The identification of transcriptional targets associated with osteoblast apoptosis signaling in response to growth factor withdrawal
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Preface Trends in Apoptosis Research in Hematology Development of Sepsis Therapeutics and Molecular Diagnostics Apoptosis During Pregnancy Cytochemical and Apoptotic Markers of Tissue Remodeling Understanding the Molecular Pathways for Renal Tubular Epithelial Cell Apoptosis Multisite Phosphorylation of the cAMP Response Element-Binding Protein (CREB) by a Diversity of Protein Kinases TNF Signaling Cascades Cell Death and Survival Profilin: From Allergen to Tumor Suppressor Yeast Therapy for the Treatment of Cancer and its Enhancement by MGN-3/Biobran, an Arabinoxylan Rice Bran Nuclear Calcium Signalling: The Nuclear Envelope Store and the Regulation of Transcription Index.
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Notch signaling pathway controls key functions in vascular and endothelial cells (ECs) where Notch4 plays a major role. However, little is known about the contribution of other Notch receptors. This study investigated regulation of Notch2 and further examined its implication in EC dysfunction.Here, we provide evidence for a novel link between Notch and TNF signaling, where Notch2 is upregulated and activated in response to TNF. Forced expression of Notch2 intracellular domain in cultured ECs promotes apoptosis and allows the significant downregulation of several cell-death-related transcripts in a dose-dependent manner. In particular, activation of Notch2 led to a rapid decrease in survivin mRNA and protein expression, while survivin upregulation was obtained by the selective knockdown of Notch2 in ECs, indicating that survivin expression is controlled at the Notch level. Moreover, Notch2 silencing and ectopic expression of survivin, but not XIAP or Bcl2, rescued ECs from TNF and Notch2-mediated apoptosis, respectively.In conclusion, TNF signaling activates Notch2 that sensitizes ECs to apoptosis via modulation of the key apoptosis regulator survivin. Overall, our findings also indicate that specific Notch receptors control distinct functions in vascular cells and inflammatory cytokines contribute to this specificity.
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XIAP
Inhibitor of apoptosis
Ectopic expression
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Abstract Signaling pathways like Wnt play a vital part in all aspects of skeletal development which include osteoblastogenesis and osteoclastogenesis. Inactivation of Wnt signaling pathway leads to bone‐related disorders, whereas activation of Wnt signaling pathway can cure bone pathologies like osteoporosis. Certain microRNA(s) have been identified that commune with Wnt signaling molecules to regulate osteogenesis. In this study we reported the identification of miR‐409‐5p as a suppressor of osteogenesis by targeting Lrp‐8 which is a positive effector of Wnt signaling. Our study showed that overexpressing miR‐409‐5p inhibits osteoblast differentiation whereas obstructing miR‐409‐5p expression by anti‐miR‐409 promotes osteoblast functions and matrix mineralization. Using tools like targetscan and 3′‐UTR luciferase reporter assay, Lrp‐8 was confirmed as a straight target of miR‐409‐5p. By over expressing miR‐409‐5p, a repression of canonical Wnt/β catenin signaling was observed. These observations were strengthened by the fact that silencing of miR‐409‐5p in ovariectomized estrogen deficient Balb/c mice restored the loss of trabecular bone microarchitecture and suppressed bone resorption. Thus, targeting miR‐409‐5p may be helpful in increasing bone density in conditions like post menopausal osteoporosis.
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BETA (programming language)
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Abstract Skeletal development requires the correct balance of osteoblast proliferation, survival, and differentiation which is modulated by a network of signaling pathways and transcription factors. We have examined the role of the AKT (PKB), and ERK1/2 signaling pathways in the osteoblast response to FGFs, which inhibit differentiation, and to IGF‐1 and Wnt signaling, which promote it. Using osteoblastic cell lines as well as primary calvarial osteoblasts, we show that ERK1/2 and AKT have distinct effects in FGF‐induced osteoblast proliferation and differentiation. ERK1/2 is a primary mediator of FGF‐induced proliferation, but also contributes to osteoblast differentiation, while AKT is important for osteoblast survival. Signaling by IGF‐1, that promotes osteoblast differentiation, strongly activates AKT and weakly ERK1/2, while the opposite results are obtained with FGF, which inhibits differentiation. By introducing a constitutively active form of AKT, we found that increased AKT activity drives osteoblasts to differentiation. Increasing the AKT signal in osteoblasts that harbor FGFR2 activating mutations, found in Crouzon (342Y) and Apert (S22W) syndromes, is also able to drive differentiation in these cells, that normally fail to differentiate. Wnt signals, that promotes differentiation, also induce AKT phosphorylation, and cells expressing active AKT have increased levels of stabilized beta‐catenin, a central molecule in Wnt signaling. Our results indicate that the relative strengths of ERK and AKT signaling pathways determine whether osteoblasts are driven into proliferation or differentiation, and that the effects of AKT may be due, in part, to synergy with the Wnt pathway as well as with the Runx2 transcription factor. J. Cell. Physiol. 215: 442–451, 2008. © 2007 Wiley‐Liss, Inc.
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Beta-catenin
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INTRODUCTION: WNT5A belongs to the Wnt family of secreted signaling molecules. Using transcriptional profiling, we previously identified WNT5A as target of the antiapoptotic transcription factor CUX1 and demonstrated high expression levels in pancreatic cancer. However, the impact of WNT5A on drug resistance and the signaling pathways employed by WNT5A remain to be elucidated. OBJECTIVES: This project aims to decipher the impact of WNT5A on resistance to apoptosis and the signaling pathways employed by WNT5A in pancreatic cancer. METHODS: The impact of WNT5A and its downstream effectors on tumor growth and drug resistance was studied in vitro and in xenograft models in vivo. Tissue microarrays of pancreatic cancer specimens were employed for immuno-histochemical studies. RESULTS: Knockdown of WNT5A results in a significant increase in drug-induced apoptosis. In contrast, overexpression of WNT5A or addition of recombinant WNT5A mediates resistance to apoptosis in vitro. In our attempt to identify downstream effectors of WNT5A, we identified the transcription factor nuclear factor of activated T cells c2 (NFATc2) as transcriptional target of WNT5A signaling. NFATc2 confers a strong antiapoptotic phenotype mediating at least in part the effects of WNT5A on drug resistance and tumor cell survival. In vivo, WNT5A expression leads to resistance to gemcitabine-induced apoptosis in a xenograft model, which is paralleled by up-regulation of NFATc2. Both WNT5A and NFATc2 proteins are highly expressed in human pancreatic cancer tissues and their expression levels correlated significantly. CONCLUSION: We identified the WNT5A-NFATc2 axis as important mediator of drug resistance in pancreatic cancer.
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Osteocyte plays an essential role in bone metabolism by regulating osteoblast and osteoclast activities. Dysfunction or apoptosis of osteocyte will severely endanger the bone homeostasis and result in bone diseases such as osteoporosis. Osteoporosis has been considered as one of the diabetes complications; however, the mechanism is still to be discovered. Advanced glycation end products (AGEs), as the main pathogenic factor of diabetes mellitus, have the capacity to induce osteocyte apoptosis thus sabotaging bone homeostasis. Here, we examined the role of AGE during osteocyte apoptosis and how this effect would affect osteocyte's regulation of osteoblast and osteoclast. Mouse osteocyte-like MLO-Y4 cells were used to study the properties of osteocyte and to examine its biological and pathological function. MTT assay and Annexin V assay showed that AGE significantly induce MLO-Y4 cell apoptosis. qPCR and Western blot results have shown that AGE upregulates proapoptotic gene p53 and its downstream target gene Bax, which leads to enhanced activation of caspase-3, thus inducing apoptosis in MLO-Y4 cells. Increased expression of sclerostin and RANKL in osteocytes has shown that AGE induces osteocyte dysfunction thus severely damaging the bone homeostasis by decreasing osteoblast and increasing osteoclast activities. Furthermore, the role of the transcription factor FOXO1, which is intensely associated with apoptosis, has been determined. Western blot has shown that AGE significantly decreases Akt activities. Immunofluorescence has shown that AGE promotes FOXO1 nuclei localization and enhances FOXO1 expression. Silencing of FOXO1 suppressed AGE-enhanced apoptosis; mRNA and protein expressions of cleaved caspase-3, sclerostin, and RANKL were downregulated as well. Moreover, exogenous FOXO1 increased caspase-3 mRNA levels and caspase-3 transcriptional activity. Lastly, ChIP assay has established the capacity of FOXO1 binding directly on the caspase-3, sclerostin, and RANKL promoter region in AGE environment, providing the mechanism of the AGE-induced osteocyte apoptosis and dysfunction. Our results have shown that FOXO1 plays a crucial role in AGE-induced osteocyte dysfunction and apoptosis through its regulation of caspase-3, sclerostin, and RANKL. This study provides new insight into diabetes-enhanced risk of osteoporosis given the critical role of AGE in the pathogenesis of diabetes and the essential part of osteocyte in bone metabolism.
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Bone remodeling
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Cell Signaling
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SOCS2
SOCS6
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The apoptosis of retinal ganglion cells (RGCs) is a hallmark of several optic neuropathies. MicroRNAs (miRNAs) are recently identified regulators of various biological processes. However, the role of miRNAs in regulating RGC apoptosis remains largely unknown. We herein aimed to demonstrate that miR-137 acts as a hypoxia-responsive gene in RGCs that is downregulated under hypoxic conditions. It was observed that overexpression of miR-137 markedly aggravated hypoxia-induced cell apoptosis, whereas inhibition of miR-137 effectively protected RGCs against hypoxia-induced apoptosis. Hypoxia induced Notch1 expression and signaling activation, while blocking Notch signaling significantly aggravated hypoxia-induced cell apoptosis. Further data revealed that the pro-survival Akt signaling pathway was involved in miR-137-Notch signaling pathway-mediated RGC protection. Knockdown of Notch significantly reversed the effect of anti‑miR-137 on RGC protection and Akt signaling activation. In addition, blocking Akt signaling also significantly abrogated the protective effect of anti-miR-137 on hypoxia-induced cell injury. Overall, the results of the present study demonstrated that miR-137 targets Notch1 expression, revealing a novel link between miR-137 and Notch signaling, and suggesting that a miR-137/Notch1 axis may serve as a potential molecular target for the treatment of hypoxia-induced retinal diseases.
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In this study, we have uncovered a novel crosstalk between TGFβ and IGF-1R signaling pathways. We show for the first time that expression and activation of IRS-1, an IGF-1R adaptor protein, is decreased by TGFβ/Smad3 signaling. Loss or attenuation of TGFβ activation leads to elevated expression and phosphorylation of IRS-1 in colon cancer cells, resulting in enhanced cell proliferation, decreased apoptosis and increased tumor growth in vitro and in vivo. Downregulation of IRS-1 expression reversed Smad3 knockdown-mediated oncogenic phenotypes, indicating that TGFβ/Smad3 signaling inhibits cell proliferation and increases apoptosis at least partially through the inhibition of IRS-1 expression and activation. Additionally, the TGFβ/Smad3/IRS-1 signaling axis regulates expression of cyclin D1 and XIAP, which may contribute to TGFβ/Smad3/IRS-1-mediated cell cycle progression and survival. Given that loss of TGFβ signaling occurs frequently in colon cancer, an important implication of our study is that IRS-1 could be a potential therapeutic target for colon cancer treatment.
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