Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The active form of the Xenopus X-box binding protein 1 (xXBP1) partially synergizes and partially antagonizes with BMP-4 signaling. xXBP1 overexpression inhibits mesoderm differentiation and formation of neural tissues. A functional knockdown promotes differentiation of lateral and dorsal mesoderm but not of ventral mesoderm and of neuroectoderm. We show that the active form of xXBP1 in gastrula and early neurula stage embryos is generated by removal of exon 4 and not by an endoribonuclease activity in the endoplasmic reticulum. The N-terminal region of xXBP1 which contains the basic leucine-zipper also contains a nuclear localization signal and both, the N-terminal as well as the C-terminal regions are required for xXBP1 function. The effects of xXBP1 are in part correlated to a regulatory loop between xXBP1 and BMP-4. xXBP1 and BMP-4 stimulate mutually the transcription of each other, but xXBP1 inhibits the BMP-4 target gene, Xvent-2. Both, in vitro and in vivo assays demonstrate that xXBP1 interacts with BMP-4 and Xvent-2B promoters. GST-pulldown assays reveal that xXBP1 can interact with c-Jun, the transcriptional co-activator p300 and with the BMP-4 responsive Smad1. On the other hand, xXBP1 also binds to the inhibitory Smads, Smad6 and Smad7, that can act as transcriptional co-repressors. Based on these data, we conclude that xXBP1 might function as an inhibitor of mesodermal and neural tissue formation by acting either as transcriptional activator or as repressor. This dual activity depends upon binding of co-factors being involved in the formation of distinct transcription complexes.
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PMID:XBP1 forms a regulatory loop with BMP-4 and suppresses mesodermal and neural differentiation in Xenopus embryos. 1627 78

The intensity and duration of activation of a signal transduction system are important determinants of the specificity of the cellular response to the stimulus. It is unclear how different cells can generate a signal of varying intensity and duration in response to the same cytokine. We investigated the role of the transcriptional activator and Smad1/4 cofactor OAZ in regulating bone morphogenetic protein (BMP) signaling. We demonstrate that upon BMP4 stimulation, an OAZ-Smad1/4 complex binds to and activates the gene encoding Smad6, a specific inhibitor of the BMP pathway. Removal of endogenous OAZ from pluripotent embryonal carcinoma cells prevents the induction of Smad6 by BMP4 and extends the period of detection of phosphorylated Smad1 after BMP stimulation. Conversely, in cells that do not normally express OAZ, such as myoblasts and smooth muscle cells, forced OAZ expression leads to faster and higher Smad6 induction in response to BMP4, decrease of Smad1 phosphorylation, and attenuation of BMP-mediated responses. Our results demonstrate that OAZ can alter the intensity and duration of the BMP stimulus through Smad6 and indicate that the tissue-specific expression of OAZ is a critical determinant of the cellular response to the BMP signal.
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PMID:OAZ regulates bone morphogenetic protein signaling through Smad6 activation. 1637 39

BMPs and Hox proteins play crucial roles in developmental processes. Beyond their mutual regulation of gene expression, little is known about the relations between their mechanisms of actions. Previously, we have shown that Hoxc8 acts as a downstream repressor in the BMP signaling pathway. Smad1 and Smad6 interact with Hoxc8 and regulate its repression activities. The Hox family contains 39 genes divided into 13 paralogs. In this report, we systemically examined the potential functions of all the paralogous Hox proteins as BMP downstream transcription factors. Representative Hox proteins from each paralog were tested. In the gel-shift assay, we found that Smad1, Smad4, and Smad6 interacted with most of the Hox proteins in ways similar to their interactions with Hoxc8. The interactions were confirmed in mammalian cells. We also examined the effects of Smads on Hox-induced transactivation. Particularly, we determined that for Hoxd10 as a transcriptional activator, both Smad1 and Smad6 opposed its activity. In addition, Smad6 also inhibited Hoxc8- and Hoxb7-induced osteoprotegerin (OPG) transactivation. Furthermore, Smad1 inhibited Hoxb4-mediated target gene Irx5 expression during early Xenopus development. Our findings suggest that Hox proteins act as general downstream DNA-binding proteins in BMP signaling cascade and their transcriptional activities are regulated by Smads.
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PMID:Smads oppose Hox transcriptional activities. 1640 60