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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Schwann cell is a cell type that forms myelin sheath and provides trophic supports for neuronal cells by producing neurotrophic factors in both normal and traumatic situations. It was recently reported that after lesion of sciatic nerve, mRNA for glial cell line-derived neurotrophic factor (GDNF) is induced in nonneuronal cells in the nerve. However, the mechanism regulating GDNF-mRNA has remained largely unknown. In the present study, we searched for factors regulating the GDNF-mRNA expression in Schwann cells. First, we found that after transfer into explant culture as an in vitro lesion model, sciatic nerve segments began to express mRNA for bone morphogenetic protein-2 (BMP2) concomitantly with the induction of GDNF-mRNA. Treatment of the Schwann cells isolated from the sciatic nerve with combination of BMP2 and retinoic acid (RA) dramatically induced GDNF-mRNA, while BMP2 or RA alone had no effect. Furthermore, ionomycin, a calcium ionophore, which had even stronger activity on the induction of GDNF-mRNA also induced also BMP2-mRNA in cultured Schwann cells. Effects of inhibitors of intracellular signaling pathways such as protein kinase C inhibitor and MAPKK inhibitor suggested that the molecular mechanism of the induction of GDNF-mRNA is distinct from that of BMP2-mRNA. These results suggest that the Schwann cell-produced BMP2 plays an important role in the induction of GDNF after nerve injury in an autocrine fashion.
Brain Res Mol Brain Res 2003 Oct 07
PMID:Autocrine action of BMP2 regulates expression of GDNF-mRNA in sciatic Schwann cells. 1455 57

We have previously shown that Nkx3.2, a transcriptional repressor that is expressed in the sclerotome and developing cartilage, can activate the chondrocyte differentiation program in somitic mesoderm in a bone morphogenetic protein (BMP)-dependent manner. In this work, we elucidate how BMP signaling modulates the transcriptional repressor activity of Nkx3.2. We have found that Nkx3.2 forms a complex, in vivo, with histone deacetylase 1 (HDAC1) and Smad1 and -4 in a BMP-dependent manner. The homeodomain and NK domain of Nkx3.2 support the interaction of this transcription factor with HDAC1 and Smad1, respectively, and both of these domains are required for the transcriptional repressor activity of Nkx3.2. Furthermore, the recruitment of an HDAC/Sin3A complex to Nkx3.2 requires that Nkx3.2 interact with Smad1 and -4. Indeed, Nkx3.2 both fails to associate with the HDAC/Sin3A complex and represses target gene transcription in a cell line lacking Smad4, but it performs these functions if exogenous Smad4 is added to these cells. While prior work has indicated that BMP-dependent Smads can support transcriptional activation, our findings indicate that BMP-dependent Smads can also potentiate transcriptional repression, depending upon the identity of the Smad-interacting transcription factor.
Mol Cell Biol 2003 Dec
PMID:Smad-dependent recruitment of a histone deacetylase/Sin3A complex modulates the bone morphogenetic protein-dependent transcriptional repressor activity of Nkx3.2. 1461 11

Smad6 and Smad7 are inhibitory Smads induced by transforming growth factor beta-Smad signal transduction pathways in a negative-feedback mechanism. Previously it has been thought that inhibitory Smads bind to the type I receptor and block the phosphorylation of receptor-activated Smads, thereby inhibiting the initiation of Smad signaling. Conversely, few studies have suggested the possible nuclear functions of inhibitory Smads. Here, we present compelling evidence demonstrating that Smad6 repressed bone morphogenetic protein-induced Id1 transcription through recruiting transcriptional corepressor C-terminal binding protein (CtBP). A consensus CtBP-binding motif, PLDLS, was identified in the linker region of Smad6. Our findings show that mutation in the motif abolished the Smad6 binding to CtBP and subsequently its repressor activity of transcription. We conclude that the nuclear functions and physical interaction of Smad6 and CtBP provide a novel mechanism for the transcriptional regulation by inhibitory Smads.
Mol Cell Biol 2003 Dec
PMID:Smad6 recruits transcription corepressor CtBP to repress bone morphogenetic protein-induced transcription. 1464 20

The mechanisms controlling differentiation and lineage specification of neural stem cells are still poorly understood, and many of the molecules involved in this process and their specific functions are yet unknown. We investigated the effect of apoptosis signal-regulating kinase 1 (ASK1) on neural stem cells by infecting adult hippocampus-derived rat progenitors with an adenovirus encoding the constitutively active form of ASK1. Following ASK1 overexpression, a significantly larger number of cells differentiated into neurons and a substantial increase in Mash1 transcription was observed. Moreover, a marked depletion of glial cells was observed, persisting even after additional treatment of ASK1-infected cultures with potent glia inducers such as leukemia inhibitory factor and bone morphogenetic protein. Analysis of the promoter for glial fibrillary acidic protein revealed that ASK1 acts as a potent inhibitor of glial-specific gene transcription. However, the signal transducers and activators of transcription 3 (STAT3)-binding site in the promoter was dispensable, while the activation of p38 mitogen-activated protein kinase was crucial for this effect, suggesting the presence of a novel mechanism for the inhibition of glial differentiation.
Mol Cell Biol 2004 Jan
PMID:ASK1 inhibits astroglial development via p38 mitogen-activated protein kinase and promotes neuronal differentiation in adult hippocampus-derived progenitor cells. 1467 62

To date, the only neurotrophin that has been shown to influence the development of the enteric nervous system (ENS) is neurotrophin-3 (NT-3). NT-3 plays an essential role in the development of both the neural-crest-derived peripheral nervous system and the central nervous system (i.e., Chalazonitis, 1996, Mol. Neurobiol., 12: 39-53; Sieber-Blum, 1999, Neurotrophins and the Neural Crest, CRC Press, Boca Raton). This review integrates data obtained from our laboratory and from our collaboration with other investigators that demonstrate a late-acting role for NT-3 in the development of enteric neurons in vitro and in vivo. Studies of the biological actions of NT-3 on enteric neuronal precursors in vitro demonstrate that NT-3 acts directly on the precursor cells and that it also acts in combination with other neurotrophic factors such as glial cell line-derived neurotrophic factor and a ciliary neurotrophic factor-like molecule, to promote the survival and differentiation of enteric neurons and glia. Importantly, bone morphogenetic protein-2 (BMP-2) and BMP-4, members of the transforming growth factor-beta (TGF-beta) superfamily, regulate the onset of action of NT-3 during fetal gut development. Analyzes performed on mice deficient in the genes encoding NT-3 or its transducing tyrosine kinase receptor, TrkC, and conversely on transgenic mice that overexpress NT-3 substantiate a physiological role for NT-3 in the development and maintenance of a subset of enteric neurons. There is loss of neurons in both the myenteric and submucosal plexuses of mice lacking NT-3/TrkC signaling and selective hyperplasia in the myenteric plexus of mice overexpressing NT-3. Analyzes performed on transgenic mice that overexpress noggin, a specific BMP-4 antagonist, show significant decreases in the density of TrkC-expressing neurons but significant increase in overall neuronal density of both plexuses. Conversely, overexpression of BMP-4 is sufficient to produce, an increase in the proportion of TrkC-expressing neurons in both plexuses. Overall, our data point to a regulatory role of BMP-4 in the responses of subsets of myenteric and submucosal neurons to NT-3. NT-3 is required for the differentiation, maintenance and proper physiological function of late-developing enteric neurons that are important for the control of gut peristalsis.
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PMID:Neurotrophin-3 in the development of the enteric nervous system. 1469 68

Transforming growth factor beta (TGF-beta)/bone morphogenetic protein (BMP) family ligands interact with specific membrane receptor complexes that have serine/threonine kinase activities. The receptor phosphorylation and activation induced by the ligands leads to phosphorylation of the Smad proteins, which translocate to the nucleus, controlling gene expression. Thus, regulation of Smad proteins is a key step in TGF-beta/BMP-induced signal transduction. Here we report a novel mechanism of the regulation of SMAD-mediated signaling, by which the Smad1 protein level is controlled through expression of the CHIP protein. CHIP is a U-box-dependent E3 ubiquitin ligase, previously identified as a cochaperon protein. However, we have isolated CHIP as a Smad-interacting protein in a yeast two-hybrid screen using Smad1 as bait. Furthermore we have shown CHIP-Smad interaction using the (35)S-labeled CHIP protein, which can interact with glutathione S-transferase (GST)-Smad1 and GST-Smad4 in an in vitro protein-binding assay. The CHIP-Smad interaction has been confirmed in vivo in mammalian cells through coimmunoprecipitation. Interestingly, we demonstrate that the coexpression of Smad1 and Smad4 with the CHIP protein results in the degradation of the Smad proteins through a ubiquitin-mediated process. Consistent with the observation that CHIP induces Smad1 degradation, we further show that the expression of CHIP can inhibit the transcriptional activities of the Smad1/Smad4 complex induced by BMP signals. Intriguingly, pBS/U6/CHIPi, which diminishes CHIP expression, significantly enhanced Smad1/Smad4- or BMPRIB(QD)-induced gene transcription. These results suggest that CHIP can interact with the Smad1/Smad4 proteins and block BMP signal transduction through the ubiquitin-mediated degradation of Smad proteins.
Mol Cell Biol 2004 Jan
PMID:CHIP mediates degradation of Smad proteins and potentially regulates Smad-induced transcription. 1470 56

Transforming growth factor beta (TGFbeta) and hepatocyte growth factor (HGF) promote glioma progression. Using U87human astrocytoma cells, which express TGFbeta receptors (TbetaRs), we show (1) mRNA expression of Smads (2, 3, 4), bone morphogenetic protein (BMP)- and activin-A receptors; (2) TGFbeta1 inhibits and HGF induces proliferation; (3) TGFbeta1 and activin-A equipotently inhibit HGF secretion more than BMP-2, but none alters c-Met expression. Because interfering with TbetaR signaling might nullify the beneficial inhibition of HGF secretion, activin-A should instead be considered for combination glioma therapy.
Brain Res Mol Brain Res 2004 Feb 05
PMID:Transforming growth factor beta receptor family ligands inhibit hepatocyte growth factor synthesis and secretion from astrocytoma cells. 1496 47

Delivery of genes to the pulmonary vascular endothelium is a rational approach for the investigation and potential therapy of pulmonary vascular diseases. Furthermore, in view of the exposure of this vascular bed to the entire cardiac output, this technique could be used as an efficient basis to achieve systemic delivery of secreted factors. The attraction of direct gene delivery to endothelium for the therapy of vascular disease has been especially heightened in the last couple of years in view of the new discoveries concerning the genetic basis of primary pulmonary hypertension (PPH). In brief, mutations in the bone morphogenetic protein receptor type 2 (BMPR2, a member of the transforming growth factor-beta [TGF-beta] family of receptors) gene have been found in many patients with familial PPH. Subsequent in vitro studies have confirmed an association between BMPR2 mutations and abnormal proliferative responses in pulmonary endothelial and smooth-muscle cells (2). Other TGF-beta signaling pathways may also be involved in this process, and the mechanisms involved may also have relevance for the more common cases of pulmonary vascular disease secondarily associated with chronic airways obstruction, connective tissue diseases, and perhaps HIV infection. Additionally, new evidence is emerging concerning the role of the vasculature in the pathogenesis of emphysema.
Methods Mol Biol 2004
PMID:Delivery of DNA to pulmonary endothelium using adenoviral vectors. 1497 May 86

A ligand-receptor pair, bone morphogenetic protein-7 (BMP7) and activin receptor IIB (actRIIB), was identified from a pool of DNA fragments recovered from MCF7 cells treated with 17beta-estradiol (E2) by chromatin immunoprecipitation with antiestrogen receptor-alphaantibody. The E2 responsiveness of both genes was confirmed in MCF cells and in the mouse uterus. Repeated treatment with E2 resulted in decreased expression of both actRIIB and BMP7 mRNA in the uteri of ovariectomized mice. A single oral administration of bisphenol A (BPA), an environmental estrogen, inhibited actRIIB and BMP7 expression and apoptosis in the luminal epithelium of the mouse uterus at diestrus (or early proestrus). This decrease, due to BPA administration, was restored by an estrogen receptor (ER) antagonist suggesting that it is mediated through ERs. These results suggest that E2 and BPA suppress estrogen-dependent apoptosis of epithelial cells of the endometrium through down-regulation of actRIIB and BMP7. Thus, we propose that BMP7 and actRIIB, a ligand-receptor pair, are involved in regulation of the apoptotic signaling pathway and might therefore be new biomarkers of the effects of environmental estrogens on the female reproductive tract.
J Biochem Mol Toxicol 2004
PMID:BMP7/ActRIIB regulates estrogen-dependent apoptosis: new biomarkers for environmental estrogens. 1499 73

Primary pulmonary hypertension (PPH) is defined clinically by sustained elevation of pulmonary arterial pressure without a demonstrable cause, and is a progressive, often-fatal disease. PPH can be associated with ingestion of appetite suppressants, human immunodeficiency virus infection and certain autoimmune diseases. Familial PPH is known to account for 6% of all cases. Mutations in the gene encoding the bone morphogenetic protein (BMP) type II receptor have been identified in 72% of affected families and 26% of apparently sporadic cases. BMPs are members of the transforming growth factor b superfamily and affect intracellular signalling via Smads and mitogen-activated protein kinases. Evidence supports a 'two-hit' hypothesis in which PPH is triggered by accumulation of genetic and environmental insults in a susceptible individual. Elucidation of the precise molecular and cellular mechanisms underlying PPH will provide a powerful basis for the development of novel therapeutic strategies in the treatment of this devastating condition.
Expert Rev Mol Med 2004 Mar 09
PMID:Primary pulmonary hypertension: molecular basis and potential for therapy. 1500 57


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