Chemical, Oncogene and Growth Factor Inhibition of Gap Junctional Intercellular Communication: An Integrative Hypothesis of Carcinogenesis

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

doi:10.1159/000163596

Cited by 140 publications

(62 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Since G JI C serves growth-inhibitory functions in many tissues [49], it may logically be expected to diminish during the growth/repair phases of wound healing. Both epidermal growth factor and platelet-derived growth factor, which promote SM C proliferation and migration, inhibit G J function in N R K and Balb/C 3T3 cell lines [50].…”

Section: Cx43 Mrna In Smooth Muscle Cellsmentioning

confidence: 99%

Connexin43 Gene Expression in the Rabbit Arterial Wall: Effects of Hypercholesterolemia, Balloon Injury and Their Combination

Polacek

Bech²,

McKinsey³

et al. 1997

J Vasc Res

View full text Add to dashboard Cite

The specialized functions of endothelium require intercellular communication between endothelial cells within the monolayer, and between endothelium and other cells present in the vessel wall. This is accomplished by a combination of paracrine soluble mediators and direct gap-junctional intercellular communication (GJIC) mediated by a family of connexin proteins. A prominent connexin expressed by vascular cells in vivo and in vitro is connexin 43 (Cx43). We have investigated the in vivo gene regulation of Cx43 in the context of vascular pathology, as a result of mechanical injury, hypercholesterolemia or both. The aortoiliac bifurcation in the rabbit was examined following three types of insult: (1) diet-induced hypercholesterolemia resulting in macrophage-rich fatty streak lesions, (2) mechanical, stretch-denudation injury resulting in intimal smooth muscle cell (SMC) proliferation and (3) mechanical injury superimposed on hypercholesterolemia resulting in a complex vascular lesion having characteristics of both interventions. The normal rabbit iliac artery expressed approximately equal levels of Cx43 mRNA in the medial SMC layers and in the endothelium. In hypercholesterolemia-induced atherosclerosis, Cx43 expression was most prominent in macrophage foam cells even though normocholesterolemic precursor monocytes did not express Cx43 mRNA. Antibodies directed specifically to Cx43 protein confirmed the expression of macrophage gap junction protein in these cells. Medial SMC in hypercholesterolemia exhibited less Cx43 than their normal counterparts in control animals. Mechanical injury in the absence of hypercholesterolemia resulted in intimal thickening in which Cx43 expression in the intimal SMC was equivalent to that in the subjacent medial SMC, both being approximately equivalent to normal uninjured rabbit medial SMC expression. Cell-specific expression of Cx43 in combined mechanical injury/hypercholesterolemia was similar to that observed in hypercholesterolemia alone: Cx43 upregulation in macrophages, while medial SMC were downregulated. Normo- and hypercholesterolemic alveolar macrophages of the lung and Kupffer cells of the liver did not exhibit induction of Cx43 mRNA, nor did macrophages isolated from peritoneal or bronchial lavage fluid of the same animals. This work extends our previous finding of Cx43 upregulation in human atherectomy tissue and demonstrates that atherosclerotic lesions in situ, in a controlled animal model of atherosclerosis, exhibit cell-specific changes in Cx43 gene expression. Changes in medial SMC migration, proliferation and phenotype, as well as enhanced interactions between adherent/infiltrating monocytes and endothelium may be related to modified GJIC pathways in the vessel wall.

show abstract

Section: Cx43 Mrna In Smooth Muscle Cellsmentioning

confidence: 99%

Connexin43 Gene Expression in the Rabbit Arterial Wall: Effects of Hypercholesterolemia, Balloon Injury and Their Combination

Polacek

Bech²,

McKinsey³

et al. 1997

J Vasc Res

View full text Add to dashboard Cite

show abstract

“…Gap junctional intercellular communication is involved in cell growth, differentiation, and apoptosis; aberrant control of gap junctional intercellular communication might also play an important role in cancer development (18)(19)(20)(21). Several oncogene products have been shown to reduce gap junction channel permeability and connexin expression in vitro and in vivo (22,23). It is anticipated that SAHA will work as an enhancer of gap junctional intercellular communication in both normal and cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Suberoylanilide Hydroxamic Acid Enhances Gap Junctional Intercellular Communication via Acetylation of Histone Containing Connexin 43 Gene Locus

et al. 2005

View full text Add to dashboard Cite

A histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), induces apoptosis in neoplastic cells, but its effect on gap junctional intercellular communication in relation to apoptosis was unclear. Therefore, we carried out a comparative study of the effects of two HDAC inhibitors, SAHA and trichostatin-A, on gap junctional intercellular communication in nonmalignant human peritoneal mesothelial cells (HPMC) and tumorigenic ras oncogenetransformed rat liver epithelial cells (WB-ras) that showed a significantly lower level of gap junctional intercellular communication than did HPMC. Gap junctional intercellular communication was assessed by recovery rate of fluorescence recovery after photobleaching. Treatment of HPMC with SAHA at nanomolar concentrations caused a dose-dependent increase of recovery rate without inducing apoptosis. This effect was accompanied by enhanced connexin 43 (Cx43) mRNA and protein expression and increased presence of Cx43 protein on cell membrane. Trichostatin-A induced apoptosis in HPMC but was less potent than SAHA in enhancing the recovery rate. In contrast, treatment of WB-ras cells with SAHA or trichostatin-A induced apoptosis at low concentrations, in spite of smaller increases in recovery rate, Cx43 mRNA, and protein than in HPMC. Chromatin immunoprecipitation analysis revealed that SAHA enhanced acetylated histones H3 and H4 in the chromatin fragments associated with Cx43 gene in HPMC. These results indicate that SAHA at low concentrations selectively up-regulates Cx43 expression in normal human cells without induction of apoptosis, as a result of histone acetylation in selective chromatin fragments, in contrast to the apoptotic effect observed in tumorigenic WB-ras cells. These results support a cancer therapeutic and preventive role for specific HDAC inhibitors. (Cancer Res 2005; 65(21): 9771-8)

show abstract

“…The correlation between neoplastic transformation and reduced gap junctional communication (Atkinson et al, 1981;Azarnia and Loewenstein, 1984;de Feijter et al, 1990) has led to the hypothesis that reduced cell-cell communication is a critical step in multistage carcinogenesis (Fitzgerald and Yamasaki, 1990;Trosko et al, 1990). PKC has received considerable attention because PKC activators (e.g.…”

mentioning

confidence: 99%

Connexin43 phosphorylation at S368 is acute during S and G2/M and in response to protein kinase C activation

Solan

Fry

TenBroek

et al. 2003

Journal of Cell Science

125

View full text Add to dashboard Cite

Phorbol esters such as 12-O-tetradeconylphorbol-13-acetate (TPA)activate protein kinase C, increase Connexin43 (Cx43) phosphorylation, and decrease cell-cell communication via gap junctions in many cell types. Previous work has implicated protein kinase C (PKC) in the direct phosphorylation of Cx43 at S368, which results in a change in single channel behavior that contributes to a decrease in intercellular communication. We have examined Cx43 phosphorylation in several cell lines with an antibody specific for phosphorylated S368. We show that this antibody detects Cx43 only when it is phosphorylated at S368 and, consistent with previous results, TPA treatment causes a dramatic increase in phosphorylation at S368. However, in some cell types, the increased phosphorylation at S368 did not cause a detectable shift in migration as compared with the nonphosphorylated Cx43. Immunofluorescence showed increased S368 immunolabeling in cytoplasmic and plasma membrane structures in response to TPA. Immunoblot analysis of synchronized cells showed increased phosphorylation at S368 during S and G2/M phases of the cell cycle. S-phase cells contained more total Cx43 but assembled fewer functional gap junctional channels than G0-phase cells. Since M-phase cells also communicate poorly and contain few assembled gap junctions, phosphorylation at S368 appears to be negatively correlated with gap junction assembly. Thus, both gap junctional communication and S368 phosphorylation change during S phase and G2/M, implying that phosphorylation at S368 might play a role in key cell-cycle events.

show abstract

Chemical, Oncogene and Growth Factor Inhibition of Gap Junctional Intercellular Communication: An Integrative Hypothesis of Carcinogenesis

Cited by 140 publications

References 65 publications

Connexin43 Gene Expression in the Rabbit Arterial Wall: Effects of Hypercholesterolemia, Balloon Injury and Their Combination

Connexin43 Gene Expression in the Rabbit Arterial Wall: Effects of Hypercholesterolemia, Balloon Injury and Their Combination

Suberoylanilide Hydroxamic Acid Enhances Gap Junctional Intercellular Communication via Acetylation of Histone Containing Connexin 43 Gene Locus

Connexin43 phosphorylation at S368 is acute during S and G2/M and in response to protein kinase C activation

Contact Info

Product

Resources

About