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Bone morphogenetic protein-7 is a MYC target with pro-survival functions in childhood medulloblastoma

ABSTRACT: Medulloblastoma (MB) is the most common malignant brain tumor in children, among whom overexpression or amplification of MYC oncogenes has been associated with poor clinical outcome. Although the MYC functions during normal development and oncogenesis in various systems have been extensively investigated, the transcriptional targets mediating MYC effects in MB are still elusive. Their identification and roles during MB onset and progression are important and will ultimately suggest novel potential therapeutic targets. cDNA microarray analysis was used to compare the effects of overexpressing and silencing MYC on the transcriptome of a MB-derived cell line. We identified 209 genes with potential relevance to MYC-dependent cellular responses in MB. Among the MYC-responsive genes, we found members of the bone morphogenetic protein (BMP) signaling pathway, which plays a crucial role during the development of the cerebellum. In particular, the cytokine gene BMP7 was identified as a direct target of MYC in MB cells. Similar to the effect induced by BMP7 silencing by siRNA, the use of a small-molecule inhibitor of the BMP/SMAD signaling pathway reduced cell viability in a panel of MB cells. Altogether, our findings indicate that high MYC levels drive BMP7 expression in MB to induce pro-survival and pro-proliferative cellular pathways. This observation suggests that targeting the BMP/SMAD pathway may be a new therapeutic concept for the treatment of childhood MB.

ORGANISM(S): Homo sapiens

PROVIDER: GSE22139 | GEO | 2011/05/16

SECONDARY ACCESSION(S): PRJNA127579

REPOSITORIES: GEO

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Bone morphogenetic protein-7 is a MYC target with pro-survival functions in childhood medulloblastoma

Project description:Medulloblastoma (MB) is the most common malignant brain tumor in children, among whom overexpression or amplification of MYC oncogenes has been associated with poor clinical outcome. Although the MYC functions during normal development and oncogenesis in various systems have been extensively investigated, the transcriptional targets mediating MYC effects in MB are still elusive. Their identification and roles during MB onset and progression are important and will ultimately suggest novel potential therapeutic targets. cDNA microarray analysis was used to compare the effects of overexpressing and silencing MYC on the transcriptome of a MB-derived cell line. We identified 209 genes with potential relevance to MYC-dependent cellular responses in MB. Among the MYC-responsive genes, we found members of the bone morphogenetic protein (BMP) signaling pathway, which plays a crucial role during the development of the cerebellum. In particular, the cytokine gene BMP7 was identified as a direct target of MYC in MB cells. Similar to the effect induced by BMP7 silencing by siRNA, the use of a small-molecule inhibitor of the BMP/SMAD signaling pathway reduced cell viability in a panel of MB cells. Altogether, our findings indicate that high MYC levels drive BMP7 expression in MB to induce pro-survival and pro-proliferative cellular pathways. This observation suggests that targeting the BMP/SMAD pathway may be a new therapeutic concept for the treatment of childhood MB. 6 samples (3 replicates for each sample): wild-type MB cell line, empty vector-transfected control cell line, 2 c-MYC-overexpressing clones, 1 clone upon c-MYC silencing, 1 silencing control cell line.

2011-05-16 | E-GEOD-22139 | biostudies-arrayexpress

Transcriptomic analysis by AmpliSeq Ion Torrent to study the involvement of CXXC5 in the regulation of TGFβ/BMP target genes in glioblastoma

Project description:The aim of this work was to elucidate the role of the transcription factor CXXC5 in glioblastoma and study its involvement in the regulation of TGFβ and BMP target genes in this context. To this end we used the patient derived glioblastoma stem cells U3034MG that were either transfected with siRNA targeting CXXC5 or with a non-targeting pool (as control) followed by stimulation with either 5ng/ml TGFβ or 30ng/ml BMP7 for 24 h. Then we analysed how silencing CXXC5 affects the expression of TGFβ and/or BMP7 target genes using Ion torrent AmpliseqTM.

2021-05-01 | E-MTAB-9813 | biostudies-arrayexpress

Beta cell dysfunction and dedifferentiation induced by Bone Morphogenetic Protein (BMP)-2 is associated with histone modifications and decreased NeuroD1 chromatin binding

Project description:Insufficient insulin secretion is a hallmark of type 2 diabetes and has been attributed to beta cell identity loss characterized by a decreased expression of several key beta cell genes. The pro-inflammatory factor BMP-2 is upregulated in islets of Langerhans from diabetic individuals and acts as an inhibitor of beta cell function and proliferation. Exposure to BMP-2 induces expression of Id1-4, Hes-1 and Hey-1, transcriptional regulators associated with loss of differentiation. The aim of this study was to investigate the mechanism of BMP-2 induced beta cell dysfunction and identity loss. Mouse islets exposed to BMP-2 for 10 days showed impaired insulin secretion and beta cell proliferation. BMP-2-induced beta cell dysfunction was associated with decreased expression of beta cell specific identity and proliferation markers such as Ins1, Ucn3 and Ki67 but increased expression of Id1-4, Hes-1 and Hey-1. BMP-2 regulated mRNA expression significantly correlated with corresponding protein expression. BMP-2 induced gene expression changes were associated with a predominant reduction in the H3K27ac mark and a decrease in NeuroD1 chromatin binding activity. These results show that BMP-2-induced beta cell dysfunction is associated with epigenetic changes, predominantly a reduction in H3K27ac and a decrease in NeuroD1 DNA binding resulting in altered beta cell gene expression.

2023-07-20 | PXD036655 | Pride

Proteomic profiling of murine melanoma treated with bone morphogenetic protein (BMP) signaling inhibitor

Project description:Melanoma is a highly aggressive skin cancer, which has the fastest and second fastest growing incidence of any cancer in men and women, respectively. Although melanoma accounts for 5% of skin cancers, it is responsible for 80% of deaths related to skin cancers. The lifetime risk of melanoma is currently estimated to be 1 in 75 and is rising every year. The present study shows that inhibition of bone morphogenetic protein (BMP) signaling pathway is a potential target for treating metastatic melanoma. To characterize the underlying signaling mechanism, comparative proteomic profile of the mouse melanoma tissue treated with and BMP inhibitor (LDN193189) with untreated controls was performed using liquid chromatography-tandem mass spectrometry. Our mass spectrometry data analysis leads to identification of a total of 3231 nonredundant proteins. Of the 3231 proteins, 117 were up-regulated (fold change≥ 1.5) while 14 were down-regulated (fold change ≤ 0.66). Pathway enrichment analysis showed that altered proteins were primarily grouped into: regulation of actin cytoskeleton, phagosomes, proteoglycans in cancer, Focal adhesion, ECM receptor interaction and fatty acid metabolism pathway. Our studies suggest that inhibition of the BMP signaling cascade with small molecule inhibitors decreased the expression of the MT1 and MT2 (metallothionine 1 and 2) which are well known for the antiapoptotic, antioxidant, proliferative, and angiogenic effects in cancer.

2022-02-15 | PXD016088 | Pride

Human breast cancer cell lines: vehicle vs. BMP7 incubation

Project description:Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily of growth factors. They are known for their roles in regulation of osteogenesis and developmental processes and, in recent years, evidence has accumulated of their crucial functions in tumor biology. BMP7, in particular, has been implicated in breast cancer. However, little is known about BMP target genes in the context of tumor. We therefore explored the effects of BMP7 treatment on global gene transcription in five breast cancer cell lines during a 6-point time series. Data analysis included hierarchical clustering of differentially expressed genes, gene ontology enrichment analyses and model based clustering of temporal data. BMP7 had a strong effect on gene expression. The cellular functions most strongly affected were regulation of transcription and development. The observed transcriptional response followed a temporal sequence. Hierarchical clustering revealed distinct differences in the response of individual cell lines to BMP7, but also highlighted a synexpression group of genes. Finally, this study provides a list of potential novel BMP target genes relevant in breast cancer. Two-condition experiment, vehicle-treated vs. BMP7-treated. Five cell lines were tested at six time points each, what makes a total of 30 samples. RNA samples from three biological replicates were pooled before hybridization.

2012-03-22 | E-GEOD-31604 | biostudies-arrayexpress

Polycomb dysregulation in gliomagenesis targets a Zfp423-dependent differentiation network [ChIP-Seq]

Project description:Malignant gliomas constitute one of the most significant areas of unmet medical need, due to the invariable failure of surgical eradication and their marked molecular heterogeneity. Accumulating evidence has revealed a critical contribution by the Polycomb axis of epigenetic repression. However, a coherent understanding of the regulatory networks affected by Polycomb during gliomagenesis is still lacking. Here we integrate transcriptomic and epigenomic analyses to define Polycomb-dependent networks that promote gliomagenesis, validating them both in two independent mouse models and in a large cohort of human samples. We found that Polycomb dysregulation in gliomagenesis affects transcriptional networks associated to invasiveness and de-differentiation. The dissection of these networks uncovers Zfp423 as a crtitical Polycomb-dependent transcription factor whose silencing negatively impacts survival. The anti-gliomagenic activity of Zfp423 requires interaction with the SMAD proteins within the BMP signaling pathway, pointing to a novel synergic circuit through which Polycomb inhibits BMP signaling. Analysis of H3K27me3 distribition in two different stages of gliomagenesis

2016-03-02 | E-GEOD-76289 | biostudies-arrayexpress

Polycomb dysregulation in gliomagenesis targets a Zfp423-dependent differentiation network [RNA-Seq]

Project description:Malignant gliomas constitute one of the most significant areas of unmet medical need, due to the invariable failure of surgical eradication and their marked molecular heterogeneity. Accumulating evidence has revealed a critical contribution by the Polycomb axis of epigenetic repression. However, a coherent understanding of the regulatory networks affected by Polycomb during gliomagenesis is still lacking. Here we integrate transcriptomic and epigenomic analyses to define Polycomb-dependent networks that promote gliomagenesis, validating them both in two independent mouse models and in a large cohort of human samples. We found that Polycomb dysregulation in gliomagenesis affects transcriptional networks associated to invasiveness and de-differentiation. The dissection of these networks uncovers Zfp423 as a crtitical Polycomb-dependent transcription factor whose silencing negatively impacts survival. The anti-gliomagenic activity of Zfp423 requires interaction with the SMAD proteins within the BMP signaling pathway, pointing to a novel synergic circuit through which Polycomb inhibits BMP signaling. Transcriptomic analysis of two different stages of gliomagenesis

2016-03-02 | E-GEOD-76291 | biostudies-arrayexpress

Quantitative proteomics of the SMAD transcription factor family reveals IPO5 as a BMP Receptor-SMAD specific importin

Project description:Gene-specific transcription factors (GSTFs) control of gene transcription by DNA binding and specific protein complex recruitment, which regulates promoter accessibility for transcription initiation by RNA polymerase II. GSTFs that are frequently mutated in colon and rectal carcinomas are Suppressor of Mothers Against Decapentaplegic 2 (SMAD2) and SMAD4, which play an important role in the TGF-β signaling pathways controlling cell fate and proliferation (ref.). The SMAD protein family is a diverse and it can be divided into three subclasses: receptor activated SMADs, inhibitory SMADs and the common SMAD4 co-activator. To study protein interactors of the SMAD protein family we generated a quantitative proteomics pipeline that allows for inducible expression of GFP-tagged SMAD proteins followed by affinity purification and MS analysis. The nuclear importin IPO5 was identified as a novel interacting protein of SMAD1. Overexpression of IPO5 shows forced BMP R-SMAD nuclear localization confirming a functional relationship between BMP but not TGF-β R-SMADs and IPO5. Finally we provide evidence that the length of the lysine stretch in the NLS is involved in importin selection.

2016-10-10 | PXD004529 | Pride

Human breast cancer cell lines: vehicle vs. BMP7 incubation

2012-03-22 | GSE31604 | GEO

Neuronal target-derived gene activation mediated by widespread use of a BMP-activation element

Project description:In Drosophila, efferent neurons gain access to a target-derived BMP signal in the periphery that is required for differentiation and/or synaptic growth and neurotransmission. This requires transcriptional activity of the BMP-activated Smad transcription factors, but the Smad-bound enhancers and BMP-regulated effector genes they control remain unidentified. In the absence of insight into how BMP signaling controls these fundamental aspects of neuronal development and function, here we test whether Smads act directly at widely-deployed archetypal Smad-binding motifs to directly co-regulate batteries of BMP-responsive genes. To target these motifs for analysis, we employed a bioinformatics approach to identify candidate motifs conforming to the consensus 15bp BMP-Activation Element (BMP-AE). After filtering for high conservation and proximity to neuronally-expressed genes, we prioritized 62 BMP-AEs for analysis. Testing the in vivo enhancer activity of 58 genomic fragments containing these BMP-AEs in transgenic reporters, we show that 61% are functional BMP enhancers in diverse motoneuron and neuropeptidergic neuronal populations, and that the BMP-AE motif itself is required for activity. Moreover, 60% of these functional BMP-AEs were located within 20kb of at least one BMP activated gene, as identified by RNAseq analysis. Finally, we show that the BMP-AE motif plays a conserved activator function in the vertebrate nervous system, by electroporation in the developing chick neural tube. Our results provide evidence that BMP signaling controls neuronal development and function by directly coordinating networks of genes through widespread deployment of conserved, consensus Smad-binding motifs.

2018-10-25 | GSE106650 | GEO

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