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Catenin Levels (catenin + level)
Selected AbstractsUpregulation of ,-Catenin Levels in Superior Frontal Cortex of Chronic AlcoholicsALCOHOLISM, Issue 6 2008Ali M. Al-Housseini Background:, Chronic and excessive alcohol misuse results in neuroadaptive changes in the brain. The complex nature of behavioral, psychological, emotional, and neuropathological characteristics associated with alcoholism is likely a reflection of the network of proteins that are affected by alcohol-induced gene expression patterns in specific brain regions. At the molecular level, however, knowledge remains limited regarding alterations in protein expression levels affected by chronic alcohol abuse. Thus, novel techniques that allow a comprehensive assessment of this complexity will enable the simultaneous assessment of changes across a group of proteins in the relevant neural circuitry. Methods:, A proteomics analysis was performed using antibody microarrays to determine differential protein levels in superior frontal cortices between chronic alcoholics and age- and gender-matched control subjects. Seventeen proteins related to the catenin signaling pathway were analyzed, including ,-, ,-, and ,-catenins, their upstream activators cadherin-3 (type I cadherin) and cadherin-5 (type II cadherin), and 5 cytoplasmic regulators c-Src, CK1,, GSK-3,, PP2A-C,, and APC, as well as the nuclear complex partner of ,-catenin CBP and 2 downstream genes Myc and cyclin D1. ILK, G,1, G,1, and G,2, which are activity regulators of GSK-3,, were also analyzed. Results:, Both ,- and ,-catenin showed significantly increased levels, while ,-catenin did not change significantly, in chronic alcoholics. In addition, the level of the ,-catenin downstream gene product Myc was significantly increased. Average levels of the catenin regulators c-Src, CK1,, and APC were also increased in chronic alcoholics, but the changes were not statistically significant. Conclusion:, Chronic and excessive alcohol consumption leads to an upregulation of ,- and ,-catenin levels, which in turn increase downstream gene expressions such as Myc that is controlled by ,-catenin signaling. This study showed that the ,-catenin signal transduction pathway was upregulated by chronic alcohol abuse, and prompts further investigation of mechanisms underlying the upregulation of ,- and ,-catenins in alcoholism, which may have considerable pathogenic and therapeutic relevance. [source] HuR regulates gap junctional intercellular communication by controlling ,-catenin levels and adherens junction integrity,HEPATOLOGY, Issue 5 2009Niloofar Ale-Agha Gap junctional intercellular communication (GJIC) plays a critical role in the regulation of tissue homeostasis and carcinogenesis and is modulated by the levels, subcellular localization, and posttranslational modification of gap junction proteins, the connexins (Cx). Here, using oval cell-like rat liver epithelial cells, we demonstrate that the RNA-binding protein HuR promotes GJIC through two mechanisms. First, HuR silencing lowered the levels of Cx43 protein and Cx43 messenger RNA (mRNA), and decreased Cx43 mRNA half-life. This regulation was likely due to the direct stabilization of Cx43 mRNA by HuR, because HuR associated directly with Cx43 mRNA, a transcript that bears signature adenylate-uridylate-rich (AU-rich) and uridylate-rich (U-rich) sequences in its 3,-untranslated region. Second, HuR silencing reduced both half-life and the levels of ,-catenin mRNA, also a target of HuR; accordingly, HuR silencing lowered the levels of whole-cell and membrane-associated ,-catenin. Coimmunoprecipitation experiments showed a direct interaction between ,-catenin and Cx43. Small interfering RNA (siRNA)-mediated depletion of ,-catenin recapitulated the effects of decreasing HuR levels: it attenuated GJIC, decreased Cx43 levels, and redistributed Cx43 to the cytoplasm, suggesting that depletion of ,-catenin in HuR-silenced cells contributed to lowering Cx43 levels at the membrane. Finally, HuR was demonstrated to support GJIC after exposure to a genotoxic agent, doxorubicin, or an inducer of differentiation processes, retinoic acid, thus pointing to a crucial role of HuR in the cellular response to stress and in physiological processes modulated by GJIC. Conclusion: HuR promotes gap junctional intercellular communication in rat liver epithelial cells through two related regulatory processes, by enhancing the expression of Cx43 and by increasing the expression of ,-catenin, which, in turn, interacts with Cx43 and is required for proper positioning of Cx43 at the plasma membrane. (HEPATOLOGY 2009.) [source] Nmi (N-Myc interactor) inhibits Wnt/,-catenin signaling and retards tumor growthINTERNATIONAL JOURNAL OF CANCER, Issue 3 2009Rebecca A. Fillmore Abstract We found that the expression levels of N-Myc interactor (Nmi) were low in aggressive breast cancer cell lines when compared with less aggressive cell lines. However, the lower levels in the aggressive lines were inducible by interferon-, (IFN-,). Because Nmi has been reported to be a transcription cofactor that augments IFN-, induced transcription activity, we decided to test whether Nmi regulates expression of Dkk1, which is also inducible by IFN-,. We established stable clones constitutively expressing Nmi in MDA-MB-231 (breast) and MDA-MB-435 (melanoma) cell lines. Dkk1 was significantly up-regulated in the Nmi expressing clones concurrent with reduced levels of the critical transcription cofactor of Wnt pathway, ,-catenin. Treatment of the Nmi expressors with blocking antibody to Dkk1 restored ,-catenin protein levels. c-Myc is a known downstream target of activated ,-catenin signaling. Treatment of Nmi expressors with the proteosome inhibitor MG132, resulted in elevated ,-catenin levels with concomitant elevation of c-Myc levels. Our functional studies showed that constitutive expression of Nmi reduced the ability of tumor cells for the invasion, anchorage independent growth and tumor growth in vivo. Collectively, the data suggest that overexpression of Nmi inhibits the Wnt/,-catenin signaling via up-regulation of Dkk1 and retards tumor growth. © 2009 UICC [source] Effects of Secreted Frizzled-Related Protein 3 on Osteoblasts In Vitro,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2004Yoon-Sok Chung Abstract To examine if sFRP3s act as decoy receptors for Wnt, we examined the effects of recombinant sFRP3 on mouse osteoblast proliferation and differentiation. We found that sFRP3 unexpectedly increased osteoblast differentiation, suggesting it may act through other mechanisms besides acting as a decoy receptor for Wnt's. Introduction: Secreted frizzled-related proteins (sFRPs) are a truncated form of frizzled receptor, missing both the transmembrane and cytosolic domains. Because previous studies have shown that sFRPs bind and act as decoy receptors for Wnt proteins that promote osteoblast differentiation, we postulated that sFRP3 acts as an inhibitor of osteoblast differentiation. Materials and Methods: We examined the effects of mouse recombinant sFRP3 and/or Wnt-3A on cell proliferation and differentiation using MC3T3-E1 mouse osteoblasts and primary cultures of mouse bone marrow stromal cells. We evaluated the effects of sFRP3 on ,-catenin levels using Western immunoblot analyses. Results: We found that sFRP3 suppressed osteoblast cell number in a dose-dependent manner that was the result of a decrease in proliferation and not because of an increase in apoptosis. Surprisingly, sFRP3 increased osteoblast differentiation, which could not be explained based on sFRP3 acting as a decoy receptor for stimulatory Wnt's. Furthermore, sFRP3 did not inhibit Wnt3A-induced increase in alkaline phosphatase (ALP) activity. Wnt3A, but not sFRP3 treatment, increased cellular ,-catenin levels, and sFRP3 failed to block Wnt3A-induced increase in cellular ,-catenin levels. Treatment with endostatin, an agent known to degrade ,-catenin, did not inhibit sFRP3-induced increase in ALP activity. sFRP1, like sFRP3, inhibited proliferation and stimulated ALP activity in MC3T3-E1 mouse osteoblasts. Conclusions: Based on our findings, we conclude that sFRP3 decreased osteoblast proliferation and unexpectedly increased parameters of osteoblast differentiation. Based on our findings, we propose that sFRP3 may stimulate differentiation through a ,-catenin-independent pathway in addition to its previously known function as a decoy receptor for Wnt's. [source] Presenilin 1 mediates retinoic acid-induced differentiation of SH-SY5Y cells through facilitation of Wnt signalingJOURNAL OF NEUROSCIENCE RESEARCH, Issue 2 2003Kengo Uemura Abstract Presenilin 1 interacts with ,-catenin, an essential component of the Wnt signaling pathway. To elucidate the role of presenilin 1-,-catenin interaction in neuronal differentiation, we established SH-SY5Y cells stably expressing wild-type presenilin 1, P117L mutant presenilin 1, which is linked to the early-onset familial form of Alzheimer's disease, and D385A mutant presenilin 1, which has no aspartyl proteinase activity. We demonstrate that SH-SY5Y cells stably expressing D385A mutant presenilin 1 failed to differentiate in response to retinoic acid treatment. Retinoic acid caused an increase in nuclear ,-catenin levels in SH-SY5Y cells, which was followed by an increase in cyclin D1 protein levels. Abnormal cellular accumulation of ,-catenin was observed in D385A mutant transfected cells, whereas nuclear ,-catenin and cellular cyclin D1 levels failed to increase. Conversely, SH-SY5Y cells expressing the P117L mutant differentiated normally and showed increased nuclear ,-catenin and cellular cyclin D1 levels. These findings suggest that neuronal differentiation of SH-SY5Y cells involves the Wnt signaling pathway and that presenilin 1 plays a crucial role in Wnt signal transduction by regulating the nuclear translocation of ,-catenin. © 2003 Wiley-Liss, Inc. [source] Upregulation of ,-Catenin Levels in Superior Frontal Cortex of Chronic AlcoholicsALCOHOLISM, Issue 6 2008Ali M. Al-Housseini Background:, Chronic and excessive alcohol misuse results in neuroadaptive changes in the brain. The complex nature of behavioral, psychological, emotional, and neuropathological characteristics associated with alcoholism is likely a reflection of the network of proteins that are affected by alcohol-induced gene expression patterns in specific brain regions. At the molecular level, however, knowledge remains limited regarding alterations in protein expression levels affected by chronic alcohol abuse. Thus, novel techniques that allow a comprehensive assessment of this complexity will enable the simultaneous assessment of changes across a group of proteins in the relevant neural circuitry. Methods:, A proteomics analysis was performed using antibody microarrays to determine differential protein levels in superior frontal cortices between chronic alcoholics and age- and gender-matched control subjects. Seventeen proteins related to the catenin signaling pathway were analyzed, including ,-, ,-, and ,-catenins, their upstream activators cadherin-3 (type I cadherin) and cadherin-5 (type II cadherin), and 5 cytoplasmic regulators c-Src, CK1,, GSK-3,, PP2A-C,, and APC, as well as the nuclear complex partner of ,-catenin CBP and 2 downstream genes Myc and cyclin D1. ILK, G,1, G,1, and G,2, which are activity regulators of GSK-3,, were also analyzed. Results:, Both ,- and ,-catenin showed significantly increased levels, while ,-catenin did not change significantly, in chronic alcoholics. In addition, the level of the ,-catenin downstream gene product Myc was significantly increased. Average levels of the catenin regulators c-Src, CK1,, and APC were also increased in chronic alcoholics, but the changes were not statistically significant. Conclusion:, Chronic and excessive alcohol consumption leads to an upregulation of ,- and ,-catenin levels, which in turn increase downstream gene expressions such as Myc that is controlled by ,-catenin signaling. This study showed that the ,-catenin signal transduction pathway was upregulated by chronic alcohol abuse, and prompts further investigation of mechanisms underlying the upregulation of ,- and ,-catenins in alcoholism, which may have considerable pathogenic and therapeutic relevance. [source] Modulation of the oncogenic potential of ,-catenin by the subcellular distribution of plakoglobin,MOLECULAR CARCINOGENESIS, Issue 10 2007Laiji Li Abstract Plakoglobin (Pg) and ,-catenin are homologous proteins that function in cell,cell adhesion and signaling. The cadherin-associated form of these proteins mediates adhesion, whereas the cytosolic/nuclear form has a signaling role. Despite their interactions with common cellular partners, ,-catenin has a well-documented oncogenic potential while Pg has a less characterized tumor suppressor activity. We showed previously that Pg overexpression in Pg-deficient SCC9 cells (SCC9-Pg-WT) induced Bcl-2 expression and inhibited apoptosis. To assess the exact role of Pg in Bcl-2 expression, we generated and characterized SCC9 transfectants expressing Pg with a restricted cytoplasmic (Pg-NES) or nuclear (Pg-NLS) distribution. We show that Bcl-2 was expressed regardless of Pg localization, although its level was substantially lower in SCC9-Pg-NLS cells. Bcl-2 expression coincided with increased nuclear ,-catenin levels (Pg-NES) or a decrease in the level of total and nuclear ,-catenin associated with N-cadherin and ,-catenin (Pg-WT and -NLS) cells. Bcl-2 expression also was induced in SCC9 cells overexpressing ,-catenin. In contrast, SCC9 cells expressing mutant Pg proteins, unable to interact with N-cadherin and ,-catenin, had noticeably lower Bcl-2 levels. Our data suggest that Bcl-2 expression is induced by ,-catenin and modulated by Pg. We show that the inhibition of ,-catenin-dependent TCF transactivation had no effect on Bcl-2 levels, suggesting that induction of Bcl-2 expression by ,-catenin and its modulation by Pg may involve factors other than, or in addition, to, TCF. These results provide a possible mechanism for the tumor suppressor activity of Pg via its role as a regulator of the oncogenic potential ,-catenin. © 2007 Wiley-Liss, Inc. [source] ,-Catenin expression in human neural cell lines following exposure to cytokines and growth factorsNEUROPATHOLOGY, Issue 2 2000Jun-ichi Satoh ,-Catenin acts as a key mediator of the Wnt/Wingless signaling pathway involved in cell proliferation, differentiation and survival. Recent studies have shown that an unstable interaction between ,-catenin and the mutant presenilin-1 induces neuronal apoptosis, and that ,-catenin levels are decreased in the brains of patients with Alzheimer's disease (AD). Since activated microglia and astrocytes play a role in the process of neuronal degeneration in AD, the cytokine/growth factor-regulated expression of ,-catenin in human neural cell lines, including NTera2 teratocarcinoma-derived differentiated neurons (NTera2-N), IMR-32 neuroblastoma, SKN-SH neuroblastoma and U-373MG astrocytoma, was studied quantitatively following exposure to epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), brain-derived neurotrophic factor (BDNF), tumor necrosis factor-, (TNF-,), interleukin (IL)-1,, IL-6, interferon (IFN)-,, transforming growth factor (TGF)-,1, dibutyryl cyclic adenosine 3,,5,-cyclic monophosphate (cAMP) (dbcAMP) or phorbol 12-myristate 13-acetate (PMA). ,-Catenin mRNA expressed constitutively in all of these cell lines was unaffected by treatment with any factors examined. In contrast, ,-catenin protein levels were reduced markedly in NTera2-N cells by exposure to dbcAMP, EGF or bFGF, and in U-373MG cells by treatment with dbcAMP or PMA, but were unaffected in any cell lines by BDNF, TNF-,, IL-1,, IL-6, IFN-, or TGF-,1. These results indicate that ,-catenin is expressed constitutively in human neural cells and downregulated at a protein level by a set of growth factors in a cell type-specific manner. [source] Transcriptional activation of the ,- catenin gene at the invasion front of colorectal liver metastases,THE JOURNAL OF PATHOLOGY, Issue 3 2009Obul R Bandapalli Abstract ,-Catenin is a pivotal molecule of the Wnt-signalling pathway, involved in regulation of developmental and oncogenic processes as well as in intercellular adhesion. So far, ,-catenin has been thought to be regulated mainly at the protein level. Here, we provide evidence for a transcriptional mechanism of ,-catenin regulation at the invasion front of colorectal liver metastases. In a nude mouse/LS174T cell xenograft model of colorectal liver metastases, we observed ,-catenin up-regulation at the mRNA and protein levels and a 13.7-fold increase of ,-catenin promoter activity in the cancer cells of the invasion front. In addition, the promoter activity was five-fold higher in the interior of the tumour than in cells growing in cell culture. In vitro studies revealed binding of TCF-4 to the ,-catenin promoter and reduced promoter activity by over-expression of dominant negative TCF-4, or ,-catenin knock-down and increased activity by ,-catenin over-expression, indicating that ,-catenin acts as co-transcription factor of its own promoter. In 55% (7/13) of clinical specimens, ,-catenin mRNA was markedly elevated in the cancer cells of the invasion front. Elevation of mRNA was paralleled by increased nuclear and cytoplasmic ,-catenin protein concentrations. These data indicate that transcriptional regulation contributes to the dynamic changes of ,-catenin levels upon the confrontation of tumour cells with the host microenvironment. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] | |||||||||||||||||||