Abstract
TGF-beta signaling is essential for development and proliferative homeostasis. During embryogenesis, maternal determinants act in concert with TGF-beta signals to form mesoderm and endoderm. In contrast, ectoderm specification requires the TGF-beta response to be attenuated, although the mechanisms by which this is achieved remain unknown. In a functional screen for ectoderm determinants, we have identified Ectodermin (Ecto). In Xenopus embryos, Ecto is essential for the specification of the ectoderm and acts by restricting the mesoderm-inducing activity of TGF-beta signals to the mesoderm and favoring neural induction. Ecto is a RING-type ubiquitin ligase for Smad4, a TGF-beta signal transducer. Depletion of Ecto in human cells enforces TGF-beta-induced cytostasis and, moreover, plays a causal role in limiting the antimitogenic effects of Smad4 in tumor cells. We propose that Ectodermin is a key switch in the control of TGF-beta gene responses during early embryonic development and cell proliferation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Base Sequence
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Blastula / cytology
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Blastula / metabolism*
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Bone Morphogenetic Protein Receptors
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Cell Differentiation / physiology
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Cell Nucleus / metabolism*
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Cell Proliferation
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Cells, Cultured
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Colon / cytology
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Colon / metabolism
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / pathology
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Gene Library
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Germ Layers / cytology
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Germ Layers / metabolism*
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Humans
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Molecular Sequence Data
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Receptors, Growth Factor / metabolism
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Signal Transduction / physiology
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Smad4 Protein
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transforming Growth Factor beta / metabolism
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Tripartite Motif Proteins
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Xenopus / embryology
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Xenopus Proteins / genetics
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Xenopus Proteins / metabolism*
Substances
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DNA-Binding Proteins
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Receptors, Growth Factor
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SMAD4 protein, human
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Smad4 Protein
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Trans-Activators
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Transforming Growth Factor beta
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Tripartite Motif Proteins
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Xenopus Proteins
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Ubiquitin-Protein Ligases
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trim33 protein, Xenopus
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Bone Morphogenetic Protein Receptors