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At least 253 records · Page 14Linked to original sources

PubMed2001

Suppressor of cytokine signaling 1 interacts with the macrophage colony-stimulating factor receptor and negatively regulates its proliferation signal.

Macrophage colony-stimulating factor receptor (M-CSF-R) is a tyrosine kinase that regulates proliferation, differentiation, and cell survival during monocytic lineage development. Upon activation, M-CSF-R dimerizes and autophosphorylates on specific tyrosines, creating binding sites for several cytoplasmic SH2-containing signaling molecules that relay and modulate the M-CSF signal. Here we show that M-CSF-R interacts with suppressor of cytokine signaling 1 (Socs1), a negative regulator of various cytokine and growth factor signaling pathways. Using the yeast two-hybrid system, in vitro glutathione S-transferase-M-CSF-R pull-down, and in vivo coimmunoprecipitation experiments, we demonstrated a direct interaction between the SH2 domain of Socs1 and phosphorylated tyrosines 697 or 721 of the M-CSF-R kinase insert region. Moreover, Socs1 is tyrosine-phosphorylated in response to M-CSF. Ectopic expression of Socs1 in FDC-P1/MAC and EML hematopoietic cell lines decreased their growth rates in the presence of limiting concentrations of M-CSF. However, Socs1 expression did not totally suppress long term cell growth in the presence of saturating M-CSF concentrations, in contrast to other cytokines such as stem cell factor and interleukin 3. Taken together, these results suggest that Socs1 is an M-CSF-R-binding partner involved in negative regulation of proliferation signaling and that it differentially affects cytokine receptor signals.

Animals↗

PubMed2003

Suppressor of cytokine signaling 1 attenuates IL-15 receptor signaling in CD8+ thymocytes.

SOCS1-/- mice die prematurely of increased interferon-gamma (IFNgamma) signaling with severe thymic atrophy and accelerated maturation of T cells. However, it was unclear whether the thymic defects were caused by SOCS1 deficiency or by increased IFNgamma signaling. Using SOCS1-/- IFNgamma-/- mice, we show in this study that SOCS1 deficiency skews thymocyte development toward CD8 lineage independently of IFNgamma. Fetal thymic organ cultures and intrathymic transfer of CD4-CD8- precursors into Rag1-/- mice show that the lineage skewing in SOCS1-/- mice is a T-cell autonomous defect. Interestingly, SOCS1 is not required for attenuating interleukin-7 (IL-7) signaling at the CD4-CD8- stage but is essential for regulating IL-15 and IL-2 signaling in CD8+ thymocytes. IL-15 selectively stimulates SOCS1-/- CD8+ thymocytes, inducing sustained signal transducer and activator of transcription 5 (STAT5) phosphorylation and massive proliferation. IL-15 also strongly up-regulates Bcl-xL and CD44 in CD8+ thymocytes lacking SOCS1. The SOCS1 gene is induced in CD4+ thymocytes by gammac cytokines, whereas CD8+ thymocytes constitutively express SOCS1 mRNA even in the absence of cytokine stimulation. Because many different cell types express IL-15, our results strongly suggest that SOCS1 functions as an indispensable attenuator of IL-15 receptor signaling in developing CD8+ thymocytes.

Animals↗

PubMed2003

Suppressor of cytokine signaling 1 regulates IL-15 receptor signaling in CD8+CD44high memory T lymphocytes.

T lymphocyte survival, proliferation, and death in the periphery are dependent on several cytokines. Many of these cytokines induce the expression of suppressor of cytokine signaling-1 (SOCS1), a feedback inhibitor of JAK kinases. However, it is unclear whether the cytokines that regulate T lymphocyte homeostasis are critically regulated by SOCS1 in vivo. Using SOCS1(-/-)IFN-gamma(-/-) mice we show that SOCS1 deficiency causes a lymphoproliferative disorder characterized by decreased CD4/CD8 ratio due to chronic accumulation of CD8+CD44(high) memory phenotype T cells. SOCS1-deficient CD8+ T cells express elevated levels of IL-2Rbeta, show increased proliferative response to IL-15 and IL-2 in vitro, and undergo increased bystander proliferation and vigorous homeostatic expansion in vivo. Sorted CD8+CD44(high) T cells from SOCS1(-/-)IFN-gamma(-/-) mice respond 5 times more strongly than control cells, indicating that SOCS1 is a critical regulator of IL-15R signaling. Consistent with this idea, IL-15 stimulates sustained STAT5 phosphorylation in SOCS1-deficient CD8+ T cells. IL-15 strongly induces TNF-alpha production in SOCS1-deficient CD8+ T cells, indicating that SOCS1 is also a critical regulator of CD8+ T cell activation by IL-15. However, IL-15 and IL-2 induce comparable levels of Bcl-2 and Bcl-x(L) in SOCS1-deficient and SOCS1-sufficient CD8+ T cells, suggesting that cytokine receptor signals required for inducing proliferation and cell survival signals are not identical. These results show that SOCS1 differentially regulates common gamma-chain cytokine signaling in CD8+ T cells and suggest that CD8+ T cell homeostasis is maintained by distinct mechanisms that control cytokine-mediated survival and proliferation signals.

Animals↗

PubMed1995

A novel endocytosis signal related to the KKXX ER-retrieval signal.

Membrane proteins often contain a sorting signal in their cytoplasmic tail that promotes their clustering into coated vesicles at a specific cellular site. ERGIC-53 contains a cytoplasmic ER-retrieval signal, KKFF. However, overexpressed ERGIC-53 is transported to the cell surface and rapidly endocytosed. Here we report that ERGIC-53 carries a previously undescribed endocytosis signal. Surprisingly, the signal was KKFF and like the ER-retrieval signal required a C-terminal position. In fact, the minimal consensus sequence determined by substitutional mutagenesis (K-K/R-F/Y-F/Y) was related to the ER-retrieval consensus (K-K-X-X). Furthermore, we provide evidence that internalization of VIP36, a protein that cycles between plasma membrane and Golgi, is mediated by a signal at its C-terminus that matches the internalization consensus sequence. The relatedness of the two signals suggests that coatomer-mediated retrieval of proteins may be mechanistically more related to clathrin-dependent sorting than previously anticipated.

Amino Acid Sequence↗

PubMed2005

NMDA receptor-dependent oscillatory signal outputs from the retrosplenial cortex triggered by a non-NMDA receptor-dependent signal input from the visual cortex.

The retrosplenial cortex is located at a critical juncture between the visual cortex and hippocampal formation. Functions of the retrosplenial cortex at the local circuit level, however, remain unclear. Herein, we show how signals traveling from the visual cortex behave in local circuits of the retrosplenial cortex, using optical recording methods and application of caffeine to rat brain slices. Electrical signals evoked in the primary visual cortex penetrated into the deep layer of the retrosplenial granular a cortex (RSGa) and propagated further toward postsubiculum and upper layer. Non-N-methyl-D-aspartate (NMDA) receptor-dependent initial traveling signal from the visual cortex triggered NMDA receptor-dependent neural oscillation in the RSGa. Oscillatory signals originated from the local area in the deep layer of the RSGa, and the signal spread back and forth toward the visual cortex and postsubiculum, in addition to spreading toward the upper layer. From the perspective of the RSGa, extrinsic signal inputs from the visual cortex switched on neural oscillators in the RSGa that deliver NMDA receptor-dependent intrinsic signal outputs. Opening and strengthening of non-NMDA receptor-dependent input pathways from the visual cortex required NMDA receptor-dependent oscillatory neural activities. These input and output relationships indicate that the retrosplenial cortex may represent an important relay station between the visual cortex and hippocampal formation.

Animals↗

PubMed2006

Evaluation of a novel short polyadenylation signal as an alternative to the SV40 polyadenylation signal.

The soluble neuropilin-1 (sNRP-1) gene employs an extremely short dual function polyadenylation (pA) signal/stop codon that is efficient for termination of gene transcription and translation in vivo. However, the functionality and usefulness of this signal in regard to other genes is unknown. This quantitative study compares the levels of humanized Renilla green fluorescent protein (hrGFP) mRNA polyadenylated with either the sNRP-1 pA signal or the much larger, more widely used SV40 pA signal. We show that the overall starting copy number of hrGFP for equally loaded RNAs is equivalent between the two groups. Our data show little to no difference between levels of mRNA generated by the sNRP-1 polyadenylation signal and the SV40 polyadenylation signal despite a remarkable size difference in signal length. An extremely short polyadenylation signal could potentially alleviate gene insert size restrictions associated with cloning or with therapeutic vectors such as adeno-associated virus.

Base Sequence↗

PubMed1990

Gonadal responses of the male Syrian hamster to programmed infusions of melatonin are sensitive to signal duration and frequency but not to signal phase nor to lesions of the suprachiasmatic nuclei.

This study investigated the roles of the melatonin signal and the circadian system in the induction of photoperiodic responses in the male Syrian hamster. Pinealectomized animals received programmed s.c. infusions of saline or melatonin. Saline infusions for 10 h or melatonin for 4 h during the night had no effect on the reproductive axis whereas nightly 10-h infusions of melatonin induced gonadal atrophy. Animals that received 10-h infusions of melatonin arranged such that consecutive daily signals were delivered alternately during the day and night also exhibited gonadal atrophy, whereas melatonin signals delivered every 48 h, exclusively during either the day or night, were without effect. These results demonstrate that the brain is able to read melatonin signals delivered at different phases of the circadian cycle and to use them in combination to generate an appropriate photoperiodic response. Melatonin signals lasting 10 h delivered to pinealectomized (PX) animals every 24 h induced gonadal regression. Melatonin delivered at periodicities of 20 h, 23 h, and 25 h also caused gonadal regression whereas infusions every 28 h were without effect, demonstrating that the systems responsive to melatonin are sensitive to signal frequency but do not need to receive the signal on a strictly circadian basis. These results are discussed in the context of the significance of the melatonin-free interval. PX animals that received sham or bilateral lesions of the suprachiasmatic nuclei (SCN) were infused nightly for 10 h with saline or melatonin. Melatonin infusions were equally effective at inducing gonadal atrophy and lowering serum testosterone levels in both sham- and SCN-lesioned animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1998

The effect of spatial separation of signal and noise on masking in the free field as a function of signal frequency and age in the mouse.

Masking of low- (4 kHz) and high-frequency (25 kHz) signals by one-octave bandpass maskers either spatially coincident with the signal or contralateral to it was examined in mice, 4-6 and 20-22 months of age, in the free field. Signals were presented 120 ms prior to a startle stimulus and differences in their inhibition of the startle reflex, relative to startle stimulus alone trials, were used to measure the severity of masking. Inhibition was reduced or eliminated by spatially coincident noise for weak but not for relatively intense signals, providing the type of "loudness recruitment" effect characteristic of human listeners in similar stimulus conditions. The spatial separation of the signal and its masker relieved this maskinglike effect for the high-frequency pair in both young and old mice. In contrast there was no beneficial effect of the shift in spatial location for the low-frequency pair at either age. This finding of masking release for high- but not low-frequency stimuli supports the hypothesis that the sound shadow provided by the head and pinna would yield a favorable signal-to-noise level difference for a contralateral masker and an ipsilateral signal only at very high frequencies in the mouse. The presence of masking release in these old mice, a first generation hybrid strain with near-normal high-frequency hearing in ABR measures, agrees with reports that the masking release resulting from a similar manipulation in aged human listeners with minimal high-frequency hearing loss is the equal of that obtained in the young listener.

Age Factors↗

PubMed1988

Responding of pigeons under variable-interval schedules of unsignaled, briefly signaled, and completely signaled delays to reinforcement.

In Experiment 1, three pigeons' key pecking was maintained under a variable-interval 60-s schedule of food reinforcement. A 1-s unsignaled nonresetting delay to reinforcement was then added. Rates decreased and stabilized at values below those observed under immediate-reinforcement conditions. A brief stimulus change (key lit red for 0.5 s) was then arranged to follow immediately the peck that began the delay. Response rates quickly returned to baseline levels. Subsequently, rates near baseline levels were maintained with briefly signaled delays of 3 and 9 s. When a 27-s briefly signaled delay was instituted, response rates decreased to low levels. In Experiment 2, four pigeons' responding was first maintained under a multiple variable-interval 60-s (green key) variable-interval 60-s (red key) schedule. Response rates in both components fell to low levels when a 3-s unsignaled delay was added. In the first component delays were then briefly signaled in the same manner as Experiment 1, and in the second component they were signaled with a change in key color that remained until food was delivered. Response rates increased to near baseline levels in both components, and remained near baseline when the delays in both components were lengthened to 9 s. When delays were lengthened to 27 s, response rates fell to low levels in the briefly signaled delay component for three of four pigeons while remaining at or near baseline in the completely signaled delay component. In Experiment 3, low response rates under a 9-s unsignaled delay to reinforcement (tandem variable-interval 60 s fixed-time 9 s) increased when the delay was briefly signaled. The role of the brief stimulus as conditioned reinforcement may be a function of its temporal relation to food, and thus may be related to the eliciting function of the stimulus.

Journal Article↗

PubMed1996

Effects of cocaine on briefly signaled versus completely signaled delays to reinforcement.

Key pecking by 4 pigeons was maintained by a multiple schedule consisting of two variable-interval 60-s schedules wherein each food presentation followed a nonresetting 27-s delay that was either briefly signaled at its outset or completely signaled. Brief-signal duration was adjusted so that response rates maintained by the briefly and completely signaled delays of reinforcement were similar. In general, acute administration of small to intermediate doses (0.3 to 3.0 mg/kg) of cocaine produced either small increases in response rates in both components or no change, and larger doses (5.6 to 13.0 mg/kg) decreased response rates. Chronic (i.e., daily) cocaine administration (10.0 mg/kg) resulted in tolerance to the rate-decreasing effects in both components. Cocaine's effects were generally similar whether delays were completely or briefly signaled. Discontinuation of cocaine administration and subsequent removal of the delay signals also had similar effects in both components of the multiple schedule. Taken together, these results are consistent with the view that the two types of delay signals were equally effective in maintaining responding during the variable-interval schedules.

Animals↗

PubMed1975

[The effects of feedback signal and model signal on heart rate changes (author's transl)].

An attempt was made to modify heart rate by presenting the Ss: E1-visual feedback and model signals, E2-feedback signals, E3-model signals, or C-no signals as a control group (6 Ss in each group). Model signal was a weak light which flickered at the rate of 20% above or below the pre-stimulus base IBI. All groups were required to either raise or lower HR alternately and E1 group was instructed to synchronize the feedback signal with the model signal. Significant bidirectional HR changes were found in 3 experimental groups and most effective changes were obtained in E1 group. In the second study, extended training to one S with E1 condition resulted in HR increases of 16 bpm and decreases of 9 bpm.

Adult↗

PubMed2005

Inhibition of either phosphatidylinositol 3-kinase/Akt or the mitogen/extracellular-regulated kinase, MEK/ERK, signaling pathways suppress growth of breast cancer cell lines, but MEK/ERK signaling is critical for cell survival.

The phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways are important integrators of growth and survival signals originating from extracellular stimuli. We assessed the importance of these signaling pathways in the growth and survival of 8 breast cell lines (MCF10A, an immortalized line; and 7 cancer cell lines). The cell lines expressed variable levels of both phosphorylated ERK and phosphorylated Akt, but these were unchanged by incubation in serum-free medium. Despite continued activity of these pathways, the cells arrested growth in the absence of serum demonstrating that additional pathways are required for growth. Incubation with the PI3K inhibitor LY294002 suppressed growth of all cell lines, but most remained viable for at least 7-14 days. This long-term survival may be attributable to recovery of phospho-Akt by 24-48 h despite the continued presence of active LY294002, suggesting that alternate pathways may be activating Akt. In contrast, incubation with the MEK inhibitor U0126 not only arrested growth, but also killed all the cell lines within 2-4 days in the absence of serum; the presence of serum only slighted extended viability, except in MCF10A and MDA-MB-468 cells, in which serum provided significantly greater protection. It is likely that these signaling pathways control the level of pro-and anti-apoptotic proteins, yet assessment of Bcl-2 and Bcl-X showed dramatic reduction in level only when large numbers of cells were dead suggesting this may be a consequence rather than cause of death. Overall, the results demonstrate that the MEK/ERK pathway represents the more critical pathway for cell survival of these breast cancer cell lines, and suggest this pathways represents the better target for cancer therapy.

Blotting, Western↗

PubMedDate not supplied

Calcium channel inactivation: possible role in signal transduction and Ca2+ signaling.

Voltage gated Ca2+ channels are major routes for the entry of intracellular Ca2+ coupled to membrane depolarization that appear to vary greatly with respect to their voltage dependence and kinetics. Such variability maybe in part related to the attached signaling properties of the channel, in addition to the transport of calcium. In the present review we consider the possible role of calcium-dependent inactivation of Cav1.2 in Ca2+ signal transduction and signaling of calcium release from the cardiac sarcoplasmic reticulum. We explore the specific roles of Ca2+-sensing calmodulin-binding domains of the C-terminal tail (LA and K) of the channel in mediating Ca2+-induced Ca2+ release and signal transduction. Our experiments point to an intriguing possibility that the C-terminal tail of Cav1.2 may translocate the Ca2+ signal as a part of inactivation mechanism and the corresponding voltage-gated rearrangement of the C-terminus. We show how a dynamic and transient regulation, in a Ca2+-dependent manner, defines molecular events including Ca2+ release and signaling of cAMP-responsive element-binding protein (CREB)-dependent transcription. We propose that such Ca2+-dependent C-tail translocation that also initiates the channel inactivation, may have evolved specifically for the Cav1.2 channel.

Animals↗

PubMed2005

Wnt/beta-catenin signaling acts upstream of N-myc, BMP4, and FGF signaling to regulate proximal-distal patterning in the lung.

Branching morphogenesis in the lung serves as a model for the complex patterning that is reiterated in multiple organs throughout development. Beta-catenin and Wnt signaling mediate critical functions in cell fate specification and differentiation, but specific functions during branching morphogenesis have remained unclear. Here, we show that Wnt/beta-catenin signaling regulates proximal-distal differentiation of airway epithelium. Inhibition of Wnt/beta-catenin signaling, either by expression of Dkk1 or by tissue-specific deletion of beta-catenin, results in disruption of distal airway development and expansion of proximal airways. Wnt/beta-catenin functions upstream of BMP4, FGF signaling, and N-myc. Moreover, we show that beta-catenin and LEF/TCF activate the promoters of BMP4 and N-myc. Thus, Wnt/beta-catenin signaling is a critical upstream regulator of proximal-distal patterning in the lung, in part, through regulation of N-myc, BMP4, and FGF signaling.

Animals↗

PubMed2002

The endoplasmic reticulum as an integrating signalling organelle: from neuronal signalling to neuronal death.

The endoplasmic reticulum is one of the largest intracellular organelles represented by continuous network of cisternae and tubules, which occupies the substantial part of neuronal somatas and extends into finest neuronal processes. The endoplasmic reticulum controls protein synthesis as well as their post-translational processing, and generates variety of nucleus-targeted signals through Ca(2+)-binding chaperones. The normal functioning of the endoplasmic reticulum signalling cascades requires high concentrations of free calcium ions within the endoplasmic reticulum lumen ([Ca(2+)](L)), and severe alterations in [Ca(2+)](L) trigger endoplasmic reticulum stress response, manifested by either unfolded protein response (UPR) or endoplasmic reticulum overload response (EOR). At the same time, the endoplasmic reticulum is critically involved in fast neuronal signalling, by producing local or global cytosolic calcium signals via Ca(2+)-induced Ca(2+) release (CICR) or inositol-1,4,5-trisphosphate-induced Ca(2+) release (IICR). Both CICR and IICR are important for synaptic transmission and synaptic plasticity. Several special techniques allowing real-time [Ca(2+)](L) monitoring were developed recently. Video-imaging of [Ca(2+)](L) in neurones demonstrates that physiological signalling triggers minor decreases in overall intraluminal Ca(2+) concentration due to strong activation of Ca(2+) uptake, which prevents severe [Ca(2+)](L) alterations. The endoplasmic reticulum lumen also serves as a "tunnel" which allows rapid transport of Ca(2+) ions within highly polarised nerve cells. Fluctuations of intraluminal free Ca(2+) concentration represent a universal mechanism, which integrates physiological cellular signalling with protein synthesis and processing. In pathological conditions, fluctuations in [Ca(2+)](L) may initiate either adaptive or fatal stress responses.

Animals↗

PubMedDate not supplied

The signal sequence of nascent preprolactin interacts with the 54K polypeptide of the signal recognition particle.

Hydrophobic signal sequences direct the translocation of nascent secretory proteins and many membrane proteins across the membrane of the endoplasmic reticulum. Initiation of this process involves the signal recognition particle (SRP), which consists of six polypeptide chains and a 7S RNA and interacts with ribosomes carrying nascent secretory polypeptide chains. In the case of aminoterminal, cleavable signal sequences, in the absence of microsomal membranes it exerts a site-specific translational arrest in vitro. The size of the arrested fragment (60-70 amino-acid residues) suggests that elongation stops when the signal sequence has emerged fully from the ribosome. However, a direct interaction between the signal sequence and SRP has not previously been demonstrated and has even been questioned recently. We now show for the first time a direct interaction between the signal sequence of a secretory protein and a component of SRP, the 45K polypeptide (relative molecular mass (Mr) 54,000). This was achieved by means of a new method of affinity labelling which involves the translational incorporation of an amino acid, carrying a photoreactive group, into nascent polypeptides.

Affinity Labels↗

PubMed2004

Inhibition of mammalian target of rapamycin activates apoptosis signal-regulating kinase 1 signaling by suppressing protein phosphatase 5 activity.

Under serum-free conditions, rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), induces a cellular stress response characterized by rapid and sustained activation of the apoptosis signal-regulating kinase 1 (ASK1) signaling pathway and selective apoptosis of cells lacking functional p53. Here we have investigated how mTOR regulates ASK1 signaling using p53-mutant rhabdomyosarcoma cells. In Rh30 cells, ASK1 was found to physically interact with protein phosphatase 5 (PP5), previously identified as a negative regulator of ASK1. Rapamycin did not affect either protein level of PP5 or association of PP5 with ASK1. Instead, rapamycin caused rapid dissociation of the PP2A-B" regulatory subunit (PR72) from the PP5-ASK1 complex, which was associated with reduced phosphatase activity of PP5. This effect was dependent on expression of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). Down-regulation of PP5 activity by rapamycin coordinately activated ASK1, leading to elevated phosphorylation of c-Jun. Amino acid deprivation, which like rapamycin inhibits mTOR signaling, also inhibited PP5 activity, caused rapid dissociation of PR72, and activated ASK1 signaling. Overexpression of PP5, but not the PP2A catalytic subunit, blocked rapamycin-induced phosphorylation of c-Jun, and protected cells from rapamycin-induced apoptosis. The results suggest that PP5 is downstream of mTOR, and positively regulated by the mTOR pathway. The findings suggest that in the absence of serum factors, mTOR signaling suppresses apoptosis through positive regulation of PP5 activity and suppression of cellular stress.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Suppressor of cytokine signaling 7 inhibits prolactin, growth hormone, and leptin signaling by interacting with STAT5 or STAT3 and attenuating their nuclear translocation.

We report here the role of one of the less studied members of the family of suppressors of cytokine signaling (SOCS), namely SOCS-7, in cytokine signaling. We demonstrate that SOCS-7 inhibits prolactin (PRL), growth hormone (GH), or leptin (LEP) signaling mediated through STAT3 and STAT5 in a dose-dependent manner. SOCS-7 also attenuated STAT3 and STAT5 signaling induced by overexpression of JH1, the catalytic subdomain of JAK2. Since SOCS-7 interacted with phosphorylated STAT3 or STAT5, we assumed that SOCS-7 acts at the level of STAT proteins. Indeed, we showed that SOCS-7 inhibits PRL- and leptin-induced STAT5 and STAT3 phosphorylation and prevented the nuclear translocation of activated STAT3. Taken together, our results indicate that SOCS-7 is a physiological dysregulator of PRL, leptin, and probably also GH signaling and that its mode of action is a novel variation of SOCS protein inhibition of cytokine-inducible STAT-mediated signal transduction.

Active Transport, Cell Nucleus↗