Expression profiling in palatal mesenchymal cells stimulated with TGF-beta2 in the presence and absence of TGFbRI and Tak1 kinase inhibitors
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE45491 | GEO | 2013/03/27
SECONDARY ACCESSION(S): PRJNA194531
REPOSITORIES: GEO
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Project description:TGF-beta signaling in neural crest cells is required for normal craniofacial development. This signaling can be transduced via TGF-beta type I receptors (TGFbRI) using Smad-dependent or Smad independent signaling pathways. We used microarrays to identify TGF-beta-responsive genes that are dependent either on TGFbRI kinase, Tak1 kinase or both. Primary palatal mesenchymal cell cultures were established. Cultured cells were stimulated with TGF-beta2 in the presence or absence of TGFbRI kinase and Tak1 kinase inhibitors. Unstimulated cells were used as controls. Total RNAs were isolated and hybridized on Affymetrix microarrays.
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Project description:Transforming growth factor-b (TGF-b) regulates various aspects of vascular development, yet the signaling mechanisms of TGF-b in the control of angiogenesis remain poorly characterized. Here we show that homeodomain interacting protein kinases, HIPK1 and HIPK2, are transcriptional corepressors that regulate TGF-b-depednent angiogenesis during embryonic development. Loss of HIPK1 and HIPK2 leads to marked up-regulations of several potent angiogenic genes, including Vegf and Mmp10, which result in excessive endothelial proliferation and poor adherens junction formation. This robust phenotype can be recapitulated by siRNA knock down of Hipk1 and Hipk2 in human umbilical vein endothelial cells, as well as in endothelial cell-specific TGF-b type II receptor (TbRII) conditional mutants. The effects of HIPK proteins are mediated through its interaction with MEF2C and HDAC7, and this interaction can be further enhanced by TGF-b and TAK1. Remarkably, TGF-b-TAK1 signaling activates HIPK2 by phosphorylating a highly conserved tyrosine residue Y-361 within the kinase domain. Point mutation in this tyrosine completely eliminates the effect of HIPK2 in the transcriptional suppression of target genes. Together, these results reveal a previously unrecognized role of HIPK proteins in connecting TGF-b signaling pathway with the transcriptional programs for angiogenesis in early embryonic development.
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Project description:Transforming growth factor-b (TGF-b) regulates various aspects of vascular development, yet the signaling mechanisms of TGF-b in the control of angiogenesis remain poorly characterized. Here we show that homeodomain interacting protein kinases, HIPK1 and HIPK2, are transcriptional corepressors that regulate TGF-b-depednent angiogenesis during embryonic development. Loss of HIPK1 and HIPK2 leads to marked up-regulations of several potent angiogenic genes, including Vegf and Mmp10, which result in excessive endothelial proliferation and poor adherens junction formation. This robust phenotype can be recapitulated by siRNA knock down of Hipk1 and Hipk2 in human umbilical vein endothelial cells, as well as in endothelial cell-specific TGF-b type II receptor (TbRII) conditional mutants. The effects of HIPK proteins are mediated through its interaction with MEF2C and HDAC7, and this interaction can be further enhanced by TGF-b and TAK1. Remarkably, TGF-b-TAK1 signaling activates HIPK2 by phosphorylating a highly conserved tyrosine residue Y-361 within the kinase domain. Point mutation in this tyrosine completely eliminates the effect of HIPK2 in the transcriptional suppression of target genes. Together, these results reveal a previously unrecognized role of HIPK proteins in connecting TGF-b signaling pathway with the transcriptional programs for angiogenesis in early embryonic development. In this study, a total of 36,000 transcripts and ESTs (a total of 30,000 unique genes) was used to acquire expression profiles among the control, Hipk1-/-, Hipk2-/-, and Hipk1-/-;Hipk2-/- E9.5 embryos. This will allow us unsupervised and successfully to analyze the transcriptomes and finally to reveal the role of HIPK1 and HIPK2 in the signal transduction mechanism downstream of TGF-b and the transcriptional control of angiogenic gene expression during the critical stages of vascular morphogenesis.
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Project description:The NFκB transcription factor is constitutively active in a number of hematologic and solid tumors, and many signaling pathways implicated in cancer are likely connected to NFκB activation. A critical mediator of NFκB activity is TGFβ-activated kinase 1 (TAK1). Here, we identify TAK1 as a novel interacting protein and direct target of fibroblast growth factor receptor 3 (FGFR3) tyrosine kinase activity. We further demonstrate that activating mutations in FGFR3 associated with both multiple myeloma and bladder cancer can modulate expression of genes which regulate NFκB signaling, and promote both NFκB transcriptional activity and cell adhesion in a manner dependent on TAK1 expression in both cancer cell types. Our findings suggest TAK1 as a potential therapeutic target for FGFR3-associated cancers, and other malignancies in which TAK1 contributes to constitutive NFκB activation.
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