6,672 research outputs found
Predicting the future of signaling for 2018
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Science Signaling
Chief Scientific Editor Michael B. Yaffe looks forward to what this year has in store for signaling research.
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Looking Ahead to the Past
No full textChief Scientific Editor Michael Yaffe makes his predictions for exciting new areas of signaling-related research.</jats:p
<i>Science Signaling</i> Podcast: 4 January 2011
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Chief Scientific Editor Michael Yaffe reviews the past year in
Science Signaling
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Molecular Analysis of TTP, a Key Regulator of TNFα Activity
No full textThe immediate-early protein tristetraprolin (TTP) is induced by numerous extracellular stimuli and during some apoptotic events. TTP and the related proteins TIS11b and TIS11d (TTP/TIS11 proteins) are members of a family with highly conserved Cys3His zinc fingers that are associated with RNA binding. In mice, lack of TTP causes an inflammatory syndrome that is mediated by TNFα 1, and evidence indicates that TTP can bind and destabilize TNFα and other cytokine mRNAs2. In vitro, all three TTP/TIS11 proteins possess this activity and it is present within the zinc finger region3. Several precedents suggest however that TTP/TIS11 proteins may also be implicated in survival, growth, or apoptotic pathways; a model we have addressed in this study.Breast Cancer Research Program (U.S.) (17-94-J-4063)National Institutes of Health (U.S.) (Grant PO1 HD17461)Arthritis Foundation (Postdoctoral Fellowship
Salvaging the septic heart through targeting the IL-6/p38 MAPK signaling network
No full textDepression of myocardial function during severe sepsis, which currently accounts for approx. 200,000 deaths/year in the United States (1), is characterized by a decrease in contractility and a poor response to fluid therapy (2). Since the md-1980s it has been recognized that the decreased cardiac function, which undoubtedly contributes to the overall pathophysiology of the septic state, does not arise from factors that are intrinsic to the myocardium, but instead results from the presence of circulating myocardial depressant factors (3, 4). Since much of the massive inflammation and multi-organ dysfunction in sepsis result from the secretion of various cytokines, it was long suspected that these proteins were also responsible, at least in part, for the observed myocardial dysfunction, although their identification, and the molecular basis for their effects on myocyte function were poorly understood
Fixin' to Divide
No full textIn this issue of Molecular Cell, Yata et al. (2012) show that the mitotic kinase and cell-cycle regulator Plk1 can directly stimulate the DNA repair process, providing a potential mechanism of crosstalk between DNA repair and cell-cycle signaling
Signaling netwErks get the global treatment
No full textTwo landmark studies of cell signaling, by RNA interference and phosphoproteomics, provide complementary global views of the pathways downstream of receptor kinases, including those regulated by Erks
Human neutrophil elastase mediates fibrinolysis shutdown through competitive degradation of plasminogen and generation of angiostatin
No full textBACKGROUND A subset of trauma patients undergo fibrinolysis shutdown rather than pathologic hyperfibrinolysis, contributing to organ failure. The molecular basis for fibrinolysis shutdown in trauma is incompletely understood. Elastase released from primed/activated human neutrophils (HNE) has historically been described as fibrin(ogen)olytic. However, HNE can also degrade plasminogen (PLG) to angiostatin (ANG), retaining the kringle domains but not the proteolytic function, and could thereby compete for generation of active plasmin by tissue plasminogen activator (tPA). We hypothesized that HNE can drive fibrinolysis shutdown rather than fibrinolysis. METHODS Turbidometry was performed using light scatter (λ = 620 nm) in a purified fibrinogen + PLG system and in healthy citrate plasma clotted with Ca2+/thrombin ± tPA, ±HNE, and ±ANG to evaluate HNE effects on fibrinolysis, quantified by time to transition midpoint (Tm). ΔTmfrom control is reported as percent of control ±95% CI. Purified HNE coincubated with PLG or tPA was analyzed by western blot to identify cleavage products. Exogenous HNE was mixed ex vivo with healthy volunteer blood (n = 7) and used in TEG ± tPA to evaluate effects on fibrinolysis. RESULTS HNE did not cause measurable fibrinolysis on fibrin clots, clotted plasma, or whole blood as assessed by turbidometry or TEG in the absence of tPA. Upon tPA treatment, all three methods of evaluating fibrinolysis showed delays and decreases in fibrinolysis caused by HNE relative to control: fibrin clot turbidometry ΔTm= 110.7% (CI 105.0-116.5%), clotted citrate plasma (n = 6 healthy volunteers) ΔTm= 126.1% (CI 110.4-141.8%), and whole blood native TEG (n = 7 healthy volunteers) with ΔLY30 = 28% (p = 0.043). Western blot analysis of HNE-PLG co-incubation confirmed that HNE generates angiostatin K1-3, and plasma turbidity assays treated with angiostatin K1-3 delayed fibrinolysis. CONCLUSION HNE degrades PLG and generates angiostatin K1-3, which predominates over HNE cleavage of fibrin(ogen). These findings suggest that neutrophil release of elastase may underlie trauma-induced fibrinolytic shutdown.National Institutes of Health (U.S.) (Grant F32-HL134244)National Institutes of Health (U.S.) (Grant L30-GM120751United States. Department of Defense (Grant 151953
Halting a Runaway Train: Reforming Teacher Pensions for the 21st Century
No full textWhen it comes to public-sector pensions, writes lead author Michael B. Lafferty in this report, "A major public-policy (and public-finance) problem has been defined and measured, debated and deliberated, but not yet solved. Except where it has been." As recounted in "Halting a Runaway Train: Reforming Teacher Pensions for the 21st Century", these exceptions turn out to be revealing -- and encouraging
14-3-3 Proteins, FHA Domains and BRCT Domains in the DNA Damage Response
No full textThe DNA damage response depends on the concerted activity of protein serine/threonine kinases and modular phosphoserine/threonine-binding domains to relay the damage signal and recruit repair proteins. The PIKK family of protein kinases, which includes ATM/ATR/DNA-PK, preferentially phosphorylate Ser-Gln sites, while their basophilic downstream effecter kinases, Chk1/Chk2/MK2 preferentially phosphorylate hydrophobic-X-Arg-X-X-Ser/Thr-hydrophobic sites. A subset of tandem BRCT domains act as phosphopeptide binding modules that bind to ATM/ATR/DNA-PK substrates after DNA damage. Conversely, 14-3-3 proteins interact with substrates of Chk1/Chk2/MK2. FHA domains have been shown to interact with substrates of ATM/ATR/DNA-PK and CK2. In this review we consider how substrate phsophorylation together with BRCT domains, FHA domains and 14-3-3 proteins function to regulate ionizing radiation-induced nuclear foci and help to establish the G2/M checkpoint. We discuss the role of MDC1 a molecular scaffold that recruits early proteins to foci, such as NBS1 and RNF8, through distinct phosphodependent interactions. In addition, we consider the role of 14-3-3 proteins and the Chk2 FHA domain in initiating and maintaining cell cycle arrest
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