Gene Summary

Gene:SMAD6; SMAD family member 6
Aliases: AOVD2, MADH6, MADH7, HsT17432
Summary:The protein encoded by this gene belongs to the SMAD family of proteins, which are related to Drosophila 'mothers against decapentaplegic' (Mad) and C. elegans Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein functions in the negative regulation of BMP and TGF-beta/activin-signalling. Multiple transcript variants have been found for this gene.[provided by RefSeq, Sep 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:mothers against decapentaplegic homolog 6
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: SMAD6 (cancer-related)

Jiao J, Zhang R, Li Z, et al.
Nuclear Smad6 promotes gliomagenesis by negatively regulating PIAS3-mediated STAT3 inhibition.
Nat Commun. 2018; 9(1):2504 [PubMed] Free Access to Full Article Related Publications
To date, the molecular mechanism underlying constitutive signal transducer and activator of transcription 3 (STAT3) activation in gliomas is largely unclear. In this study, we report that Smad6 is overexpressed in nuclei of glioma cells, which correlates with poor patient survival and regulates STAT3 activity via negatively regulating the Protein Inhibitors of Activated STAT3 (PIAS3). Mechanically, Smad6 interacts directly with PIAS3, and this interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and the Ring domain of PIAS3. Smad6 recruits Smurf1 to facilitate PIAS3 ubiquitination and degradation, which also depends on the MH2 domain and the PY motif of Smad6. Consequently, Smad6 reduces PIAS3-mediated STAT3 inhibition and promotes glioma cell growth and stem-like cell initiation. Moreover, the Smad6 MH2 transducible protein restores PIAS3 expression and subsequently reduces gliomagenesis. Collectively, we conclude that nuclear-Smad6 enhances glioma development by inducing PIAS3 degradation and subsequent STAT3 activity upregulation.

Chen Z, Lu X, Jia D, et al.
Hepatic SMARCA4 predicts HCC recurrence and promotes tumour cell proliferation by regulating SMAD6 expression.
Cell Death Dis. 2018; 9(2):59 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) is the most common form of liver cancer and is typically diagnosed at advanced stages. Identification and characterisation of genes within amplified and deleted chromosomal loci can provide new insights into the pathogenesis of cancer and lead to new approaches for diagnosis and therapy. In our previous study, we found a recurrent region of copy number amplification at 19p13.2 in hepatocellular carcinoma (HCC). In the present study, we performed integrated copy number analysis and expression profiling at this locus and a putative cancer gene, SMARCA4/BRG1, was uncovered in this region. BRG1 is a part of the large ATP-dependent chromatin remodelling complex SWI/SNF. The function of BRG1 in various cancers is unclear, including its role in HCC tumorigenesis. Here, we found that BRG1 is upregulated in HCC and that its level significantly correlates with cancer progression in HCC patients. Importantly, we also found that nuclear expression of BRG1 predicts early recurrence for HCC patients. Furthermore, we demonstrated that BRG1 promotes HCC cell proliferation in vitro and in vivo. BRG1 was observed not only to facilitate S-phase entry but also to attenuate cell apoptosis. Finally, we discovered that one of the mechanisms by which BRG1 promotes cell proliferation is the upregulation of SMAD6. These findings highlight the important role of BRG1 in the regulation of HCC proliferation and provide valuable information for cancer prognosis and treatment.

Du C, Pan P, Jiang Y, et al.
Microarray data analysis to identify crucial genes regulated by CEBPB in human SNB19 glioma cells.
World J Surg Oncol. 2016; 14(1):258 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Glioma is one of the most common primary malignancies in the brain or spine. The transcription factor (TF) CCAAT/enhancer binding protein beta (CEBPB) is important for maintaining the tumor initiating capacity and invasion ability. To investigate the regulation mechanism of CEBPB in glioma, microarray data GSE47352 was analyzed.
METHODS: GSE47352 was downloaded from Gene Expression Omnibus, including three samples of SNB19 human glioma cells transduced with non-target control small hairpin RNA (shRNA) lentiviral vectors for 72 h (normal glioma cells) and three samples of SNB19 human glioma cells transduced with CEBPB shRNA lentiviral vectors for 72 h (CEBPB-silenced glioma cells). The differentially expressed genes (DEGs) were screened using limma package and then annotated. Afterwards, the Database for Annotation, Visualization, and Integrated Discovery (DAVID) software was applied to perform enrichment analysis for the DEGs. Furthermore, the protein-protein interaction (PPI) network and transcriptional regulatory network were constructed using Cytoscape software.
RESULTS: Total 529 DEGs were identified in the normal glioma cells compared with the CEBPB-silenced glioma cells, including 336 up-regulated and 193 down-regulated genes. The significantly enriched pathways included chemokine signaling pathway (which involved CCL2), focal adhesion (which involved THBS1 and THBS2), TGF-beta signaling pathway (which involved THBS1, THBS2, SMAD5, and SMAD6) and chronic myeloid leukemia (which involved TGFBR2 and CCND1). In the PPI network, CCND1 (degree = 29) and CCL2 (degree = 12) were hub nodes. Additionally, CEBPB and TCF12 might function in glioma through targeting others (CEBPB → TCF12, CEBPB → TGFBR2, and TCF12 → TGFBR2).
CONCLUSIONS: CEBPB might act in glioma by regulating CCL2, CCND1, THBS1, THBS2, SMAD5, SMAD6, TGFBR2, and TCF12.

Sayagués JM, Corchete LA, Gutiérrez ML, et al.
Genomic characterization of liver metastases from colorectal cancer patients.
Oncotarget. 2016; 7(45):72908-72922 [PubMed] Free Access to Full Article Related Publications
Metastatic dissemination is the most frequent cause of death of sporadic colorectal cancer (sCRC) patients. Genomic abnormalities which are potentially characteristic of such advanced stages of the disease are complex and so far, they have been poorly described and only partially understood. We evaluated the molecular heterogeneity of sCRC tumors based on simultaneous assessment of the overall GEP of both coding mRNA and non-coding RNA genes in primary sCRC tumor samples from 23 consecutive patients and their paired liver metastases. Liver metastases from the sCRC patients analyzed, systematically showed deregulated transcripts of those genes identified as also deregulated in their paired primary colorectal carcinomas. However, some transcripts were found to be specifically deregulated in liver metastases (vs. non-tumoral colorectal tissues) while expressed at normal levels in their primary tumors, reflecting either an increased genomic instability of metastatic cells or theiradaption to the liver microenvironment. Newly deregulated metastatic transcripts included overexpression of APOA1, HRG, UGT2B4, RBP4 and ADH4 mRNAS and the miR-3180-3p, miR-3197, miR-3178, miR-4793 and miR-4440 miRNAs, together with decreased expression of the IGKV1-39, IGKC, IGKV1-27, FABP4 and MYLK mRNAS and the miR-363, miR-1, miR-143, miR-27b and miR-28-5p miRNAs. Canonical pathways found to be specifically deregulated in liver metastatic samples included multiple genes related with intercellular adhesion and the metastatic processes (e.g., IGF1R, PIK3CA, PTEN and EGFR), endocytosis (e.g., the PDGFRA, SMAD2, ERBB3, PML and FGFR2), and the cell cycle (e.g., SMAD2, CCND2, E2F5 and MYC). Our results also highlighted the activation of genes associated with the TGFβ signaling pathway, -e.g. RHOA, SMAD2, SMAD4, SMAD5, SMAD6, BMPR1A, SMAD7 and MYC-, which thereby emerge as candidate genes to play an important role in CRC tumor metastasis.

Wang Z, Nakamura K, Jinnin M, et al.
Establishment and gene expression analysis of disease-derived induced pluripotent stem cells of scleroderma.
J Dermatol Sci. 2016; 84(2):186-196 [PubMed] Related Publications
BACKGROUND: We recently generated induced pluripotent stem cells (iPSCs) from cultured dermal fibroblasts of systemic sclerosis (SSc-iPSC) to study the disease mechanisms.
OBJECTIVE: In the present study, we have performed gene expression analysis using cultured SSc dermal fibroblasts, SSc-iPSC, and fibroblasts re-differentiated from SSc-iPSC (SSc-iPSC-FB).
METHODS: mRNA and protein levels of collagen and integrins were analyzed using PCR array, PCR, immunoblotting, and immunofluorescence.
RESULTS: We compared expression pattern of TGF-β-related genes between normal iPSC (NS-iPSC) and SSc-iPSC by PCR array, and found constitutive and significant down-regulation of S100A8, Smad6, and TGF-β2 in SSc-iPSC. The expression of these genes was not altered in cultured SSc fibroblasts or SSc-iPSC-FB compared to NS fibroblasts or NS-iPSC-FB, respectively. On the other hand, the expression of collagen, integrin α and β was up-regulated in SSc fibroblasts, while SSc-iPSC-FB showed normalized levels of collagen and integrin β.
CONCLUSIONS: So far, there have been no reports investigating disease-derived iPSCs of SSc. Our results suggest that S100A8, Smad6, and TGF-β2 may be the key molecules of this disease. On the other hand, the normalization of collagen and integrins by iPSC reprogramming suggests that epigenetic modifications of genes may play a role in the mechanism of collagen accumulation seen in SSc fibroblasts, and that gene reprogramming may become novel therapeutic approach. As the limitation of this study, we established only one iPSC line from each patient, which may not be enough to discuss disease-specific phenotypes. Larger studies including increased number of iPSC lines are needed in the future.

Komatsubara M, Hara T, Hosoya T, et al.
Melatonin regulates catecholamine biosynthesis by modulating bone morphogenetic protein and glucocorticoid actions.
J Steroid Biochem Mol Biol. 2017; 165(Pt B):182-189 [PubMed] Related Publications
Melatonin is functionally involved in the control of circadian rhythm and hormonal secretion. In the present study, we investigated the roles of melatonin in the interaction of catecholamine synthesis with adrenocortical steroids by focusing on bone morphogenetic protein (BMP)-4 expressed in the adrenal medulla using rat pheochromocytoma PC12 cells. Melatonin treatment significantly reduced the mRNA expression of catecholamine synthases, including the rate-limiting enzyme tyrosine hydroxylase (Th), 3,4-dihydroxyphenylalanine decarboxylase and dopamine-β-hydroxylase expressed in PC12 cells. In accordance with changes in the expression levels of enzymes, dopamine production and cAMP synthesis determined in the culture medium and cell lysate were also suppressed by melatonin. The MT1 receptor, but not the MT2 receptor, was expressed in PC12 cells, and luzindole treatment reversed the inhibitory effect of melatonin on Th expression, suggesting that MT1 is a functional receptor for the control of catecholamine synthesis. Interestingly, melatonin enhanced the inhibitory effect of BMP-4 on Th mRNA expression in PC12 cells. Melatonin treatment accelerated BMP-4-induced phosphorylation of SMAD1/5/8 and transcription of the BMP target gene Id1. Of note, melatonin significantly upregulated Alk2 and Bmpr2 mRNA levels but suppressed inhibitory Smad6/7 expression, leading to the enhancement of SMAD1/5/8 signaling in PC12 cells, while BMP-4 did not affect Mt1 expression. Regarding the interaction with adrenocortical steroids, melatonin preferentially enhanced glucocorticoid-induced Th mRNA through upregulation of the glucocorticoid receptor and downregulation of Bmp4 expression, whereas melatonin repressed Th mRNA expression induced by aldosterone or androgen without affecting expression levels of the receptors for mineralocorticoid and androgen. Collectively, the results indicate that melatonin plays a modulatory role in catecholamine synthesis by cooperating with BMP-4 and glucocorticoid in the adrenal medulla.

de Boeck M, Cui C, Mulder AA, et al.
Smad6 determines BMP-regulated invasive behaviour of breast cancer cells in a zebrafish xenograft model.
Sci Rep. 2016; 6:24968 [PubMed] Free Access to Full Article Related Publications
The transforming growth factor-β (TGF-β) family is known to play critical roles in cancer progression. While the dual role of TGF-β is well described, the function of bone morphogenetic proteins (BMPs) is unclear. In this study, we established the involvement of Smad6, a BMP-specific inhibitory Smad, in breast cancer cell invasion. We show that stable overexpression of Smad6 in breast cancer MCF10A M2 cells inhibits BMP signalling, thereby mitigating BMP6-induced suppression of mesenchymal marker expression. Using a zebrafish xenograft model, we demonstrate that overexpression of Smad6 potentiates invasion of MCF10A M2 cells and enhances the aggressiveness of breast cancer MDA-MB-231 cells in vivo, whereas a reversed phenotype is observed after Smad6 knockdown. Interestingly, BMP6 pre-treatment of MDA-MB-231 cells induced cluster formation at the invasive site in the zebrafish. BMP6 also stimulated cluster formation of MDA-MB-231 cells co-cultured on Human Microvascular Endothelial Cells (HMEC)-1 in vitro. Electron microscopy illustrated an induction of cell-cell contact by BMP6. The clinical relevance of our findings is highlighted by a correlation of high Smad6 expression with poor distant metastasis free survival in ER-negative cancer patients. Collectively, our data strongly indicates the involvement of Smad6 and BMP signalling in breast cancer cell invasion in vivo.

Mullapudi N, Ye B, Suzuki M, et al.
Genome Wide Methylome Alterations in Lung Cancer.
PLoS One. 2015; 10(12):e0143826 [PubMed] Free Access to Full Article Related Publications
Aberrant cytosine 5-methylation underlies many deregulated elements of cancer. Among paired non-small cell lung cancers (NSCLC), we sought to profile DNA 5-methyl-cytosine features which may underlie genome-wide deregulation. In one of the more dense interrogations of the methylome, we sampled 1.2 million CpG sites from twenty-four NSCLC tumor (T)-non-tumor (NT) pairs using a methylation-sensitive restriction enzyme- based HELP-microarray assay. We found 225,350 differentially methylated (DM) sites in adenocarcinomas versus adjacent non-tumor tissue that vary in frequency across genomic compartment, particularly notable in gene bodies (GB; p<2.2E-16). Further, when DM was coupled to differential transcriptome (DE) in the same samples, 37,056 differential loci in adenocarcinoma emerged. Approximately 90% of the DM-DE relationships were non-canonical; for example, promoter DM associated with DE in the same direction. Of the canonical changes noted, promoter (PR) DM loci with reciprocal changes in expression in adenocarcinomas included HBEGF, AGER, PTPRM, DPT, CST1, MELK; DM GB loci with concordant changes in expression included FOXM1, FERMT1, SLC7A5, and FAP genes. IPA analyses showed adenocarcinoma-specific promoter DMxDE overlay identified familiar lung cancer nodes [tP53, Akt] as well as less familiar nodes [HBEGF, NQO1, GRK5, VWF, HPGD, CDH5, CTNNAL1, PTPN13, DACH1, SMAD6, LAMA3, AR]. The unique findings from this study include the discovery of numerous candidate The unique findings from this study include the discovery of numerous candidate methylation sites in both PR and GB regions not previously identified in NSCLC, and many non-canonical relationships to gene expression. These DNA methylation features could potentially be developed as risk or diagnostic biomarkers, or as candidate targets for newer methylation locus-targeted preventive or therapeutic agents.

Ordóñez R, Gallo-Oller G, Martínez-Soto S, et al.
Genome-wide microarray expression and genomic alterations by array-CGH analysis in neuroblastoma stem-like cells.
PLoS One. 2014; 9(11):e113105 [PubMed] Free Access to Full Article Related Publications
Neuroblastoma has a very diverse clinical behaviour: from spontaneous regression to a very aggressive malignant progression and resistance to chemotherapy. This heterogeneous clinical behaviour might be due to the existence of Cancer Stem Cells (CSC), a subpopulation within the tumor with stem-like cell properties: a significant proliferation capacity, a unique self-renewal capacity, and therefore, a higher ability to form new tumors. We enriched the CSC-like cell population content of two commercial neuroblastoma cell lines by the use of conditioned cell culture media for neurospheres, and compared genomic gains and losses and genome expression by array-CGH and microarray analysis, respectively (in CSC-like versus standard tumor cells culture). Despite the array-CGH did not show significant differences between standard and CSC-like in both analyzed cell lines, the microarray expression analysis highlighted some of the most relevant biological processes and molecular functions that might be responsible for the CSC-like phenotype. Some signalling pathways detected seem to be involved in self-renewal of normal tissues (Wnt, Notch, Hh and TGF-β) and contribute to CSC phenotype. We focused on the aberrant activation of TGF-β and Hh signalling pathways, confirming the inhibition of repressors of TGF-β pathway, as SMAD6 and SMAD7 by RT-qPCR. The analysis of the Sonic Hedgehog pathway showed overexpression of PTCH1, GLI1 and SMO. We found overexpression of CD133 and CD15 in SIMA neurospheres, confirming that this cell line was particularly enriched in stem-like cells. This work shows a cross-talk among different pathways in neuroblastoma and its importance in CSC-like cells.

Wang Y, Wu J, Lin B, et al.
Galangin suppresses HepG2 cell proliferation by activating the TGF-β receptor/Smad pathway.
Toxicology. 2014; 326:9-17 [PubMed] Related Publications
Galangin can suppress hepatocellular carcinoma (HCC) cell proliferation. In this study, we demonstrated that galangin induced autophagy by activating the transforming growth factor (TGF)-β receptor/Smad pathway and increased TGF-β receptor I (RI), TGF-βRII, Smad1, Smad2, Smad3 and Smad4 levels but decreased Smad6 and Smad7 levels. Autophagy induced by galangin appears to depend on the TGF-β receptor/Smad signalling pathway because the down-regulation of Smad4 by siRNA or inhibition of TGF-β receptor activation by LY2109761 blocked galangin-induced autophagy. The down-regulation of Beclin1, autophagy-related gene (ATG) 16L, ATG12 and ATG3 restored HepG2 cell proliferation and prevented galangin-induced apoptosis. Our findings indicate a novel mechanism for galangin-induced autophagy via activation of the TGF-β receptor/Smad pathway. The induction of autophagy thus reflects the anti-proliferation effect of galangin on HCC cells.

Hu CY, Mohtat D, Yu Y, et al.
Kidney cancer is characterized by aberrant methylation of tissue-specific enhancers that are prognostic for overall survival.
Clin Cancer Res. 2014; 20(16):4349-60 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Even though recent studies have shown that genetic changes at enhancers can influence carcinogenesis, most methylomic studies have focused on changes at promoters. We used renal cell carcinoma (RCC), an incurable malignancy associated with mutations in epigenetic regulators, as a model to study genome-wide patterns of DNA methylation at a high resolution.
EXPERIMENTAL DESIGN: Analysis of cytosine methylation status of 1.3 million CpGs was determined by the HELP assay in RCC and healthy microdissected renal tubular controls.
RESULTS: We observed that the RCC samples were characterized by widespread hypermethylation that preferentially affected gene bodies. Aberrant methylation was particularly enriched in kidney-specific enhancer regions associated with H3K4Me1 marks. Various important underexpressed genes, such as SMAD6, were associated with aberrantly methylated, intronic enhancers, and these changes were validated in an independent cohort. MOTIF analysis of aberrantly hypermethylated regions revealed enrichment for binding sites of AP2a, AHR, HAIRY, ARNT, and HIF1 transcription factors, reflecting contributions of dysregulated hypoxia signaling pathways in RCC. The functional importance of this aberrant hypermethylation was demonstrated by selective sensitivity of RCC cells to low levels of decitabine. Most importantly, methylation of enhancers was predictive of adverse prognosis in 405 cases of RCC in multivariate analysis. In addition, parallel copy-number analysis from MspI representations demonstrated novel copy-number variations that were validated in an independent cohort of patients.
CONCLUSIONS: Our study is the first high-resolution methylome analysis of RCC, demonstrates that many kidney-specific enhancers are targeted by aberrant hypermethylation, and reveals the prognostic importance of these epigenetic changes in an independent cohort.

Yu SL, Lee DC, Son JW, et al.
Histone deacetylase 4 mediates SMAD family member 4 deacetylation and induces 5-fluorouracil resistance in breast cancer cells.
Oncol Rep. 2013; 30(3):1293-300 [PubMed] Related Publications
Histone deacetylases (HDACs) have been shown to play important roles in the regulation of chromatin remodeling by histone deacetylation, and their expression is induced in several types of cancer. In addition, they are known to be associated with resistance to anticancer drugs. However, the relevance of HDAC4 in chemoresistance remains unclear. Therefore, we investigated the interaction between HDAC4 expression and chemoresistance in breast cancer cells. We found that increased HDAC4 expression in MDA-MB-231 cells was associated with resistance to the anticancer drug 5-fluorouracil (5-FU). To verify these results, a cell line stably overexpressing HDAC4 was generated using MCF-7 cells (HDAC4OE). This cell line displayed increased 5-FU resistance, and HDAC4 knockdown in HDAC4OE cells restored 5-FU sensitivity. Consequently, we concluded that HDAC4 is a critical gene associated with 5‑FU chemoresistance. Further investigation using a microarray approach revealed that 355 genes were differentially expressed following HDAC4 overexpression. Based on functional annotation of the array results, HDAC4 overexpression was found to downregulate genes related to the transforming growth factor (TGF) β signaling pathway, including SMAD4, SMAD6, bone morphogenetic protein 6, inhibitor of DNA binding 1 and TGFβ2. We also found that HDAC4 expression regulates SMAD4 expression by inducing deacetylation of histone H3 in the SMAD4 promoter region. In addition, SMAD4 knockdown in MCF‑7 cells increased 5-FU resistance. In summary, our data suggest that HDAC4‑mediated deacetylation of the SMAD4 promoter may lead to 5-FU resistance in breast cancer cells.

Omaruddin RA, Roland TA, Wallace HJ, Chaudhry MA
Gene expression as a biomarker for human radiation exposure.
Hum Cell. 2013; 26(1):2-7 [PubMed] Related Publications
Accidental exposure to ionizing radiation can be unforeseen, rapid, and devastating. The detonation of a radiological device leading to such an exposure can be detrimental to the exposed population. The radiation-induced damage may manifest as acute effects that can be detected clinically or may be more subtle effects that can lead to long-term radiation-induced abnormalities. Accurate identification of the individuals exposed to radiation is challenging. The availability of a rapid and effective screening test that could be used as a biomarker of radiation exposure detection is mandatory. We tested the suitability of alterations in gene expression to serve as a biomarker of human radiation exposure. To develop a useful gene expression biomonitor, however, gene expression changes occurring in response to irradiation in vivo must be measured directly. Patients undergoing radiation therapy provide a suitable test population for this purpose. We examined the expression of CC3, MADH7, and SEC PRO in blood samples of these patients before and after radiotherapy to measure the in vivo response. The gene expression after ionizing radiation treatment varied among different patients, suggesting the complexity of the response. The expression of the SEC PRO gene was repressed in most of the patients. The MADH7 gene was found to be upregulated in most of the subjects and could serve as a molecular marker of radiation exposure.

Li Q, Wu H, Chen B, et al.
SNPs in the TGF-β signaling pathway are associated with increased risk of brain metastasis in patients with non-small-cell lung cancer.
PLoS One. 2012; 7(12):e51713 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Brain metastasis (BM) from non-small cell lung cancer (NSCLC) is relatively common, but identifying which patients will develop brain metastasis has been problematic. We hypothesized that genotype variants in the TGF-β signaling pathway could be a predictive biomarker of brain metastasis.
PATIENTS AND METHODS: We genotyped 33 SNPs from 13 genes in the TGF-β signaling pathway and evaluated their associations with brain metastasis risk by using DNA from blood samples from 161 patients with NSCLC. Kaplan-Meier analysis was used to assess brain metastasis risk; Cox hazard analyses were used to evaluate the effects of various patient and disease characteristics on the risk of brain metastasis.
RESULTS: The median age of the 116 men and 45 women in the study was 58 years; 62 (39%) had stage IIIB or IV disease. Within 24 months after initial diagnosis of lung cancer, brain metastasis was found in 60 patients (37%). Of these 60 patients, 16 had presented with BM at diagnosis. Multivariate analysis showed the GG genotype of SMAD6: rs12913975 and TT genotype of INHBC: rs4760259 to be associated with a significantly higher risk of brain metastasis at 24 months follow-up (hazard ratio [HR] 2.540, 95% confidence interval [CI] 1.204-5.359, P = 0.014; and HR 1.885, 95% CI 1.086-3.273, P = 0.024), compared with the GA or CT/CC genotypes, respectively. When we analyzed combined subgroups, these rates showed higher for those having both the GG genotype of SMAD6: rs12913975 and the TT genotype of INHBC: rs4760259 (HR 2.353, 95% CI 1.390-3.985, P = 0.001).
CONCLUSIONS: We found the GG genotype of SMAD6: rs12913975 and TT genotype of INHBC: rs4760259 to be associated with risk of brain metastasis in patients with NSCLC. This finding, if confirmed, can help to identify patients at high risk of brain metastasis.

Kaminska B, Kocyk M, Kijewska M
TGF beta signaling and its role in glioma pathogenesis.
Adv Exp Med Biol. 2013; 986:171-87 [PubMed] Related Publications
Transforming growth factor beta (TGF-β) signaling is involved in the regulation of proliferation, differentiation and survival/or apoptosis of many cells, including glioma cells. TGF-β acts via specific receptors activating multiple intracellular pathways resulting in phosphorylation of receptor-regulated Smad2/3 proteins that associate with the common mediator, Smad4. Such complex translocates to the nucleus, binds to DNA and regulates transcription of many genes. Furthermore, TGF-β-activated kinase-1 (TAK1) is a component of TGF-β signaling and activates mitogen-activated protein kinase cascades. Negative regulation of TGF-β/Smad signaling may occur through the inhibitory Smad6/7. Increased expression of TGF-β1-3 correlates with a degree of malignancy of human gliomas. TGF-β may contribute to tumor pathogenesis by direct support of tumor growth, self-renewal of glioma initiating stem cells and inhibiting of anti-tumor immunity. TGF-β1,2 stimulate expression of the vascular endothelial growth factor as well as the plasminogen activator inhibitor and some metalloproteinases that are involved in vascular remodeling, angiogenesis and degradation of the extracellular matrix. Inhibitors of TGF-β signaling reduce viability and invasion of gliomas in animal models and show promises as novel, potential anti-tumor therapeutics.

Zhang L, Sun H, Zhao F, et al.
BMP4 administration induces differentiation of CD133+ hepatic cancer stem cells, blocking their contributions to hepatocellular carcinoma.
Cancer Res. 2012; 72(16):4276-85 [PubMed] Related Publications
CD133+ cancer stem cells (CSC) contribute to hepatocellular carcinoma (HCC) progression and resistance to therapy. Bone morphogenetic protein BMP4 plays an important role in hepatogenesis and hepatic stem cell differentiation, but little is known about its function in hepatic CSCs. In this study, we showed that high-dose exogenous BMP4 promotes CD133+ HCC CSC differentiation and inhibits the self-renewal, chemotherapeutic resistance, and tumorigenic capacity of these cells. Interestingly, we found that low-dose exogenous BMP4 upregulated CD133 protein expression in vitro, and endogenous BMP4 was preferentially expressed in CD133+ HCC CSCs, suggesting that low doses of BMP4 may facilitate CSC maintenance. A reduction in endogenous BMP4 levels decreased CD133 protein expression in vitro. In HCC tissues, expression of the BMP4 signaling target gene SMAD6 was positively correlated with CD133 expression. Activation of the Erk1/2 signaling pathway led to BMP4-mediated reduction in CD133 expression, which was reversed by treatment with MEK inhibitors. Taken together, our findings indicated that BMP4 might be a potent therapeutic agent in HCC that targets CSCs.

Bakhshayesh M, Zaker F, Hashemi M, et al.
TGF- β1-mediated apoptosis associated with SMAD-dependent mitochondrial Bcl-2 expression.
Clin Lymphoma Myeloma Leuk. 2012; 12(2):138-43 [PubMed] Related Publications
BACKGROUND: Transforming growth factor (TGF) β1 can elicit various cellular responses, including inhibition of cell growth, migration, differentiation, and apoptosis. In addition, TGF-β1 is able to induce apoptosis in certain lymphomas.
METHODS: In the present study, the role of SMADs, Bax, Bcl-xl, and Bcl2 was characterized in 2 B-lymphoma cell lines, Burkitt and pre-B cell.
RESULTS: Apoptosis was detected after exposure of TGF-β on Raji and Nalm 6 cell lines and was evaluated by flow cytometry by using annexin V, reverse transcriptase-polymerase chain reaction, and Western blot analysis. Flow Cytometry With Cell Sorting analysis showed that apoptosis could be observed after 24 hours of TGF-β treatment and was continued after 48 hours. TGF-β downregulated the Bcl-xl and Bcl-2, whereas the Bax was upregulated. Furthermore, messenger RNA of SMAD6 and SMAD7 showed the significant upregulation.
CONCLUSION: The results indicated that alteration in gene expression and protein level may determine the induction of apoptosis pathway in these lymphoma cell lines exposed to TGF-β.

Riester M, Taylor JM, Feifer A, et al.
Combination of a novel gene expression signature with a clinical nomogram improves the prediction of survival in high-risk bladder cancer.
Clin Cancer Res. 2012; 18(5):1323-33 [PubMed] Free Access to Full Article Related Publications
PURPOSE: We aimed to validate and improve prognostic signatures for high-risk urothelial carcinoma of the bladder.
EXPERIMENTAL DESIGN: We evaluated microarray data from 93 patients with bladder cancer managed by radical cystectomy to determine gene expression patterns associated with clinical and prognostic variables. We compared our results with published bladder cancer microarray data sets comprising 578 additional patients and with 49 published gene signatures from multiple cancer types. Hierarchical clustering was utilized to identify subtypes associated with differences in survival. We then investigated whether the addition of survival-associated gene expression information to a validated postcystectomy nomogram utilizing clinical and pathologic variables improves prediction of recurrence.
RESULTS: Multiple markers for muscle invasive disease with highly significant expression differences in multiple data sets were identified, such as fibronectin 1 (FN1), NNMT, POSTN, and SMAD6. We identified signatures associated with pathologic stage and the likelihood of developing metastasis and death from bladder cancer, as well as with two distinct clustering subtypes of bladder cancer. Our novel signature correlated with overall survival in multiple independent data sets, significantly improving the prediction concordance of standard staging in all data sets [mean ΔC-statistic: 0.14; 95% confidence interval (CI), 0.01-0.27; P < 0.001]. Tested in our patient cohort, it significantly enhanced the performance of a postoperative survival nomogram (ΔC-statistic: 0.08, 95% CI, -0.04-0.20; P < 0.005).
CONCLUSIONS: Prognostic information obtained from gene expression data can aid in posttreatment prediction of bladder cancer recurrence. Our findings require further validation in external cohorts and prospectively in a clinical trial setting.

Frullanti E, Colombo F, Falvella FS, et al.
Association of lung adenocarcinoma clinical stage with gene expression pattern in noninvolved lung tissue.
Int J Cancer. 2012; 131(5):E643-8 [PubMed] Related Publications
Associations between clinical outcome of cancer patients and the gene expression signature in primary tumors at time of diagnosis have been reported. To test whether gene expression patterns in noninvolved lung tissue might correlate with clinical stage in lung adenocarcinoma (ADCA) patients, we compared the transcriptome of noninvolved lung samples from 60 ADCA smoker patients of clinical stage I versus 60 patients with stage>I. Quantitative PCR of 10 genes with the most significant differential expression confirmed the statistical association with clinical stage in eight genes, six of which were downregulated in high-stage patients. Five of these six genes were also downregulated in lung ADCA tissue as compared to noninvolved tissue. Studies in vitro indicated that four of the genes (SLC14A1, SMAD6, TMEM100 and TXNIP) inhibited colony formation of lung cancer cell lines transfected to overexpress the genes, suggesting their potential tumor-suppressor activity. Our findings suggest that individual variations in the transcriptional profile of noninvolved lung tissue may reflect the lung ADCA patient's predisposition to tumor aggressiveness.

Yin J, Lu K, Lin J, et al.
Genetic variants in TGF-β pathway are associated with ovarian cancer risk.
PLoS One. 2011; 6(9):e25559 [PubMed] Free Access to Full Article Related Publications
The transforming growth factor-β (TGF-β) signaling pathway is involved in a diverse array of cellular processes responsible for tumorigenesis. In this case-control study, we applied a pathway-based approach to evaluate single-nucleotide polymorphisms (SNPs) in the TGF-β signaling pathway as predictors of ovarian cancer risk. We systematically genotyped 218 SNPs from 21 genes in the TGF-β signaling pathway in 417 ovarian cancer cases and 417 matched control subjects. We analyzed the associations of these SNPs with ovarian cancer risk, performed haplotype analysis and identified potential cumulative effects of genetic variants. We also performed analysis to identify higher-order gene-gene interactions influencing ovarian cancer risk. Individual SNP analysis showed that the most significant SNP was SMAD6: rs4147407, with an adjusted odds ratio (OR) of 1.60 (95% confidence interval [CI], 1.14-2.24, P = 0.0066). Cumulative genotype analysis of 13 SNPs with significant main effects exhibited a clear dose-response trend of escalating risk with increasing number of unfavorable genotypes. In gene-based analysis, SMAD6 was identified as the most significant gene associated with ovarian cancer risk. Haplotype analysis further revealed that two haplotype blocks within SMAD6 were significantly associated with decreased ovarian cancer risk, as compared to the most common haplotype. Gene-gene interaction analysis further categorized the study population into subgroups with different ovarian cancer risk. Our findings suggest that genetic variants in the TGF-β signaling pathway are associated with ovarian cancer risk and may facilitate the identification of high-risk subgroups in the general population.

Yu L, van der Valk M, Cao J, et al.
Sclerostin expression is induced by BMPs in human Saos-2 osteosarcoma cells but not via direct effects on the sclerostin gene promoter or ECR5 element.
Bone. 2011; 49(6):1131-40 [PubMed] Related Publications
Sclerostin is a secreted inhibitor of Wnt signaling and plays an essential role in the regulation of bone mass. The expression of sclerostin is largely restricted to osteocytes although its mode of transcriptional regulation is not well understood. We observed regulated expression of sclerostin mRNA and protein that was directly correlated with the mineralization response in cultured human Saos-2 osteosarcoma cells and rat primary calvarial cells. Sclerostin mRNA and protein levels were increased following treatment of cells with BMP2, BMP4 and BMP7. Analysis of deletion mutants from the -7.4 kb upstream region of the human sclerostin promoter did not reveal any specific regions that were responsive to BMPs, Wnt3a, PTH, TGFβ1 or Activin A in Saos-2 cells. The downstream ECR5 element did not show enhancer activity in Saos-2 cells and also was not affected when Saos-2 cells were treated with BMPs or PTH. Genome-wide microarray analysis of Saos-2 cells treated with BMP2 showed significant changes in expression of several transcription factors with putative consensus DNA binding sites in the region of the sclerostin promoter. However, whereas most factors tested showed either a range of inhibitory activity (DLX family, MSX2, HEY1, SMAD6/7) or lack of activity on the sclerostin promoter including SMAD9, only MEF2B showed a positive effect on both the promoter and ECR5 element. These results suggest that the dramatic induction of sclerostin gene expression by BMPs in Saos-2 cells occurs indirectly and is associated with late stage differentiation of osteoblasts and the mineralization process.

Singh P, Wig JD, Srinivasan R, Radotra BD
A comprehensive examination of Smad4, Smad6 and Smad7 mRNA expression in pancreatic ductal adenocarcinoma.
Indian J Cancer. 2011 Apr-Jun; 48(2):170-4 [PubMed] Related Publications
BACKGROUND: Smad4, Smad6 and Smad7 are important molecules in TGF-beta pathway, which plays an important role in pancreatic ductal adenocarcinoma (PDAC) biology. Aims : This study examined the expression profiles of Smad4, Smad6 and Smad7 mRNA in patient samples of PDAC and their relationship to Smad protein expression, SMAD4 gene mutations, clinicopathological parameters and patient survival.
SETTINGS AND DESIGN: Surgically resected, paired normal and tumor tissues of 25 patients of PDAC were studied.
MATERIALS AND METHODS: Protein and mRNA levels were assessed by immunohistochemistry and RT-PCR, respectively.
STATISTICAL METHODS: Statistical analysis was done using Student's t-test, Pearson's chi-square test, Spearman's Rank Correlation, Pearson's Correlation test and Kaplan-Meier Logrank test.
RESULTS: While there was a highly significant difference in the protein levels of all three Smads in tumor as compared to normal samples, mRNA levels were significantly different only for Smad4. Protein levels did not correlate significantly with mRNA levels for any of the three Smads. The mRNA levels of Smad4 and Smad6, Smad4 and Smad7, and Smad6 and Smad7 in tumor samples showed a significant positive correlation. The relationship of Smad4 mRNA expression to SMAD4 gene status and Smad4 protein expression was discordant and there was no significant correlation between mRNA expression and clinicopathological parameters and patient survival.
CONCLUSION: The absence of concordance between SMAD4 gene status, mRNA expression and Smad4 protein expression suggests the presence of other regulatory mechanisms in Smad4 transcription and translation in PDAC.

Scollen S, Luccarini C, Baynes C, et al.
TGF-β signaling pathway and breast cancer susceptibility.
Cancer Epidemiol Biomarkers Prev. 2011; 20(6):1112-9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: TGF-β acts as a suppressor of primary tumor initiation but has been implicated as a promoter of the later malignant stages. Here associations with risk of invasive breast cancer are assessed for single-nucleotide polymorphisms (SNP) tagging 17 genes in the canonical TGF-β ALK5/SMADs 2&3 and ALK1/SMADs 1&5 signaling pathways: LTBP1, LTBP2, LTBP4, TGFB1, TGFB2, TGFB3, TGFBR1(ALK5), ALK1, TGFBR2, Endoglin, SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD6, and SMAD7 [Approved Human Gene Nomenclature Committee gene names: ACVRL1 (for ALK1) and ENG (for Endoglin)].
METHODS: Three-hundred-fifty-four tag SNPs (minor allele frequency > 0.05) were selected for genotyping in a staged study design using 6,703 cases and 6,840 controls from the Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) study. Significant associations were meta-analyzed with data from the NCI Polish Breast Cancer Study (PBCS; 1,966 cases and 2,347 controls) and published data from the Breast Cancer Association Consortium (BCAC).
RESULTS: Associations of three SNPs, tagging TGFB1 (rs1982073), TGFBR1 (rs10512263), and TGFBR2 (rs4522809), were detected in SEARCH; however, associations became weaker in meta-analyses including data from PBCS and BCAC. Tumor subtype analyses indicated that the TGFB1 rs1982073 association may be confined to increased risk of developing progesterone receptor negative (PR(-)) tumors [1.18 (95% CI: 1.09-1.28), 4.1 × 10(-5) (P value for heterogeneity of ORs by PR status = 2.3 × 10(-4))]. There was no evidence for breast cancer risk associations with SNPs in the endothelial-specific pathway utilizing ALK1/SMADs 1&5 that promotes angiogenesis.
CONCLUSION: Common variation in the TGF-β ALK5/SMADs 2&3 signaling pathway, which initiates signaling at the cell surface to inhibit cell proliferation, might be related to risk of specific tumor subtypes.
IMPACT: The subtype specific associations require very large studies to be confirmed.

Butz H, Likó I, Czirják S, et al.
MicroRNA profile indicates downregulation of the TGFβ pathway in sporadic non-functioning pituitary adenomas.
Pituitary. 2011; 14(2):112-24 [PubMed] Related Publications
MicroRNAs (miRs) are small, 16-29 nucleotide long, non-coding RNA molecules which regulate the stability or translational efficiency of targeted mRNAs via RNA interference. MiRs participate in the control of cell proliferation, cell differentiation, signal transduction, cell death, and they play a role in carcinogenesis. The aims of our study were to analyse the expression profile of miRs in sporadic clinically non-functioning pituitary adenomas (NFPA) and in normal pituitary tissues, and to identify biological pathways altered in these pituitary tumors. MiR expression profiles of 12 pituitary tissue specimens (8 NFPA and 4 normal pituitary tissues) were determined using miR array based on quantitative real-time PCR with 678 different primers. Five overexpressed miRs and mRNA expression of Smads (Smad1-9), MEG and DLK1 genes were evaluated with individual Taqman assays in 10 NFPA and 10 normal pituitary tissues. Pathway analysis was performed by the DIANA-mirPath tool. Complex bioinformatical analysis by multiple algorithms and association studies between miRs, Smad3 and tumor size was performed. Of the 457 miRs expressed in both NFPA and normal tissues, 162 were significantly under- or overexpressed in NFPA compared to normal pituitary tissues Expression of Smad3, Smad6, Smad9, MEG and DLK1 was significantly lower in NFPA than in normal tissues. Pathway analysis together with in silico target prediction analysis indicated possible downregulation of the TGFβ signaling pathway in NFPA by a specific subset of miRs. Five miRs predicted to target Smad3 (miR-135a, miR-140-5p, miR-582-3p, miR-582-5p and miR-938) were overexpressed. Correlation was observed between the expression of seven overexpressed miRs and tumor size. Downregulation of the TGFβ signaling through Smad3 via miRs may have a possible role in the complex regulation of signaling pathways involved in the tumorigenesis process of NFPA.

Mangone FR, Walder F, Maistro S, et al.
Smad2 and Smad6 as predictors of overall survival in oral squamous cell carcinoma patients.
Mol Cancer. 2010; 9:106 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: To test if the expression of Smad1-8 mRNAs were predictive of survival in patients with oral squamous cell carcinoma (SCC).
PATIENTS AND METHODS: We analyzed, prospectively, the expression of Smad1-8, by means of Ribonuclease Protection Assay in 48 primary, operable, oral SCC. In addition, 21 larynx, 10 oropharynx and 4 hypopharynx SCC and 65 matched adjacent mucosa, available for study, were also included. For survival analysis, patients were categorized as positive or negative for each Smad, according to median mRNA expression. We also performed real-time quantitative PCR (QRTPCR) to asses the pattern of TGFbeta1, TGFbeta2, TGFbeta3 in oral SCC.
RESULTS: Our results showed that Smad2 and Smad6 mRNA expression were both associated with survival in Oral SCC patients. Cox Multivariate analysis revealed that Smad6 positivity and Smad2 negativity were both predictive of good prognosis for oral SCC patients, independent of lymph nodal status (P = 0.003 and P = 0.029, respectively). In addition, simultaneously Smad2- and Smad6+ oral SCC group of patients did not reach median overall survival (mOS) whereas the mOS of Smad2+/Smad6- subgroup was 11.6 months (P = 0.004, univariate analysis). Regarding to TGFbeta isoforms, we found that Smad2 mRNA and TGFbeta1 mRNA were inversely correlated (p = 0.05, R = -0.33), and that seven of the eight TGFbeta1+ patients were Smad2-. In larynx SCC, Smad7- patients did not reach mOS whereas mOS of Smad7+ patients were only 7.0 months (P = 0.04). No other correlations were found among Smad expression, clinico-pathological characteristics and survival in oral, larynx, hypopharynx, oropharynx or the entire head and neck SCC population.
CONCLUSION: Smad6 together with Smad2 may be prognostic factors, independent of nodal status in oral SCC after curative resection. The underlying mechanism which involves aberrant TGFbeta signaling should be better clarified in the future.

Lee NY, Kirkbride KC, Sheu RD, Blobe GC
The transforming growth factor-beta type III receptor mediates distinct subcellular trafficking and downstream signaling of activin-like kinase (ALK)3 and ALK6 receptors.
Mol Biol Cell. 2009; 20(20):4362-70 [PubMed] Free Access to Full Article Related Publications
Bone morphogenetic proteins (BMPs) signal through the BMP type I and type II receptors to regulate cellular processes, including embryonic development. The type I BMP receptors activin-like kinase (ALK)3 and ALK6 share a high degree of homology, yet possess distinct signaling roles. Here, we report that although the transforming growth factor (TGF)-beta type III receptor (TbetaRIII) enhanced both ALK3 and ALK6 signaling, TbetaRIII more potently enhanced ALK6-mediated stimulation of the BMP-responsive promoters XVent2 and 3GC2, and up-regulation of the early response gene Smad6. In contrast, TbetaRIII specifically enhanced ALK3-mediated up-regulation of the early response gene ID-1. TbetaRIII associated with ALK3 primarily through their extracellular domains, whereas its interaction with ALK6 required both the extracellular and cytoplasmic domains. TbetaRIII, along with its interacting scaffolding protein beta-arrestin2, induced the internalization of ALK6. In contrast, TbetaRIII colocalized with and resulted in the cell surface retention of ALK3, independently of beta-arrestin2. Although complex formation between TbetaRIII, ALK6, and beta-arrestin2 and TbetaRIII/ALK6 internalization resulted in maximal BMP signaling, the TbetaRIII mutant unable to interact with beta-arrestin2, TbetaRIII-T841A, was unable to do so. These studies support a novel role for TbetaRIII in mediating differential ALK3 and ALK6 subcellular trafficking resulting in distinct signaling downstream of ALK3 and ALK6.

Liu S, Tian Z, Yin F, et al.
Expression and functional roles of Smad1 and BMPR-IB in glioma development.
Cancer Invest. 2009; 27(7):734-40 [PubMed] Related Publications
Here we report the negative correlation of phosphorylation of Smad1 and BMPR-IB expression with the development of human glioma. Western blot analysis showed that expression of both phospho-Smad1/5/8 and BMPR-IB were decreased in malignant glioma tissues compared with normal brain tissues. Kaplan-Meier survival curves revealed that lower expression ratio of phospho-Smad1/5/8 to Smad1 expression significantly correlates with poor patient survival. Transient transfection of BMPR-IB activates Smad1 signaling and induces differentiation and apoptosis of U251 and U87 glioblastoma cells. The effects could be blocked by cotransfection of Smad6. These results might provide new molecular marker and target for glioma diagnosis and therapy.

Jeon HS, Dracheva T, Yang SH, et al.
SMAD6 contributes to patient survival in non-small cell lung cancer and its knockdown reestablishes TGF-beta homeostasis in lung cancer cells.
Cancer Res. 2008; 68(23):9686-92 [PubMed] Free Access to Full Article Related Publications
The malignant transformation in several types of cancer, including lung cancer, results in a loss of growth inhibition by transforming growth factor-beta (TGF-beta). Here, we show that SMAD6 expression is associated with a reduced survival in lung cancer patients. Short hairpin RNA (shRNA)-mediated knockdown of SMAD6 in lung cancer cell lines resulted in reduced cell viability and increased apoptosis as well as inhibition of cell cycle progression. However, these results were not seen in Beas2B, a normal bronchial epithelial cell line. To better understand the mechanism underlying the association of SMAD6 with poor patient survival, we used a lentivirus construct carrying shRNA for SMAD6 to knock down expression of the targeted gene. Through gene expression analysis, we observed that knockdown of SMAD6 led to the activation of TGF-beta signaling through up-regulation of plasminogen activator inhibitor-1 and phosphorylation of SMAD2/3. Furthermore, SMAD6 knockdown activated the c-Jun NH2-terminal kinase pathway and reduced phosphorylation of Rb-1, resulting in increased G0-G1 cell arrest and apoptosis in the lung cancer cell line H1299. These results jointly suggest that SMAD6 plays a critical role in supporting lung cancer cell growth and survival. Targeted inactivation of SMAD6 may provide a novel therapeutic strategy for lung cancers expressing this gene.

Wu WK, Sung JJ, Wu YC, et al.
Bone morphogenetic protein signalling is required for the anti-mitogenic effect of the proteasome inhibitor MG-132 on colon cancer cells.
Br J Pharmacol. 2008; 154(3):632-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND AND PURPOSE: Inhibition of proteasome has been emerging as a promising approach in pathway-directed cancer therapy. Bone morphogenetic protein (BMP) signalling, which is known to be regulated by the ubiquitin-proteasome pathway in osteoblasts, plays a crucial role in the suppression of gastrointestinal carcinogenesis. Here we sought to elucidate the anti-mitogenic effect of a proteasome inhibitor in relation to BMP signalling in colon cancer.
EXPERIMENTAL APPROACH: The effects of the proteasome inhibitor MG-132 on proliferation of SW1116 and HT-29 colon cancer cells were determined by [(3)H]-thymidine incorporation and colony-formation assay. The involvement of BMP signalling in the action of MG-132 was elucidated by western blot, real-time PCR, immunofluorescence and RNA interference.
KEY RESULTS: MG-132 significantly suppressed the proliferation of colon cancer SW1116 and HT-29 cells. In this regard, MG-132 activated BMP signalling and this was manifested as an increase in Smad1/5/8 phosphorylation and upregulation of p21(Waf1/Cip1) and p27(Kip1) expression. Knockdown of BMP receptor II abolished Smad1/5/8 phosphorylation, the induction of p21(Waf1/Cip1) and p27(Kip1) and inhibition of cell proliferation induced by MG-132. Further analysis revealed that MG-132 upregulated the expression of BMP1 and BMP2, which are secreted members of the BMP superfamily. Moreover, the expression of Smad6, an intracellular inhibitor of BMP signalling, was suppressed by MG-132.
CONCLUSIONS AND IMPLICATIONS: These findings suggest that inhibition of proteasome suppresses the proliferation of colon cancer cells via activation of BMP signalling. They also demonstrate a novel aspect of proteasome function in the regulation of colon cancer cell proliferation.

Sivertsen EA, Huse K, Hystad ME, et al.
Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells.
Eur J Immunol. 2007; 37(10):2937-48 [PubMed] Related Publications
Bone morphogenetic proteins (BMP) are multifunctional cytokines that belong to the TGF-beta superfamily. BMP have been shown to regulate haematopoietic stem cells, B lymphopoiesis and early thymocyte differentiation. In the present study we explored the role of BMP-6 in Jurkat TAg cells. BMP-6 rapidly induced phosphorylation of Smad1/5/8, p38 and ERK1/2, followed by a potent up-regulation of ID1, ID2 and ID3. ID1 and ID3 were also induced at the protein level. Genome-wide expression profiling of cells treated with BMP-6 compared to medium confirmed that ID1-ID3 were target genes of BMP-6 together with Noggin and Smad6. Furthermore, several genes involved in transcriptional regulation were also identified, including NFKBIA, HEY1, DLX2, KLF10 and early growth response 1. Stimulation with BMP-6 exerted an antiproliferative effect that was counteracted by inhibitor of DNA binding (Id)1 siRNA, indicating that Id1 is an important downstream mediator in Jurkat TAg cells. A subset of CD4(+) T cells were found to express the BMP receptors Alk-2 and Alk-3 (type I), in addition to BMPRII (type II). BMP-6 also induced phosphorylation of Smad1/5/8, followed by transcriptional increase in ID1-ID3 mRNA expression. However, we did not observe significant changes in Id protein expression in CD4(+) T cells. Altogether, the data indicate a role for BMP-6 in human T lineage cells.

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