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Query: UNIPROT:P06889 (Mol)
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Human embryonic stem (ES) cells can proliferate without a known limit and can form advanced derivatives of all three embryonic germ layers. What is less widely appreciated is that human ES cells can also form the extra-embryonic tissues that differentiate from the embryo before gastrulation. The use of human ES cells to derive early human trophoblast is particularly valuable, because it is difficult to obtain from other sources and is significantly different from mouse trophoblast. Here we describe a method by using bone morphogenetic protein (BMP)4, a member of the transforming growth factor (TGF)-beta superfamily, to induce the differentiation of human ES cells to trophoblast. Immunoassays (as well as DNA microarray and reverse-transcription polymerase chain reaction analyses--data not shown) demonstrate that the differentiated cells express a range of trophoblast markers and secrete placental hormones. When plated at low density, the BMP4-treated cells form syncytia that express chorionic gonadotrophin (CG). This technique underscores fundamental differences between human and mouse ES cells, which differentiate poorly, if at all, to trophoblast. Human ES cells thus provide a tool for studying the differentiation and function of early human trophoblast and could provide a new understanding of some of the earliest differentiation events of human postimplantation development.
Methods Mol Med 2006
PMID:In vitro induction of trophoblast from human embryonic stem cells. 1625 44

Heterozygous mutations in the type II receptor for bone morphogenetic protein (BMPR-II) and dysfunction of BMPR-II have been implicated in patients with primary pulmonary hypertension (PH). To clarify the possible involvement of BMP and BMPR-II in the development of hypoxic PH, the expression of BMP-2, BMPR-II, and their downstream signals were investigated in rat lung under normal and hypoxic conditions by RT-PCR, immunoblot, and immunohistochemical methods. In rats under normal conditions, BMP-2 is localized in the endothelium of the pulmonary artery, whereas BMPR-II is abundantly expressed in the endothelium, smooth muscle cells, and adventitial fibroblasts. After 0.5 and 3 days of exposure to hypoxia, upregulation of BMP-2 was observed in the intrapulmonary arteries. The change was accompanied by activation of its downstream signaling, p38 MAPK, and Erk1/2 MAPK, and the apoptotic process, measured by caspase-3 activity and TdT-mediated dUTP nick end labeling-positive cells. In contrast, a significant decrease in the expression of BMPR-II and inactivation of p38 MAPK and caspase-3 were observed in the pulmonary vasculature after 7-21 days of hypoxia exposure. Because BMP-2 is known to inhibit proliferation of vascular smooth muscle cells and promote cellular apoptosis, disruption of BMP signaling pathway through downregulation of BMPR-II in chronic hypoxia may result in pulmonary vascular remodeling due to the failure of critical antiproliferative/differentiation programs in the pulmonary vasculature. These results suggest abrogation of BMP signaling may be a common molecular pathogenesis in the development of PH with various pathophysiological events, including primary and hypoxic PH.
Am J Physiol Lung Cell Mol Physiol 2006 Mar
PMID:Downregulation of type II bone morphogenetic protein receptor in hypoxic pulmonary hypertension. 1636 57

The survival of cardiomyocytes is regulated by growth factors and cytokines such as bone morphogenetic protein (BMP) 2 and leukemia inhibitory factor (LIF). BMP2 and LIF induce distinct signal transduction pathways that each activate a different transcription factor [Smad1 and signal transducing activating transcriptional factor (Stat) 3, respectively] and common signal pathway [mitogen-activated protein kinase (MAPK)]. We previously demonstrated that BMP2 and LIF protect cardiomyocytes via Smad1 and STAT3 signaling pathways, respectively. On the other hand, these signals are known to act in synergy via synergistic integration of signaling pathways. Here, we examined interaction between BMP2 and LIF in primary cultured neonatal rat cardiomyocytes. LIF sustained phosphorylation/activation of Smad1 by BMP2. The role of extracellular signal-regulated kinase (ERK) 1/2 cascade activated by LIF was highlighted by the use of a MAPK/ERK kinase (MEK) 1/2 inhibitor, U0126, or overexpression of dominant-negative form of MEK1 that abolished sustained phosphorylation of Smad1 and cell survival effect induced by co-stimulation of LIF with BMP2, while BMP2 alone did not activate ERK1/2. Conversely, overexpression of the constitutive-active form of MEK1 increased BMP2-induced phosphoration of Smad1 without additional LIF. Moreover, BMP2 and LIF synergistically induced bcl-xL mRNA in doxorubicin (DOX)-injured cardiomyocytes. These findings suggest that the ERK1/2 pathway downstream of LIF is involved in sustained phosphorylation/activation of Smad1 by BMP2 and provide a possible mechanism for cooperation between intracellular signals activated by LIF and BMP2 in protection against DOX-induced injury of cardiomyocytes.
J Mol Cell Cardiol 2006 Feb
PMID:Cross-talk between bone morphogenetic protein 2 and leukemia inhibitory factor through ERK 1/2 and Smad1 in protection against doxorubicin-induced injury of cardiomyocytes. 1642 75

The bone morphogenetic protein (BMP)2 gene has been genetically linked to osteoporosis and osteoarthritis. We have shown that the 3'-untranslated regions (UTR) of BMP2 genes from mammals to fishes are extraordinarily conserved. This indicates that the BMP2 3'-UTR is under stringent selective pressure. We present evidence that the conserved region is a strong posttranscriptional regulator of BMP2 expression. Polymorphisms in cis-regulatory elements have been proven to influence susceptibility to a growing number of diseases. A common single nucleotide polymorphism (SNP) disrupts a putative posttranscriptional regulatory motif, an AU-rich element, within the BMP2 3'-UTR. The affinity of specific proteins for the rs15705 SNP sequence differs from their affinity for the normal human sequence. More importantly, the in vitro decay rate of RNAs with the SNP is higher than that of RNAs with the normal sequence. Such changes in mRNA:protein interactions may influence the posttranscriptional mechanisms that control BMP2 gene expression. The consequent alterations in BMP2 protein levels may influence the development or physiology of bone or other BMP2-influenced tissues.
Mol Endocrinol 2006 Jul
PMID:A polymorphism in a conserved posttranscriptional regulatory motif alters bone morphogenetic protein 2 (BMP2) RNA:protein interactions. 1649 30

We investigated the action of 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], a novel Gemini vitamin D(3) analog Ro-438-3582 [1alpha,25-dihydroxy-20S-21(3-hydroxy-3-methyl-butyl)-23-yne-26,27-hexafluorocholecalciferol (Ro3582)], and a classic vitamin D(3) analog Ro-26-2198 [1alpha,25-dihydroxy-16,23(Z)-diene-26,27-hexafluoro-19-nor-cholecalciferol (Ro2198)] in modulating the transforming growth factor-beta (TGF-beta)/bone morphogenetic protein (BMP) system in MCF10 immortalized breast epithelial cells. We found that 1alpha,25(OH)(2)D(3), Ro3582, and Ro2198 all enhanced BMP/Smad signaling by increasing the phosphorylation of receptor-regulated Smads. Ro3582 was more active than Ro2198, but both were considerably more active than 1alpha,25(OH)(2)D(3.) Ro3582 enhanced BMP/Smad signaling by 1) inducing the phosphorylation of receptor-regulated Smads (Smad1/5), 2) increasing the accumulation of phosphorylated Smad1/5 in the nucleus, and 3) activating BMP-mediated transcription in MCF10 breast epithelial cells. Furthermore, Ro3582 induced the synthesis of BMP-2 and BMP-6 mRNA and protein, and the expression of Smad6 mRNA in MCF10 breast epithelial cells was inhibited by Ro3582. The induction of phospho-Smad1/5 by Ro3582 was inhibited by treatment with the BMP antagonist Noggin, whereas neutralizing antibody to TGF-beta did not block the induction of phospho-Smad1/5 by Ro3582. Treatment with Noggin also blocked the effect of Ro3582 on nuclear accumulation of phospho-Smad1/5 and the induction of BMP-2 and BMP-6 mRNA synthesis. These results indicate that the activation of BMP/Smad signaling by the Gemini vitamin D(3) analog Ro3582 may be through the production of BMP ligands, including BMP-2 and BMP-6, and/or down-regulation of the inhibitory Smad6. This is the first report to show that 1alpha,25(OH)(2)D(3) and its derivatives activate BMP/Smad-specific signaling in human breast epithelial cells.
Mol Pharmacol 2006 Jun
PMID:A novel vitamin D derivative activates bone morphogenetic protein signaling in MCF10 breast epithelial cells. 1653 9

FGF8, a member of the fibroblast growth factor (FGF) family, has been shown to play important roles in different developing systems. Mouse embryonic carcinoma P19 cells could be induced by retinoic acid (RA) to differentiate into neuroectodermal cell lineages, and this process is cell aggregation dependent. In this report, we show that FGF8 expression is transiently up-regulated upon P19 cell aggregation, and the aggregation-dependent FGF8 elevation is pluripotent stem cell related. Overexpressing FGF8 promotes RA-induced monolayer P19 cell neural differentiation. Inhibition of FGF8 expression by RNA interference or blocking FGF signaling by the FGF receptor inhibitor, SU5402, attenuates neural differentiation of the P19 cell. Blocking the bone morphogenetic protein (BMP) pathway by overexpressing Smad6 in P19 cells, we also show that FGF signaling plays a BMP inhibition-independent role in P19 cell neural differentiation.
Mol Biol Cell 2006 Jul
PMID:Cell aggregation-induced FGF8 elevation is essential for P19 cell neural differentiation. 1664 68

The transforming growth factor beta (TGF-beta) superfamily, including the bone morphogenetic protein (BMP) and TGF-beta/activin A subfamilies, is regulated by secreted proteins able to sequester or present ligands to receptors. KCP is a secreted, cysteine-rich (CR) protein with similarity to mouse Chordin and Xenopus laevis Kielin. KCP is an enhancer of BMP signaling in vertebrates and interacts with BMPs and the BMP type I receptor to promote receptor-ligand interactions. Mice homozygous for a KCP null allele are hypersensitive to developing renal interstitial fibrosis, a disease stimulated by TGF-beta but inhibited by BMP7. In this report, the effects of KCP on TGF-beta/activin A signaling are examined. In contrast to the enhancing effect on BMPs, KCP inhibits both activin A- and TGF-beta1-mediated signaling through the Smad2/3 pathway. These inhibitory effects of KCP are mediated in a paracrine manner, suggesting that direct binding of KCP to TGF-beta1 or activin A can block the interactions with prospective receptors. Consistent with this inhibitory effect, primary renal epithelial cells from KCP mutant cells are hypersensitive to TGF-beta and exhibit increased apoptosis, dissociation of cadherin-based cell junctions, and expression of smooth muscle actin. Furthermore, KCP null animals show elevated levels of phosphorylated Smad2 after renal injury. The ability to enhance BMP signaling while suppressing TGF-beta activation indicates a critical role for KCP in modulating the responses between these anti- and profibrotic cytokines in the initiation and progression of renal interstitial fibrosis.
Mol Cell Biol 2006 Jun
PMID:The cysteine-rich domain protein KCP is a suppressor of transforming growth factor beta/activin signaling in renal epithelia. 1673 23

Familial forms of human pulmonary arterial hypertension (FPAH) have been linked to mutations in bone morphogenetic protein (BMP) type II receptors (BMPR2s), yet the downstream targets of these receptors remain obscure. Here we show that pulmonary vascular lesions from patients harboring BMPR2 mutations express high levels of tenascin-C (TN-C), an extracellular matrix glycoprotein that promotes pulmonary artery (PA) smooth muscle cell (SMC) proliferation. To begin to define how TN-C is regulated, PA SMCs were cultured from normal subjects and from those with FPAH due to BMPR2 mutations. FPAH SMCs expressed higher levels of TN-C than normal SMCs. Similarly, expression of Prx1, a factor that drives TN-C transcription, was elevated in FPAH vascular lesions and SMCs derived thereof. Furthermore, Prx1 and TN-C promoter activities were significantly higher in FPAH vs. normal SMCs. To delineate how BMPR2s control TN-C, we focused on receptor (R)-Smads, downstream effectors activated by wild-type BMPR2s. Nuclear localization and phosphorylation of R-Smads was greater in normal vs. FPAH SMCs. As well, indirect blockade of R-Smad signaling with a kinase-deficient BMP receptor Ib upregulated TN-C in normal SMCs. Because ERK1/2 MAPKs inhibit the transcriptional activity of R-Smads, and because ERK1/2 promotes TN-C transcription, we determined whether ERK1/2 inhibits R-Smad signaling in FPAH SMCs and whether this activity is required for TN-C transcription. Indeed, ERK1/2 activity was greater in FPAH SMCs, and inhibition of ERK1/2 resulted in nuclear localization of R-Smads and inhibition of TN-C. These studies define a novel signaling network relevant to PAH underscored by BMPR2 mutations.
Am J Physiol Lung Cell Mol Physiol 2006 Oct
PMID:Tenascin-C is induced by mutated BMP type II receptors in familial forms of pulmonary arterial hypertension. 1678 55

Synthetic triterpenoids, CDDO (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) or CDDO-imidazolide [2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid imidazolide (CDDO-Im)], induce cell differentiation in myeloid leukemia cells but their mechanism of action is not known. CDDO-Im induces monocytic differentiation markers, CD14, and nonspecific esterase in HL60 leukemia cells. We show that CDDO-Im activates the extracellular signal-regulated kinase (ERK) signaling pathway and up-regulates CCAAT/enhancer-binding protein beta, a transcription factor critical for monocytic differentiation. The monocytic differentiation induced by CDDO-Im was partially blocked by the mitogen-activated protein kinase/ERK kinase 1 inhibitor PD98059, suggesting that the mitogen-activated protein kinase-ERK1/2 pathway plays a role in the differentiation induced by CDDO-Im. Furthermore, CDDO-Im activates the transforming growth factor beta (TGF-beta)/Smad signaling pathway. CDDO-Im enhanced the phosphorylation of the receptor-regulated Smads, phospho-Smad3, and phospho-Smad1/5, but not phospho-Smad2, and induced the expression of Smad4. Monocytic differentiation induced by CDDO-Im was blocked by both TGF-beta antibody and the bone morphogenetic protein (BMP) antagonist Noggin. This indicates that activation of the Smad signaling pathway by triterpenoids is an important mechanism of monocytic differentiation. CDDO-Im induced the synthesis of mRNA for TGF-beta2, BMP6, TGF-beta type II receptor, and BMP type II receptor. CDDO-Im synergized with members of the TGF-beta superfamily or with 1alpha,25(OH)2vitamin D3 (D3) in monocytic differentiation, and the synergistic effect was particularly striking in combination with D3. The combination of triterpenoids and D3 may have a practical use in differentiation therapy of myeloid leukemia as well as for promoting the formation of bone and cartilage.
Mol Cancer Ther 2006 Jun
PMID:The synthetic triterpenoid CDDO-imidazolide induces monocytic differentiation by activating the Smad and ERK signaling pathways in HL60 leukemia cells. 1681 3

The efficient generation of mesenchymal cells such as adipocytes, osteoblasts, and chondrocytes from embryonic stem cells is achieved by following sequential steps: embryoid body formation, retinoic acid (RA) treatment, and exposure to specific reagents for differentiation. RA treatment of embryoid bodies is critical for subsequent mesengenesis. Adipogenesis, osteogenesis, and chondrogenesis occur by culturing outgrowths for 2-3 wk with insulin/triiodothyronine, bone morphogenetic protein/dexamethasone-beta/glycerophosphate/ascorbic acid, and transforming growth factor-beta3/parathyroid hormone/1% fetal bovine serum, respectively. Emergence of these mesenchymal cells using a common initial procedure suggests that embryoid body formation and subsequent RA treatment results in the generation of a common progenitor for osteoblasts and chondrocytes.
Methods Mol Biol 2006
PMID:Generation of osteoblasts and chondrocytes from embryonic stem cells. 1684 22


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