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  • Effects of TGF-beta2, BMP-4, and gremlin in the trabecular meshwork: implications for glaucoma. 17325163

    The primary causative factor of primary open-angle glaucoma (POAG) is elevated intraocular pressure (IOP) due to increased aqueous humor (AH) outflow resistance, which is associated with morphologic and biochemical changes in the trabecular meshwork (TM). Patients with glaucoma have elevated levels of transforming growth factor (TGF)-beta2 in their AH, and TGF-beta has been shown to increase TM extracellular matrix (ECM) production. The bone morphogenetic protein (BMP) signaling pathway modifies TGF-beta signaling in several different tissues, and a prior study demonstrated that TM cells and tissues express members of the BMP gene family. The purpose of this study was to determine whether BMPs can alter TGF-beta2 signaling in the TM and whether there are defects in BMP signaling in glaucoma.ELISA, Western immunoblot analysis, and immunohistochemistry were used to evaluate the expression of BMP proteins in TM cells and tissues. ELISA was used to determine the effects of TGF-beta2 and BMPs on TM fibronectin (FN) secretion. Gene expression was determined by gene microarrays and quantitative (q)PCR. Perfusion-cultured human anterior segments were used to study the effects of altered BMP signaling on IOP.The human TM synthesized and secreted BMP-4 as well as expressed BMP receptor subtypes BMPRI and BMPRII. TM cells responded to exogenous BMP-4 by phosphorylating Smad signaling proteins. Cultured human TM cells treated with TGF-beta2 significantly increased FN levels, and BMP-4 blocked this FN induction. The expression of BMP family genes in normal and glaucomatous TM cells was profiled and significant elevation of mRNA and protein levels of the BMP antagonist gremlin were found in glaucomatous TM cells. In addition, Gremlin was present in human aqueous humor and in the perfusate medium of perfusion-cultured human eyes. Gremlin blocked the negative effect of BMP-4 on TGF-beta-induction of FN. Recombinant Gremlin added to the medium of ex vivo perfusion-cultured human eye anterior segments caused the glaucoma phenotype of elevated IOP.These results are consistent with the hypothesis that, in POAG, elevated expression of Gremlin by TM cells inhibits BMP-4 antagonism of TGF-beta2 and leads to increased ECM deposition and elevated IOP.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo

  • A conserved IFN-alpha receptor tyrosine motif directs the biological response to type I IFNs. 18390731

    Mammalian type I IFNs (IFN-Is) mediate their potent biological activities through an evolutionarily conserved IFN-alpha receptor (IFNAR), consisting of IFNAR1 and IFNAR2. These two chains direct the rapid activation of two founding members of the STAT family of transcription factors, STAT1 and STAT2. To understand how IFN-Is direct the recruitment and activation of STATs, a series of mutant murine IFNAR1 and IFNAR2 receptors were generated and evaluated in IFNAR1 and IFNAR2 knockout cells. These studies reveal that a single conserved IFNAR2 tyrosine, Y(510), plays a critical role in directing the IFN-I-dependent activation of STAT1 and STAT2, both in murine fibroblasts and macrophages. A second IFNAR2 tyrosine, Y(335), plays a more minor role. Likewise, Y(510) > Y(335) play a critical role in the induction of genes and antiviral activity traditionally associated with IFN-Is.
    Tipo de documento:
    Referencia
    Referencia del producto:
    07-224
    Nombre del producto:
    Anti-phospho-STAT2 (Tyr689) Antibody

  • Oxygen tension regulates the stability of insulin receptor substrate-1 (IRS-1) through caspase-mediated cleavage. 17179152

    The insulin and insulin-like growth factor-1 (IGF-1) receptors mediate signaling for energy uptake and growth through insulin receptor substrates (IRSs), which interact with these receptors as well as with downstream effectors. Oxygen is essential not only for ATP production through oxidative phosphorylation but also for many cellular processes, particularly those involved in energy homeostasis. The oxygen tension in vivo is significantly lower than that in the air and can vary widely depending on the tissue as well as on perfusion and oxygen consumption. How oxygen tension affects IRSs and their functions is poorly understood. Our findings indicate that transient hypoxia (1% oxygen) leads to caspase-mediated cleavage of IRS-1 without inducing cell death. The IRS-1 protein level rebounds rapidly upon return to normoxia. Protein tyrosine phosphatases (PTPs) appear to be important for the IRS-1 cleavage because tyrosine phosphorylation of the insulin receptor was decreased in hypoxia and IRS-1 cleavage could be blocked either with H(2)O(2) or with vanadate, each of which inhibits PTPs. Activity of Akt, a downstream effector of insulin and IGF-1 signaling that is known to suppress caspase activation, was suppressed in hypoxia. Overexpression of dominant-negative Akt led to IRS-1 cleavage even in normoxia, and overexpression of constitutively active Akt partially suppressed IRS-1 cleavage in hypoxia, suggesting that hypoxia-mediated suppression of Akt may induce caspase-mediated IRS-1 cleavage. In conclusion, our study elucidates a mechanism by which insulin and IGF-1 signaling can be matched to the oxygen level that is available to support growth and energy metabolism.
    Tipo de documento:
    Referencia
    Referencia del producto:
    06-248
    Nombre del producto:
    Anti-IRS1 Antibody

  • Argonaute 2 complexes selectively protect the circulating microRNAs in cell-secreted microvesicles. 23077538

    Cell-secreted miRNAs are highly stable and can serve as biomarkers for various diseases and signaling molecules in intercellular communication. The mechanism underlying the stability of circulating miRNAs, however, remains incompletely understood. Here we show that Argonaute 2 (Ago2) complexes and microvesicles (MVs) provide specific and non-specific protection for miRNA in cell-secreted MVs, respectively. First, the resistance of MV-encapsulated miRNAs to RNaseA was both depended on intact vesicular structure of MVs and protease-sensitive. Second, an immunoprecipitation assay using a probe complementary to human miR-16, a miRNA primarily located in the MVs and showed a strong, protease-sensitive resistance to RNaseA, identified Ago2 as a major miR-16-associated protein. Compared with protein-free miR-16, Ago2-associated miR-16 was resistant to RNaseA in a dose- and time-dependent fashion. Third, when the miR-16/Ago2 complex was disrupted by trypaflavine, the resistance of miR-16 to RNaseA was decreased. In contrast, when the association of miR-16 with the Ago2 complexes was increased during cell apoptosis, although the total amount of miR-16 and Ago2 remained unchanged, the resistance of miR-16 to RNaseA in the MVs was enhanced. A similar correlation between the increase of miR-223/Ago2 association and the resistance of miR-223 against RNaseA was observed during all trans retinoic acid (ATRA)-induced cell differentiation of promyelocytic HL60 cells. In conclusion, the association of miRNAs with Ago2 complexes, an event that is linked to cell functional status, plays a critical role in stabilizing the circulating miRNAs in cell-secreted MVs.
    Tipo de documento:
    Referencia
    Referencia del producto:
    12-371
    Nombre del producto:
    Normal Mouse IgG

  • Persistent inhibition of oxygen-induced retinal neovascularization by anthrax lethal toxin. 21989728

    To evaluate the role of mitogen-activated protein kinase kinase (MKK) signaling in a mouse model of oxygen-induced retinopathy (OIR) that mimics retinopathy of prematurity (ROP).Postnatal day 7 mice were exposed to elevated oxygen for 5 days to induce retinopathy. Anthrax lethal toxin (LeTx), an MKK inhibitor, was injected into the vitreous after restoration to normoxia, and its effects on vascular growth were analyzed by whole mount immunofluorescence and confocal microscopy. Pericyte coverage was determined by PDGFR-β and α-SMA staining. Macrophage presence was determined by F4/80 staining. Vitreal cytokine secretion was measured by ELISA and multianalyte profiling.Intravitreal injection of LeTx over a restricted time interval after return to normoxic conditions blocked the progression of OIR. This block was independent of vascular endothelial growth factor (VEGF) release and did not alter the release of cytokines and growth factors associated with OIR. VEGFR2 expression and activation were similarly unaffected. LeTx had no statistically significant effect on macrophage recruitment. LeTx sensitivity correlated with vessel maturity, extent of hypoxia, and growth of the deep vascular plexus network.Correlation among pericyte coverage, deep vascular plexus growth, and hypoxia after LeTx treatment indicate immature vessels in a hypoxic environment are preferentially sensitive to LeTx-mediated MKK inhibition. The persistence of VEGF without concomitant induction of neovascular growth or revascularization of vaso-obliterated zones suggests MKK inhibition causes an inability of the cells that are present, or a failure to recruit cells able, to respond to proangiogenic stimuli. These results indicate the inhibition of MKK signaling presents a novel strategy for the inhibition of vascular retinopathies such as OIR and ROP.
    Tipo de documento:
    Referencia
    Referencia del producto:
    AB756P
    Nombre del producto:
    Anti-Collagen Antibody, Type IV

  • BMP4 Signaling Acts via dual-specificity phosphatase 9 to control ERK activity in mouse embryonic stem cells. 22305567

    Extrinsic BMP and LIF signaling collaboratively maintain mouse embryonic stem cell (ESC) pluripotency, whereas appropriate ERK activity is essential for ESC fate commitment. However, how the extrinsic signals restrain appropriate ERK activity remains elusive. Here, we show that, whereas LIF sustains relatively high ERK activity, BMP4 can steadily attenuate ERK activity by upregulating ERK-specific dual-specificity phosphatase 9 (DUSP9). This upregulation requires Smad1/5 and Smad4 and specifically occurs to DUSP9, but not other DUSPs, and only in ESCs. Through DUSP9-mediated inhibition of ERK activity, BMP signaling reinforces the self-renewal status of mouse ESCs together with LIF. Upon LIF withdrawal, ESCs spontaneously undergo neural differentiation, during which process DUSP9 can partially mediate BMP inhibition on neural commitment. Collectively, our findings identify DUSP9 as a critical mediator of BMP signaling to control appropriate ERK activity critical for ESC fate determination.
    Tipo de documento:
    Referencia
    Referencia del producto:
    SCR004
    Nombre del producto:
    Alkaline Phosphatase Detection Kit

  • Progesterone potentiates calcium release through IP3 receptors by an Akt-mediated mechanism in hippocampal neurons. 19081133

    Progesterone (P4) is a steroid hormone that plays multiple roles in the central nervous system (CNS) including promoting neuroprotection. However, the precise mechanisms involved in its neuroprotective effects are still unknown. Given that the regulation of the intracellular calcium (Ca(2+)) concentration is critical for cell survival, we determined if inositol 1, 4, 5-trisphosphate receptors (IP(3)Rs) are relevant targets of P4. Using primary hippocampal neurons, we tested the hypothesis that P4 controls the gain of IP3R-mediated intracellular Ca(2+) signaling in neurons and characterized the subcellular distribution and phosphorylation of potential signaling intermediates involved in P4s actions. Our results reveal that P4 treatment altered the intensity and distribution of IP3R immunoreactivity and induced the nuclear translocation of phosphorylated Akt. Further, P4 potentiated IP(3)R-mediated intracellular Ca(2+) responses. These results suggest a potential involvement of P4 in particular and of steroid hormone signaling pathways in general in the control of intracellular Ca(2+) signaling and its related functions.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo
    Nombre del producto:
    Múltiplo

  • Notch expression in developing olfactory neuroepithelium. 15076712

    Notch genes encode receptors for signaling pathways that regulate neurogenesis in various tissues. To better understand the roles of Notch genes in olfactory neurogenesis, we studied the expression of Notch family in developing mouse olfactory epithelium. In the earliest stage of olfactory development, Notch1 was observed in the mesenchyme lateral to the olfactory placode. During the developmental stage, Notch1 was mainly observed around the basal membrane, while Notch3 was observed in the lower compartment of the olfactory neuroepithelium. Notch2 was not detected during the entire observation period. As the olfactory neuroepithelium grew mature, both Notch1 and Notch3 gradually disappeared. These results suggest distinct roles of Notch1 and Notch3 in the neurogenesis of the peripheral olfactory system.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB347
    Nombre del producto:
    Anti-Growth Associated Protein 43 Antibody, clone 9-1E12

  • Cdk5 is required for memory function and hippocampal plasticity via the cAMP signaling pathway. 21984943

    Memory formation is modulated by pre- and post-synaptic signaling events in neurons. The neuronal protein kinase Cyclin-Dependent Kinase 5 (Cdk5) phosphorylates a variety of synaptic substrates and is implicated in memory formation. It has also been shown to play a role in homeostatic regulation of synaptic plasticity in cultured neurons. Surprisingly, we found that Cdk5 loss of function in hippocampal circuits results in severe impairments in memory formation and retrieval. Moreover, Cdk5 loss of function in the hippocampus disrupts cAMP signaling due to an aberrant increase in phosphodiesterase (PDE) proteins. Dysregulation of cAMP is associated with defective CREB phosphorylation and disrupted composition of synaptic proteins in Cdk5-deficient mice. Rolipram, a PDE4 inhibitor that prevents cAMP depletion, restores synaptic plasticity and memory formation in Cdk5-deficient mice. Collectively, our results demonstrate a critical role for Cdk5 in the regulation of cAMP-mediated hippocampal functions essential for synaptic plasticity and memory formation.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo
    Nombre del producto:
    Múltiplo

  • A positive role for Myc in TGFbeta-induced Snail transcription and epithelial-to-mesenchymal transition. 18978814

    Myc and transforming growth factor-beta (TGFbeta) signaling are mutually antagonistic, that is Myc suppresses the activation of TGFbeta-induced genes, whereas TGFbeta represses c-myc transcription. Here, we report a positive role for Myc in the TGFbeta response, consisting in the induction of an epithelial-to-mesenchymal transition (EMT) and the activation of the EMT-associated gene Snail. Knockdown of either Myc or the TGFbeta effectors SMAD3/4 in epithelial cells eliminated Snail induction by TGFbeta. Both Myc and SMAD complexes targeted the Snail promoter in vivo, DNA binding occurring in a mutually independent manner. Myc was bound prior to TGFbeta treatment, and was required for rapid Snail activation upon SMAD binding induced by TGFbeta. On the other hand, c-myc downregulation by TGFbeta was a slower event, occurring after Snail induction. The response of Snail to another cytokine, hepatocyte growth factor (HGF), also depended on Myc and SMAD4. Thus, contrary to their antagonistic effects on Cip1 and INK4b, Myc and SMADs cooperate in signal-dependent activation of Snail in epithelial cells. Although Myc also targeted the Snail promoter in serum-stimulated fibroblasts, it was dispensable for its activation in these conditions, further illustrating that the action of Myc in transcriptional regulation is context-dependent. Our findings suggest that Myc and TGFbeta signaling may cooperate in promoting EMT and metastasis in carcinomas.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo
    Nombre del producto:
    Múltiplo