Down-regulation of survival signaling through MAPK and Akt in occludin-deficient mouse hepatocytes in vitro

Murata, Masaki; Kojima, Takashi; Yamamoto, Takumi; Go, Mitsuru; Takano, Kenichi; Osanai, Makoto; Chiba, Hideki; Sawada, Norimasa

doi:10.1016/j.yexcr.2005.07.017

Cited by 44 publications

(45 citation statements)

References 45 publications

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“…Although another TJ protein, ZO-2, also associates with Fos, Jun, and CCAAT/enhancer binding protein, occludin directly interacts with nonreceptor tyrosine kinase c-Yes (10,11), suggesting that TJs may have a direct functional association with signal transduction pathway(s). Consistent with this, our recent study has revealed that occludin is linked with apoptotic machinery involving mitogenactivated protein kinase (MAPK) and Akt signaling pathways in murine hepatocytes (12).…”

Section: Introductionsupporting

confidence: 69%

Epigenetic Silencing of Occludin Promotes Tumorigenic and Metastatic Properties of Cancer Cells via Modulations of Unique Sets of Apoptosis-Associated Genes

Osanai¹,

Murata²,

et al. 2006

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Occludin is the first identified integral protein for the tight junction (TJ), and its long COOH-terminal domain is considered to have functions in receiving and transmitting cell survival signals. Loss of TJ-associated molecules, such as occludin, has been correlated with tumor progression in carcinogenesis; however, the precise molecular mechanisms explaining its loss of expression and whether occludin expression has any effects on cancer phenotypes remain to be clarified. Here, we show that forced expression of occludin in cancer cells exhibits enhanced sensitivity to differently acting apoptogenic factors, and thus inhibits the tumorigenicity of transformed cells, via modulation of unique sets of apoptosis-associated genes. In addition, studies using deletion mutants of occludin constructs show that 44 amino acids at the COOH-terminal end play a critical role in modifying the cellular phenotypes. Interestingly, occludin decreases cellular invasiveness and motility, thereby abrogating metastatic potencies of cancer cells. We also found that occludin expression is silenced by CpG island hypermethylation on its promoter region. Synergy with a demethylator and histone deacetylase inhibitor or retinoids that stimulate retinoic acid receptor A induces endogenous occludin, which is sufficient for apoptotic sensitization. Our results show the functional diversity of occludin and suggest that methylator phenotype of occludin provides enhanced tumorigenic, invasive, and metastatic properties of cancer cells, identifying occludin as a likely candidate for a tumor-suppressor gene in certain types of cancer. (Cancer Res 2006; 66(18): 9125-33)

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Section: Introductionsupporting

confidence: 69%

Epigenetic Silencing of Occludin Promotes Tumorigenic and Metastatic Properties of Cancer Cells via Modulations of Unique Sets of Apoptosis-Associated Genes

Osanai¹,

Murata²,

et al. 2006

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“…Thus, claudin-2 expression in MDCKII cells is regulated through at least two independent pathways, involving RhoA and JNK, respectively. Previous studies have indicated an involvement of the ERK pathway in the regulation of claudin-2 expression (Kinugasa et al, 2000;Lan et al, 2004;Singh and Harris, 2004;Yamamoto et al, 2004;Murata et al, 2005). However, treatment of only MDCKI, but not MDCKII cells, with the ERK inhibitor U0126 up-regulates claudin-2, suggesting that the ERK pathway is not implicated in the up-regulation of claudin-2 expression in MDCKII cells (Lipschutz et al, 2005).…”

Section: Discussionmentioning

confidence: 94%

“…The MAPK/extracellular signal-regulated kinase (ERK) kinase pathway has been implicated in the control of claudin-2 expression (Kinugasa et al, 2000;Lan et al, 2004;Singh and Harris, 2004;Yamamoto et al, 2004;Lipschutz et al, 2005;Murata et al, 2005). To investigate the role of this and other signaling pathways in the up-regulation of claudin-2 and ZO-3 in cingulin KD clones, cingulin-depleted cells were treated with either the MAPK/ERK inhibitor U0126, the p38 kinase inhibitor SB202190, or the JNK inhibitor SP600125 ( Figure 3A).…”

Section: Jnk Regulate Claudin-2 Expression Independently Of Cingulin mentioning

confidence: 99%

Cingulin Regulates Claudin-2 Expression and Cell Proliferation through the Small GTPase RhoA

Guillemot

Citi

2006

MBoC

100

138

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In mouse embryoid bodies, mutation of the tight junction protein cingulin results in changes in gene expression. Here, we studied the function of cingulin using a gene silencing approach in Madin-Darby canine kidney (MDCK) cells. Cingulin-depleted cells show higher protein and mRNA levels of claudin-2 and ZO-3, increased RhoA activity, activation of G 1 /S phase transition, and increased cell density. The effects of cingulin depletion on claudin-2 expression, cell proliferation, and density are reversed by coexpression of either a dominant-negative form of RhoA (RhoAN19) or the Rho-inhibiting enzyme C3 transferase. However, the increase in ZO-3 protein and mRNA levels is not reversed by inhibition of either RhoA, p38, extracellular signal-regulated kinase (ERK), or c-Jun NH 2 -terminal kinase (JNK), suggesting that cingulin modulates ZO-3 expression by a different mechanism. JNK is implicated in the regulation of claudin-2 levels independently of cingulin depletion and RhoA activity, indicating distinct roles of RhoA-and JNK-dependent pathways in the control of claudin-2 expression. Finally, cingulin depletion does not significantly alter the barrier function of monolayers and the overall molecular organization of tight junctions. These results provide novel insights about the mechanisms of cingulin function and the signaling pathways controlling claudin-2 expression in MDCK cells.

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“…Occludin-deficient mice express a complex phenotype, but one without obvious structural or functional TJ abnormalities (Saitou et al 2000). We have shown that occludin is relevant to apoptosis via MAPK and Akt signaling pathways in occludin-deficient mouse hepatocytes in vitro (Murata et al 2005). However, the physiological function of occludin in the TJ is still undefined.…”

mentioning

confidence: 99%

A Novel Monoclonal Antibody Against the Second Extracellular Loop of Occludin Disrupts Epithelial Cell Polarity

Tokunaga

Kojima

Osanai

et al. 2007

J Histochem Cytochem.

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(YT); and Otaru Kyoukai Hospital, Otaru, Japan (HT) S U M M A R Y The tight junction (TJ) regulates epithelial cell polarity and paracellular permeability. In the present study, to investigate whether the second extracellular loop of occludin affects the localization of carcinoembryonic antigen (CEA) and CD26 expressed on apical membranes, and the fence function of the TJ, the human intestinal epithelial cell line T84 was treated with the monoclonal anti-occludin antibody (MAb) 1H8, corresponding to the second extracellular loop of occludin. In T84 cells treated with MAb 1H8, occludin disappeared, and CEA and CD26 were observed to diffuse from the apical membrane to the basolateral membrane. Furthermore, a decrease in the fence function of TJ was observed without changes in the TJ strands and barrier function. When T84 cells precultured in low calcium (Ca) medium were recultured in normal Ca medium in the presence of MAb 1H8, recruitment of occludin to the apical-most membranes and recovery in distribution of CEA and CD26 were markedly retarded compared with the control. These results suggested that MAb 1H8 against the second extracellular loop of occludin selectively affected formation of the apical/basolateral intramembrane diffusion barrier and that the second extracellular loop of occludin plays a crucial role in the maintenance of epithelial cell polarity by the TJ. (J Histochem Cytochem 55:735-744, 2007)

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Down-regulation of survival signaling through MAPK and Akt in occludin-deficient mouse hepatocytes in vitro

Cited by 44 publications

References 45 publications

Epigenetic Silencing of Occludin Promotes Tumorigenic and Metastatic Properties of Cancer Cells via Modulations of Unique Sets of Apoptosis-Associated Genes

Epigenetic Silencing of Occludin Promotes Tumorigenic and Metastatic Properties of Cancer Cells via Modulations of Unique Sets of Apoptosis-Associated Genes

Cingulin Regulates Claudin-2 Expression and Cell Proliferation through the Small GTPase RhoA

A Novel Monoclonal Antibody Against the Second Extracellular Loop of Occludin Disrupts Epithelial Cell Polarity

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