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Alcohol Activates TGF-Beta but Inhibits BMP Receptor-Mediated Smad Signaling and Smad4 Binding to Hepcidin Promoter in the Liver
Lisa Nicole Gerjevic,Na Liu,Sizhao Lu,Duygu Dee Harrison-Findik
International Journal of Hepatology , 2012, DOI: 10.1155/2012/459278
Abstract: Hepcidin, a key regulator of iron metabolism, is activated by bone morphogenetic proteins (BMPs). Mice pair-fed with regular and ethanol-containing L. De Carli diets were employed to study the effect of alcohol on BMP signaling and hepcidin transcription in the liver. Alcohol induced steatosis and TGF-beta expression. Liver BMP2, but not BMP4 or BMP6, expression was significantly elevated. Despite increased BMP expression, the BMP receptor, and transcription factors, Smad1 and Smad5, were not activated. In contrast, alcohol stimulated Smad2 phosphorylation. However, Smad4 DNA-binding activity and the binding of Smad4 to hepcidin promoter were attenuated. In summary, alcohol stimulates TGF-beta and BMP2 expression, and Smad2 phosphorylation but inhibits BMP receptor, and Smad1 and Smad5 activation. Smad signaling pathway in the liver may therefore be involved in the regulation of hepcidin transcription and iron metabolism by alcohol. These findings may help to further understand the mechanisms of alcohol and iron-induced liver injury.
The Oncogenic Role of microRNA-130a/301a/454 in Human Colorectal Cancer via Targeting Smad4 Expression  [PDF]
Lin Liu, Jing Nie, Lin Chen, Guanglong Dong, Xiaohui Du, Xin Wu, Yun Tang, Weidong Han
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0055532
Abstract: Transforming growth factor (TGF)-β/Smad signaling plays an important role in colon cancer development, progression and metastasis. In this study we demonstrated that the microRNA-130a/301a/454 family is up-regulated in colon cancer tissues compared to paired adjacent normal mucosa, which share the same 3′-untranslational region (3′-UTR) binding seed sequence and are predicated to target Smad4. In colorectal cancer HCT116 and SW480 cells, overexpression of miRNA-130a/301a/454 mimics enhances cell proliferation and migration, while inhibitors of these miRNAs affect cell survival. The biological function of miRNA-130a/301a/454 on colon cancer cells is likely mediated by suppression of Smad4, and the up-regulation of the miRNAs is correlated with Smad4 down-regulation in human colon cancers. Collectively, these results suggest that miRNA-130a/301a/454 are novel oncogenic miRNAs contributing to colon tumorigenesis by regulating TGF-β/Smad signaling, which may have potential application in cancer therapy.
ChIP-seq Defined Genome-Wide Map of TGFβ/SMAD4 Targets: Implications with Clinical Outcome of Ovarian Cancer  [PDF]
Brian A. Kennedy,Daniel E. Deatherage,Fei Gu,Binhua Tang,Michael W. Y. Chan,Kenneth P. Nephew,Tim H-M. Huang,Victor X. Jin
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0022606
Abstract: Deregulation of the transforming growth factor-β (TGFβ) signaling pathway in epithelial ovarian cancer has been reported, but the precise mechanism underlying disrupted TGFβ signaling in the disease remains unclear. We performed chromatin immunoprecipitation followed by sequencing (ChIP-seq) to investigate genome-wide screening of TGFβ-induced SMAD4 binding in epithelial ovarian cancer. Following TGFβ stimulation of the A2780 epithelial ovarian cancer cell line, we identified 2,362 SMAD4 binding loci and 318 differentially expressed SMAD4 target genes. Comprehensive examination of SMAD4-bound loci, revealed four distinct binding patterns: 1) Basal; 2) Shift; 3) Stimulated Only; 4) Unstimulated Only. TGFβ stimulated SMAD4-bound loci were primarily classified as either Stimulated only (74%) or Shift (25%), indicating that TGFβ-stimulation alters SMAD4 binding patterns in epithelial ovarian cancer cells. Furthermore, based on gene regulatory network analysis, we determined that the TGFβ-induced, SMAD4-dependent regulatory network was strikingly different in ovarian cancer compared to normal cells. Importantly, the TGFβ/SMAD4 target genes identified in the A2780 epithelial ovarian cancer cell line were predictive of patient survival, based on in silico mining of publically available patient data bases. In conclusion, our data highlight the utility of next generation sequencing technology to identify genome-wide SMAD4 target genes in epithelial ovarian cancer and link aberrant TGFβ/SMAD signaling to ovarian tumorigenesis. Furthermore, the identified SMAD4 binding loci, combined with gene expression profiling and in silico data mining of patient cohorts, may provide a powerful approach to determine potential gene signatures with biological and future translational research in ovarian and other cancers.
Stromal and epithelial TGF-β signaling in mammary tumorigenesis
HL Moses, N Cheng, A Chytil, AE Gorska, M Aakre, E Forrester, EG Neilson, NA Bhowmick
Breast Cancer Research , 2005, DOI: 10.1186/bcr1045
Abstract: The importance of stromal-epithelial interactions in mammary gland development and tumorigenesis is well established. These interactions probably involve autocrine and paracrine action of multiple growth factors, including members of the TGF-β family, which are expressed in both stroma and epithelium. Again, to accomplish complete knockout of the type II TGF-β receptor gene in mammary stromal cells, FSP1-Cre and Tgfbr2flox/flox mice were crossed to attain Tgfbr2fspKO mice. The loss of TGF-β responsiveness in fibroblasts resulted in intraepithelial neoplasia in prostate and invasive squamous cell carcinoma of the forestomach with high penetrance by 6 weeks of age. Both epithelial lesions were associated with an increased abundance of stromal cells. Activation of paracrine hepatocyte growth factor (HGF) signaling was identified as one possible mechanism for stimulation of epithelial proliferation. TGF-β signaling in fibroblasts thus modulates the growth and oncogenic potential of adjacent epithelia in selected tissues.More recently, we have examined the effects of Tgfbr2fspKO fibroblasts on normal and transformed mammary epithelium. We analyzed the role of TGF-β signaling by stromal cells in mammary tumor progression. To avoid the possibility of endogenous wild-type fibroblasts masking potential effects of Tgfbr2fspKO cells on tumor progression, we implanted PyVmT mammary carcinoma cells with Tgfbr2fspKO or wild-type fibroblasts in the subrenal capsule of nude mice. Mammary tumor cells implanted with Tgfbr2fspKO cells exhibited an increase in tumor growth and intravasation associated with an increase in tumor cell survival, proliferation and an increase in tumor angiogenesis compared with tumor cells implanted with control fibroblasts. We demonstrated increased expression of several growth factors by Tgfbr2fspKO fibroblasts compared with control fibroblasts in primary culture. These included HGF, MSP and TGF-α. There was an increase in tumor cell activating phosphoryl
BRCA1 Interacts with Smad3 and Regulates Smad3-Mediated TGF-β Signaling during Oxidative Stress Responses  [PDF]
Huchun Li, Masayuki Sekine, Seyha Seng, Shalom Avraham, Hava Karsenty Avraham
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0007091
Abstract: Background BRCA1 is a key regulatory protein participating in cell cycle checkpoint and DNA damage repair networks. BRCA1 plays important roles in protecting numerous cellular processes in response to cell damaging signals. Transforming growth factor-beta (TGF-β) is a potent regulator of growth, apoptosis and invasiveness of tumor cells. TFG-β activates Smad signaling via its two cell surface receptors, the TbetaRII and ALK5/TbetaRI, leading to Smad-mediated transcriptional regulation. Methodology/Principal Findings Here, we report an important role of BRCA1 in modulating TGF-β signaling during oxidative stress responses. Wild-type (WT) BRCA1, but not mutated BRCA1 failed to activate TGF-β mediated transactivation of the TGF-β responsive reporter, p3TP-Lux. Further, WT-BRCA1, but not mutated BRCA1 increased the expression of Smad3 protein in a dose-dependent manner, while silencing of WT-BRCA1 by siRNA decreased Smad3 and Smad4 interaction induced by TGF-β in MCF-7 breast cancer cells. BRCA1 interacted with Smad3 upon TGF-β1 stimulation in MCF-7 cells and this interaction was mediated via the domain of 298–436aa of BRCA1 and Smad3 domain of 207–426aa. In addition, H2O2 increased the colocalization and the interaction of Smad3 with WT-BRCA1. Interestingly, TGF-β1 induced Smad3 and Smad4 interaction was increased in the presence of H2O2 in cells expressing WT-BRCA1, while the TGF-β1 induced interaction between Smad3 and Smad4 was decreased upon H2O2 treatment in a dose-dependent manner in HCC1937 breast cancer cells, deficient for endogenous BRCA1. This interaction between Smad3 and Smad4 was increased in reconstituted HCC1937 cells expressing WT-BRCA1 (HCC1937/BRCA1). Further, loss of BRCA1 resulted in H2O2 induced nuclear export of phosphor-Smad3 protein to the cytoplasm, resulting decreased of Smad3 and Smad4 interaction induced by TGF-β and in significant decrease in Smad3 and Smad4 transcriptional activities. Conclusions/Significance These results strongly suggest that loss or reduction of BRCA1 alters TGF-β growth inhibiting activity via Smad3 during oxidative stress responses.
Anterior Visceral Endoderm SMAD4 Signaling Specifies Anterior Embryonic Patterning and Head Induction in Mice
Cuiling Li, Yi-Ping Li, Xin-Yuan Fu, Chu-Xia Deng
International Journal of Biological Sciences , 2010,
Abstract: SMAD4 serves as a common mediator for signaling of TGF-β superfamily. Previous studies illustrated that SMAD4-null mice die at embryonic day 6.5 (E6.5) due to failure of mesoderm induction and extraembryonic defects; however, functions of SMAD4 in each germ layer remain elusive. To investigate this, we disrupted SMAD4 in the visceral endoderm and epiblast, respectively, using a Cre-loxP mediated approach. We showed that mutant embryos lack of SMAD4 in the visceral endoderm (Smad4Co/Co;TTR-Cre) died at E7.5-E9.5 without head-fold and anterior embryonic structures. We demonstrated that TGF-β regulates expression of several genes, such as Hex1, Cer1, and Lim1, in the anterior visceral endoderm (AVE), and the failure of anterior embryonic development in Smad4Co/Co;TTR-Cre embryos is accompanied by diminished expression of these genes. Consistent with this finding, SMAD4-deficient embryoid bodies showed impaired responsiveness to TGF-β-induced gene expression and morphological changes. On the other hand, embryos carrying Cre-loxP mediated disruption of SMAD4 in the epiblasts exhibited relatively normal mesoderm and head-fold induction although they all displayed profound patterning defects in the later stages of gastrulation. Cumulatively, our data indicate that SMAD4 signaling in the epiblasts is dispensable for mesoderm induction although it remains critical for head patterning, which is significantly different from SMAD4 signaling in the AVE, where it specifies anterior embryonic patterning and head induction.
Tumor suppressor FLCN inhibits tumorigenesis of a FLCN-null renal cancer cell line and regulates expression of key molecules in TGF-β signaling
Seung-Beom Hong, HyoungBin Oh, Vladimir A Valera, Jaime Stull, Duy-Tan Ngo, Masaya Baba, Maria J Merino, W Marston Linehan, Laura S Schmidt
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-160
Abstract: To examine the tumor suppressor function of FLCN, wild-type or mutant FLCN (H255R) was stably expressed in a FLCN-null renal tumor cell line, UOK257, derived from a BHD patient. When these cells were injected into nude mice, tumor development was inversely dependent upon the level of wild-type FLCN expression. We identified genes that were differentially expressed in the cell lines with or without wild-type FLCN, many of which are involved in TGF-β signaling, including TGF-β2 (TGFB2), inhibin β A chain (INHBA), thrombospondin 1 (THBS1), gremlin (GREM1), and SMAD3. In support of the in vitro data, TGFB2, INHBA, THBS1 and SMAD3 expression levels were significantly lower in BHD-associated renal tumors compared with normal kidney tissue. Although receptor mediated SMAD phosphorylation was not affected, basal and maximal TGF-β-induced levels of TGFB2, INHBA and SMAD7 were dramatically reduced in FLCN-null cells compared with FLCN-restored cells. Secreted TGF-β2 and activin A (homo-dimer of INHBA) protein levels were also lower in FLCN-null cells compared with FLCN-restored cells. Consistent with a growth suppressive function, activin A (but not TGF-β2) completely suppressed anchorage-independent growth of FLCN-null UOK257 cells.Our data demonstrate a role for FLCN in the regulation of key molecules in TGF-β signaling and confirm deregulation of their expression in BHD-associated renal tumors. Thus, deregulation of genes involved in TGF-β signaling by FLCN inactivation is likely to be an important step for tumorigenesis in BHD syndrome.Birt-Hogg-Dubé (BHD) syndrome is a familial disorder that predisposes patients to develop hair follicle hamartomas (84-90% penetrance), lung cysts (85% penetrance) and renal neoplasia (29-34% penetrance) [1-5]. BHD patients are at risk to develop bilateral, multifocal renal tumors with a variety of histologies, mainly chromophobe (34%) and oncocytic hybrid (50%) tumors with features of both chromophobe renal cell carcinoma (RCC) and renal o
Roles of TGFβ signaling Smads in squamous cell carcinoma
Gangwen Han, Xiao-Jing Wang
Cell & Bioscience , 2011, DOI: 10.1186/2045-3701-1-41
Abstract: The transforming growth factor β (TGFβ) signaling pathway has been implicated in the regulation of various biological processes including embryonic development, fibrosis, tumor development, immunity regulation and wound healing. Function of the TGFβ signaling pathway depends on the binding of ligands to cell membrane receptors, activating cytoplasm mediators into the nucleus, and regulating expression of their target gene. The ligands of the immediate TGFβ family include 3 isoforms (TGFβ 1, 2, 3). Cell-surface receptors of TGFβ signaling are mainly classified into two subtypes: type I (TGFβRI) and type II (TGFβRII). Smad-dependent TGFβ signaling from cytoplasm to nucleus are primarily three Smad isoforms in the Smad family, i.e., Smad2, 3, and 4. The binding of ligands to TGFβRII leads TGFβRI to phosphorylate Smad2 and Smad3, which then bind to Smad4 forming a trimeric complex and translocate into the nucleus. In the nucleus, the Smad trimeric complex binds the Smad binding element (SBE) of target genes, regulating expression of TGFβ response genes directly or through recruiting other co-factors (co-activators or co-repressors) to target genes [1,2] (Figure 1).The TGFβ signaling pathway has been reported to play either a suppressive or a promotive role in cancer development depending on tumor stage and type [3,4]. Evidence for the suppressive role of TGFβ signaling in cancer includes genomic deletion/mutation with several core components of TGFβ signaling identified in human cancers [5,6] and TGFβ mediated cell growth inhibition and apoptosis. However, TGFβ induces angiogenesis, inflammation and epithelial-mesenchymal transition (EMT) providing a beneficial environment for tumor progression and metastasis. The current review will focus on recent progress elucidating the role of TGFβ signaling Smads in squamous cell carcinoma (SCC).Smad2 maps to the 18q21 chromosome, near the Smad4 locus in the human genome [7]. Mutation analysis identified 6% colon cancers with miss
Smad4-expression is decreased in breast cancer tissues: a retrospective study
Christina H Stuelten, Miriam B Buck, Juergen Dippon, Anita B Roberts, Peter Fritz, Cornelius Knabbe
BMC Cancer , 2006, DOI: 10.1186/1471-2407-6-25
Abstract: Smad4 expression was investigated by immunohistochemistry in formalin-fixed, paraffin-embedded tissue from 197 samples of primary breast cancer obtained between 1986 and 1998. The prognostic value of Smad4-expression was analyzed.Smad4 expression was found to be reduced in lobular and ductal breast carcinoma as compared to surrounding uninvolved lobular and ductal breast epithelia (p < 0.001, n = 50). Smad4-expression correlated positively with expression of TGF-β-receptor I (p < 0.001, n = 197) and TGF-β-receptor II (p < 0.001, n = 197), but showed no significant correlation with tumor size, metastases, nodal status, histological grade, histological type, or estrogen receptor expression. While not achieving statistical significance, there was a trend towards longer survival times in patients with Smad4 negative tumors.According to the suggested role of Smad4 as a tumor suppressor we observed that expression of Smad4 is lower in human breast cancer than in surrounding breast epithelium. However, we also observed a trend towards longer survival times in Smad4-negative patients, indicating the complex role of TGF-β signaling in tumor progression.Transforming growth factor beta (TGF-β) is an important regulator of epithelial cell growth. Conflicting data exist about the influence of TGF-β on the development and progression of breast cancer. The growth of many human breast cancer cell lines is inhibited by TGF-β [1,2] due to an inhibition of cell division and an induction of apoptosis. This is consistent with a tumor suppressor effect in well-differentiated tumors [3,4]. On the other hand, certain highly aggressive breast cancer cell lines are refractory to suppressive effects of TGF-β on cell growth and may acquire sensitivity to pro-metastatic effects of TGF-β in later stages of tumorigenesis [5-8].Smad proteins are the principal transducers of signals from TGF-β. TGF-β binds to homodimers of the TGF-β type II receptor (TβRII) which recruits and activates homodimers o
Role of Radiation-induced TGF-beta Signaling in Cancer Therapy  [cached]
Horatiu C. Dancea,Mohammed M. Shareef,Mansoor M. Ahmed
Molecular and Cellular Pharmacology , 2009,
Abstract: TGF-β signaling regulates several different biological processes involving cell-growth, differentiation, apoptosis, motility, angiogenesis, epithelial mesenchymal transition and extracellular matrix production that affects embryonic development and pathogenesis of various diseases, including cancer, its effects depending on the cellular context and physiological environment. Growth suppression mediated by TGF-β signaling often associated with inhibition of c-myc, cdks and induction of p15, p27, Bax and p21. Despite its growth inhibitory effect, in certain conditions TGF-β may act as a promoter of cell proliferation and invasion. Loss of responsiveness to growth suppression by TGF-β due to mutation or loss of TGF-beta type II receptor (TβRII) and Smad4 in several different cancer cells are reported. In addition, TGF-β binding to its receptor activates many non-canonical signaling pathways. Radiation induced TGF-β is primarily involved in normal tissue injury and fibrosis. Seminal studies from our group have used radio-adjuvant therapies, involving classical components of the pathway such as TβRII and SMAD4 to overcome the growth promoting effects of TGF-β. The main impediment in the radiation-induced TGF-β signaling is the induction of SMAD7 that blocks TGF-β signaling in a negative feedback manner. It is well demonstrated from our studies that the use of neutralizing antibodies against TGF-β can render a robust radio-resistant effect. Thus, understanding the functional interactions of TGF-β signaling components of the pathway with other molecules may help tailor appropriate adjuvant radio-therapeutic strategies for treatment of solid tumors.
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