hepatocytes of transgenic mice does not lead to disrupted cellular homeostasis or increased spontaneous tumourigenesis

Cited by 17 publications

References 34 publications

Connexin-related signaling in cell death: to live or let die?

Connexin-related signaling in cell death: to live or let die?

Culture of porcine hepatocytes or bile duct epithelial cells by inductive serum-free media

Hepatic gap junctions in the hepatocarcinogen-resistant DRH rat

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