HER2/Neu- and TAK1-mediated Up-regulation of the Transforming Growth Factor β Inhibitor Smad7 via the ETS Protein ER81

Dowdy, Sean C.; Mariani, Andrea; Janknecht, Ralf

doi:10.1074/jbc.m307202200

Cited by 82 publications

(67 citation statements)

References 72 publications

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“…We show that TGF-b is abundantly secreted in the peritoneal milieu through autocrine and paracrine mechanisms. The existence of a functional TGF-b signaling pathway in OC has been documented in prior studies (Cardillo et al, 1997;Baldwin et al, 2003;Dowdy et al, 2003), the cytokine and its receptors being expressed in over 50% of ovarian tumors (Bartlett et al, 1997;Bristow et al, 1999;Abendstein et al, 2000). Loss of growth inhibitory effects of TGF-b in OC cells has been attributed in a minority of cases to TGF-b receptor I and II inactivating mutations (Lynch et al, 1998;Chen et al, 2001) or to alterations of cell signaling downstream of SMADs Hu et al, 2000;Baldwin et al, 2003).…”

Section: Discussionmentioning

confidence: 60%

Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer

et al. 2011

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Tissue transglutaminase (TG2), an enzyme involved in cell proliferation, differentiation and apoptosis is overexpressed in ovarian carcinomas, where it modulates epithelial-to-mesenchymal transition (EMT) and promotes metastasis. Its regulation in ovarian cancer (OC) remains unexplored. Here, we show that transforming growth factor (TGF)-b, a cytokine involved in tumor dissemination is abundantly secreted in the OC microenvironment and induces TG2 expression and enzymatic activity. This is mediated at transcriptional level by SMADs and by TGFb-activated kinase 1-mediated activation of the nuclear factor-jB complex. TGF-b-stimulated OC cells aggregate as spheroids, which enable peritoneal dissemination. We show that TGF-b-induced TG2 regulates EMT, formation of spheroids and OC metastasis. TG2 knock-down in OC cells decreases the number of cells harboring a cancer stem cell phenotype (CD44 þ /CD117 þ ). Furthermore, CD44 þ /CD117 þ cells isolated from human ovarian tumors express high levels of TG2. In summary, TGFb-induced TG2 enhances ovarian tumor metastasis by inducing EMT and a cancer stem cell phenotype.

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Section: Discussionmentioning

confidence: 60%

Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer

et al. 2011

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“…Initial observations by Brodin et al (2000) indicated that TGF-b-induced Smad7 expression depends on cooperative interactions between AP-1, Sp1 and Smad proteins. More recently, both the JNK and TAK1/p38 pathways were shown to regulate Smad7 expression, in a cell-type-specific manner (Uchida et al, 2001;Dowdy et al, 2003). Also, ultraviolet irradiation, a know activator of MAPKs, activates Smad7 transcription in a c-Jun-dependent manner (Quan et al, 2005).…”

Section: Modulation Of Smad Activity By Mapksmentioning

confidence: 99%

Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-β: implications for carcinogenesis

2005

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Transforming growth factor-b (TGF-b) superfamily members signal via membrane-bound heteromeric serinethreonine kinase receptor complexes. Upon ligand-binding, receptor activation leads to phosphorylation of cytoplasmic protein substrates of the Smad family. Following phosphorylation and oligomerization, the latter move into the nucleus to act as transcription factors to regulate target gene expression. TGF-b responses are not solely the result of the activation Smad cascade, but are highly cell-type specific and dependent upon interactions of Smad signaling with a variety of other intracellular signaling mechanisms, initiated or not by TGF-b itself, that may either potentiate, synergize, or antagonize, the rather linear TGF-b/Smad pathway. These include, (a), regulation of Smad activity by mitogen-activated protein kinases (MAPKs), (b), nuclear interaction of activated Smads with transcriptional cofactors, whether coactivators or corepressors, that may be themselves be regulated by diverse signaling mechanisms, and (c), negative feedback loops exerted by inhibitory Smads, transcriptional targets of the Smad cascade. This review focuses on how MAPKs modulate the outcome of Smad activation by TGF-b, and how cross-signaling mechanisms between the Smad and MAPK pathways may take place and affect cell fate in the context of carcinogenesis.

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“…Cells were seeded into 6-cm dishes that were coated with poly-L-lysine 12-24 h before transfection (30). Cells were then transiently transfected by the calcium phosphate coprecipitation method (31) and lysed 36 h after transfection with 50 mM Tris-HCl (pH 7.4), 150 mM NaCl, 50 mM NaF, 0.25 mM Na 3 VO 4 , 0.5% Igepal CA-630, 10 µg/ ml leupeptin, 2 µg/ml aprotinin, 1 µg/ml pepstatin A, 0.5 mM PMSF, 0.2 mM DTT. Immunoprecipitation was performed with anti-Flag M2 or anti-Myc 9E10 monoclonal antibodies as described (32).…”

Section: Introductionmentioning

confidence: 99%

Stimulation of β-catenin and colon cancer cell growth by the KDM4B histone demethylase

Berry

Kim

Janknecht

2014

International Journal of Oncology

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Abstract. The linchpin of colorectal cancer is the oncoprotein and transcriptional cofactor β-catenin, whose overexpression is causative for the neoplastic transformation of colon cells. However, the molecular details of β-catenin dependent gene transcription in cancer cells are still not comprehensively explored. Here, we show that the histone demethylase KDM4B was upregulated in colon and rectal adenocarcinomas and required for efficient growth and clonogenic activity of human HT-29 colon cancer cells. Moreover, KDM4B formed complexes with β-catenin in vitro and in vivo, which involved its central amino acids 353-740. In addition, KDM4B also interacted with the DNA-binding protein TCF4, which is the main factor recruiting β-catenin to chromatin in the intestine. KDM4B downregulation resulted in reduced expression of the β-catenin/TCF4 target genes JUN, MYC and Cyclin D1, all of which encode for oncoproteins. Collectively, our data indicate that KDM4B overexpression supports β-catenin mediated gene transcription and thereby contributes to the genesis of colorectal tumors. Accordingly, inhibition of the KDM4B histone demethylase may represent a novel avenue of fighting colorectal cancer, one of the major causes of cancer death throughout the world. IntroductionColorectal cancer is a major health issue and over 50,000 US residents alone are expected to die from this disease this year (1). A crucial defect in the vast majority of colorectal tumors is the overexpression of the oncoprotein β-catenin. This is primarily due to the loss of the tumor suppressor adenomatous polyposis coli (APC), which normally directs the intracellular destruction of β-catenin, or activating mutations in β-catenin itself (2). Unfortunately, knowledge on the devastating impact of these genetic mutations has not yet translated into improved therapy.Aside from genetic mutations, epigenetic changes are an underlying cause of tumorigenesis. Most prominently, such epigenetic changes involve the methylation of DNA on cytosine residues and the modification of histones by acetylation and methylation (3,4). In contrast to DNA methylation and histone acetylation, the methylation of histones was only recently validated as a major epigenetic mechanism. Methylation occurs on lysine and arginine residues at multiple sites on histones and the tight regulation of the histone methylation status is absolutely required for normal cell physiology and safeguards against aberrant cell growth. Thus, enzymes affecting histone methylation play seminal roles in cellular homeostasis and, accordingly, dysregulation of both histone methyltransferases as well as the opposing demethylases is thought to be capable of inducing cancer (5,6). However, the roles of the enzymes determining histone methylation in colorectal tumors are largely unexplored.The family of human Jumonji C domain containing proteins comprises 30 members, many of which have been shown to function as histone demethylases (7). These include the four related lysine-specific demethylase 4 (KDM4) proteins...

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HER2/Neu- and TAK1-mediated Up-regulation of the Transforming Growth Factor β Inhibitor Smad7 via the ETS Protein ER81

Cited by 82 publications

References 72 publications

Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer

Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer

Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-β: implications for carcinogenesis

Stimulation of β-catenin and colon cancer cell growth by the KDM4B histone demethylase

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