Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The bone morphogenetic protein (BMP) family is a conserved group of signalling molecules within the transforming growth factor-beta (TGF-beta) superfamily. This group, including the Drosophila decapentaplegic (dpp) protein and the mammalian BMPs, mediates cellular interactions and tissue differentiation during development. Here we show that a homologue of human BMPs controls a developmental switch in the life cycle of the free-living soil nematode Caenorhabditis elegans. Starvation and overcrowding induce C. elegans to form a developmentally arrested, third-stage dauer larva. The daf-4 gene, which acts to inhibit dauer larva formation and promote growth, encodes a receptor protein kinase similar to the daf-1, activin and TGF-beta receptor serine/threonine kinases. When expressed in monkey COS cells, the daf-4 receptor binds human BMP-2 and BMP-4. The daf-4 receptor is the first to be identified for any growth factor in the BMP family.
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PMID:The daf-4 gene encodes a bone morphogenetic protein receptor controlling C. elegans dauer larva development. 841 26

We found that bone morphogenetic protein (BMP) 7, a member of the BMP family, was strikingly up-regulated during the development of primary prostatic adenocarcinoma in the conditional Pten deletion mouse model. To determine the relevance of this finding to human prostate cancer, we examined the expression of BMPs and BMP receptors (BMPR) as well as the responsiveness to recombinant human BMP7 in a series of human prostate tumor cell lines. All prostatic cell lines tested expressed variable levels of BMP2, BMP4, and BMP7 and at least two of each type I and II BMPRs. In all cases, BMP7 induced Smad phosphorylation in a dose-dependent manner, with Smad5 activation clearly demonstrable. However, the biological responses to BMP7 were cell type specific. BPH-1, a cell line representing benign prostatic epithelial hyperplasia, was growth arrested at G1. In the bone metastasis-derived PC-3 prostate cancer cells, BMP7 induced epithelial-mesenchymal transdifferentiation with classic changes in morphology, motility, invasiveness, and molecular markers. Finally, BMP7 inhibited serum starvation-induced apoptosis in the LNCaP prostate cancer cell line and more remarkably in its bone metastatic variant C4-2B line. Each of the cell lines influenced by BMP7 was also responsive to BMP2 in a corresponding manner. The antiapoptotic activity of BMP7 in the LNCaP and C4-2B cell lines was not associated with a significant alteration in the levels of the proapoptotic protein Bax or the antiapoptotic proteins Bcl-2, Bcl-xl, and X-linked inhibitor of apoptosis. However, in C4-2B cells but not in LNCaP cells, a starvation-induced decrease in the level of survivin was counteracted by BMP7. Taken together, these findings suggest that BMPs are able to modulate the biological behavior of prostate tumor cells in diverse and cell type-specific manner and point to certain mechanisms by which these secreted signaling molecules may contribute to prostate cancer growth and metastasis.
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PMID:Diverse biological effect and Smad signaling of bone morphogenetic protein 7 in prostate tumor cells. 1599 52

We examined the effect of the extracellular bone morphogenetic protein (BMP) 2 and 7, which are up-regulated in the prostate adenocarcinomas of the conditional Pten deletion mouse model, on primary cultures of cancer-associated fibroblasts (CAF) derived from these tumors. In the CAF, we show that BMP2 or BMP7, but not transforming growth factor beta-1, can strikingly stimulate secretion of stromal cell-derived factor-1 (SDF-1), also known as CXCL12. The CAF cells express type I and type II BMP receptors as well as the receptor for SDF-1, CXCR4. SDF-1 activation is associated with BMP-induced Smad phosphorylation, and the stimulatory effect is blocked by BMP antagonist, noggin. The findings that BMP treatment can increase SDF-1 pre-mRNA levels in a time-dependent manner and actinomycin D treatment can abolish stimulatory effect of BMP suggest a transcriptional modulation of SDF-1 by BMP signaling. Using a human microvascular endothelial cell line, we show that SDF-1 present in the conditioned medium from the stimulated CAF can significantly induce tube formation, an effect relating to angiogenic function. Furthermore, we found that BMP2 can also protect the CAF from serum starvation-induced apoptosis independent of SDF-1, implying that BMP may induce other factors to sustain the survival of these cells. In short, this report establishes a novel BMP-SDF-1 axis in the prostate tumor along with a new prosurvival effect of BMP that when considered together with our previously described oncogenic properties of BMP indicate a circuitry for heterotypic cell interactions potentially critical in prostate cancer.
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PMID:A novel bone morphogenetic protein signaling in heterotypic cell interactions in prostate cancer. 1817 12

Bone marrow-derived mesenchymal stem cells (MSCs) are being explored for clinical applications, and genetic engineering represents a useful strategy for boosting the therapeutic potency of MSCs. Vascular endothelial growth factor (VEGF)-based gene therapy protocols have been used to treat tissue ischemia, and a combined VEGF/MSC therapeutics is appealing due to their synergistic paracrine actions. However, multiple VEGF splice variants exhibit differences in their mitogenicity, chemotactic efficacy, receptor interaction, and tissue distribution, and the differential regulatory effects of multiple VEGF isoforms on the function of MSCs have not been characterized. We expressed three rat VEGF-A splice variants VEGF120, 164, and 188 in MSCs using adenoviral vectors, and analyzed their effects on MSC proliferation, differentiation, survival, and trophic factor production. The three VEGF splice variants exert common and differential effects on MSCs. All three expressed VEGFs are potent in promoting MSC proliferation. VEGF120 and 188 are more effective in amplifying expression of multiple growth factor and cytokine genes. VEGF164 on the other hand is more potent in promoting expression of genes associated with MSC remodeling and endothelial differentiation. The longer isoform VEGF188, which is preferentially retained by proteoglycans, facilitates bone morphogenetic protein-7 (BMP7)-mediated MSC osteogenesis. Under serum starvation condition, virally expressed VEGF188 preferentially enhances serum withdrawal-mediated cell death involving nitric oxide production. This work indicates that seeking the best possible match of an optimal VEGF isoform to a given disease setting can generate maximum therapeutic benefits and minimize unwanted side effects in combined stem cell and gene therapy.
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PMID:Adenoviral expression of vascular endothelial growth factor splice variants differentially regulate bone marrow-derived mesenchymal stem cells. 1828 39

Previously we described that bone morphogenetic protein-7 (BMP7) could protect prostate cancer C4-2B cells from serum starvation-induced apoptosis via survivin induction. Here, for the first time, we identify Runx2 as a key regulator of survivin transcription. In C4-2B cells grown normally, suppression of Runx2 reduced survivin expression. Using ChIP assays, two regions of the survivin promoter, -1953 to -1812 (I) and -1485 to -1119 (II) encompassing consensus Runx-binding sites were examined. Runx2 was found to be associated with both regions, with a stronger affinity to region-I. In serum-starved cells neither region was occupied, but BMP7 restored association to region-II and not region-I. In reporter assays, transcription activity by BMP7 was significantly reduced when sequences including binding sites of region-II were deleted. Additionally, Runx2 expression was enhanced by BMP7 in these cells. Along with a strong survivin expression, a trend in increased Runx2 expression in human prostate cancer cells and tissues was noted. In the conditional Pten-knockout mouse, Runx2 level increased with growth of prostate tumor. The data define a novel role of Runx2 in regulating survivin expression in malignant epithelial cells and identify it as a critical factor in BMP signaling that protects cancer cells against apoptosis.
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PMID:Runx2 regulates survivin expression in prostate cancer cells. 1994 74

Germline mutations in the bone morphogenetic protein type II receptor (BMPRII) gene play an essential role in the pathogenesis of familial pulmonary arterial hypertension (FPAH). In view of the histological similarities between scleroderma (SSc) and FPAH arterial lesion, we examined the expression levels of BMPRII in SSc microvascular endothelial cells (MVEC). Oxidative stress and serum starvation were used to examine apoptotic responses of MVECs. BMPRII expression levels were determined by RT-PCR and by Western blot. Epigenetic regulation of BMPRII expression was examined by the addition of epigenetic inhibitors to MVECs cultures, by methylation-specific PCR, and by sequence analysis of DNA methylation pattern of the BMPRII promotor region. SSc-MVECs were more sensitive to apoptotic signals than were normal-MVECs. A significant decrease in BMPRII expression levels in SSc-MVECs was noted, whereas no significant differences in the expression levels of BMPRIA and BMPRIB were observed. Similar reduction in expression levels was noted in SSc skin biopsies. The expression level of BMPRII in SSc-MVECs was normalized by the addition of 2-deoxy-5-azacytidine and trichostatin A to cell cultures. Extensive CpG sites methylation in the BMPRII promoter region was noted in SSc-MVECs with no detectable site methylation in control-MVECs. SSc-MVECs are more sensitive to apoptotic triggers than are control-MVECs. The enhanced apoptosis may be related to epigenetic repression of BMPRII expression as apoptosis of control-MVECs can be augmented by knocking down BMPRII expression. The role of BMPRII underexpression in the pathogenesis of SSc vasculopathy is suggested and should be investigated further.
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PMID:Epigenetic repression of bone morphogenetic protein receptor II expression in scleroderma. 2385 8

Glucagon-like peptide-1 (GLP-1) is a well-known incretin hormone secreted from enteroendocrinal L cells in response to nutrients, such as glucose and dietary fat, and controls glycemic homeostasis. However, the detailed intracellular mechanisms of how L cells control GLP-1 secretion in response to nutrients still remain unclear. Here, we report that bone morphogenetic protein (BMP) signaling pathway plays a pivotal role to control GLP-1 secretion in response to nutrient replenishment in well-established mouse enteroendocrinal L cells (GLUTag cells). Nutrient starvation dramatically reduced cellular respiration and GLP-1 secretion in GLUTag cells. Transcriptome analysis revealed that nutrient starvation remarkably reduced gene expressions involved in BMP signaling pathway, whereas nutrient replenishment rescued BMP signaling to potentiate GLP-1 secretion. Transient knockdown of inhibitor of DNA binding (ID)1, a well-known target gene of BMP signaling, remarkably reduced GLP-1 secretion. Consistently, LDN193189, an inhibitor of BMP signaling, markedly reduced GLP-1 secretion in L cells. In contrast, BMP4 treatment activated BMP signaling pathway and potentiated GLP-1 secretion in response to nutrient replenishment. Altogether, we demonstrated that BMP signaling pathway is a novel molecular mechanism to control GLP-1 secretion in response to cellular nutrient status. Selective activation of BMP signaling would be a potent therapeutic strategy to stimulate GLP-1 secretion in order to restore glycemic homeostasis.
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PMID:ID1-Mediated BMP Signaling Pathway Potentiates Glucagon-Like Peptide-1 Secretion in Response to Nutrient Replenishment. 3248 41