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Signalling Responses (signalling + response)

Distribution by Scientific Domains

Life Sciences	57%
Medical Sciences	42%

Selected Abstracts

Signalling responses linked to betulinic acid-induced apoptosis are antagonized by MEK inhibitor U0126 in adherent or 3D spheroid melanoma irrespective of p53 status

INTERNATIONAL JOURNAL OF CANCER, Issue 5 2006
Manuel Rieber
Abstract MEK1/2 inhibitors like U0126 can potentiate or antagonize the antitumor activity of cytotoxic agents such as cisplatin, paclitaxel or vinblastine, depending on the drug or the target cells. We now investigated whether U0126, differentially regulates melanoma signaling in response to UV radiation or betulinic acid, a drug lethal against melanoma. This report shows that U0126 inhibits early response (ERK) kinase activation and cyclin A expression in wt p53 C8161 melanoma exposed to either UV radiation or betulinic acid. However, U0126 does not protect from UV damage, but counteracts betulinic acid-mediated apoptosis in the same cells. Protection from the latter drug by joint treatment with U0126 was also evident in wt p53 MelJuso melanoma and mutant p53 WM164 melanoma. The latter cells were the most responsive to betulinic acid, showing a selective decline in the cdk4 protein, without a comparable change in other key cell cycle proteins like cdc2, cdk2, cdk7 or cyclin A, prior to apoptosis-associated PARP fragmentation. Laser scanning cytometry also showed that betulinic acid induced a significant increase in chromatin condensation in WM164 melanoma irrespective of whether they were in adherent form or as multicellular spheroids. All these betulinic acid-induced changes were counteracted by U0126. Our data show for the first time that (a) cdk4 protein is an early target of betulinic acid-induced apoptosis and (b) unrestricted ERK signaling favours betulinic acid-induced apoptosis, but this is counteracted by U0126, partly through counteracting chromatin condensation and restoring Akt activation decreased by betulinic acid treatment. © 2005 Wiley-Liss, Inc. [source]

Proinflammatory signalling stimulated by the type III translocation factor YopB is counteracted by multiple effectors in epithelial cells infected with Yersinia pseudotuberculosis

MOLECULAR MICROBIOLOGY, Issue 5 2003
Gloria I. Viboud
Summary Type III secretion systems are used by several pathogens to translocate effector proteins into host cells. Yersinia pseudotuberculosis delivers several Yop effectors (e.g. YopH, YopE and YopJ) to counteract signalling responses during infection. YopB, YopD and LcrV are components of the translocation machinery. Here, we demonstrate that a type III translocation protein stimulates proinflammatory signalling in host cells, and that multiple effector Yops counteract this response. To examine proinflammatory signalling by the type III translocation machinery, HeLa cells infected with wild-type or Yop,Y. pseudotuberculosis strains were assayed for interleukin (IL)-8 production. HeLa cells infected with a YopEHJ, triple mutant released significantly more IL-8 than HeLa cells infected with isogenic wild-type, YopE,, YopH, or YopJ, bacteria. Complementation analysis demonstrated that YopE, YopH or YopJ are sufficient to counteract IL-8 production. IL-8 production required YopB, but did not require YopD, pore formation or invasin-mediated adhesion. In addition, YopB was required for activation of nuclear factor kappa B, the mitogen-activated protein kinases ERK and JNK and the small GTPase Ras in HeLa cells infected with the YopEHJ, mutant. We conclude that interaction of the Yersinia type III translocator factor YopB with the host cell triggers a proinflammatory signalling response that is counteracted by multiple effectors in host cells. [source]

G-protein-coupled receptor phosphorylation: where, when and by whom

BRITISH JOURNAL OF PHARMACOLOGY, Issue S1 2008
A B Tobin
Almost all G-protein coupled receptors (GPCRs) are regulated by phosphorylation and this process is a key event in determining the signalling properties of this receptor super-family. Receptors are multiply phosphorylated at sites that can occur throughout the intracellular regions of the receptor. This diversity of phospho-acceptor sites together with a lack of consensus phosphorylation sequences has led to the suggestion that the precise site of phosphorylation is not important in the phosphorylation-dependent regulation of GPCR function but rather it is the increase in bulk negative charge of the intracellular face of the receptor which is the significant factor. This review investigates the possibility that the multi-site nature of GPCR phosphorylation reflects the importance of specific phosphorylation events which mediate distinct signalling outcomes. In this way receptor phosphorylation may provide for a flexible regulatory mechanism that can be tailored in a tissue specific manner to regulate physiological processes. By understanding the flexible nature of GPCR phosphorylation if may be possible to develop agonists or allosteric modulators that promote a subset of phosphorylation events on the target GPCR and thereby restrict the action of the drug to a particular receptor mediated signalling response. British Journal of Pharmacology (2008) 153, S167,S176; doi:10.1038/sj.bjp.0707662; published online 14 January 2008 [source]

Acute signalling responses to intense endurance training commenced with low or normal muscle glycogen

EXPERIMENTAL PHYSIOLOGY, Issue 2 2010
Wee Kian Yeo
We have previously demonstrated that well-trained subjects who completed a 3 week training programme in which selected high-intensity interval training (HIT) sessions were commenced with low muscle glycogen content increased the maximal activities of several oxidative enzymes that promote endurance adaptations to a greater extent than subjects who began all training sessions with normal glycogen levels. The aim of the present study was to investigate acute skeletal muscle signalling responses to a single bout of HIT commenced with low or normal muscle glycogen stores in an attempt to elucidate potential mechanism(s) that might underlie our previous observations. Six endurance-trained cyclists/triathletes performed a 100 min ride at ,70% peak O2 uptake (AT) on day 1 and HIT (8 × 5 min work bouts at maximal self-selected effort with 1 min rest) 24 h later (HIGH). Another six subjects, matched for fitness and training history, performed AT on day 1 then 1,2 h later, HIT (LOW). Muscle biopsies were taken before and after HIT. Muscle glycogen concentration was higher in HIGH versus LOW before the HIT (390 ± 28 versus 256 ± 67 ,mol (g dry wt),1). After HIT, glycogen levels were reduced in both groups (P < 0.05) but HIGH was elevated compared with LOW (229 ± 29 versus 124 ± 41 ,mol (g dry wt),1; P < 0.05). Phosphorylation of 5,AMP-activated protein kinase (AMPK) increased after HIT, but the magnitude of increase was greater in LOW (P < 0.05). Despite the augmented AMPK response in LOW after HIT, selected downstream AMPK substrates were similar between groups. Phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) was unchanged for both groups before and after the HIT training sessions. We conclude that despite a greater activation AMPK phosphorylation when HIT was commenced with low compared with normal muscle glycogen availability, the localization and phosphorylation state of selected downstream targets of AMPK were similar in response to the two interventions. [source]

Proinflammatory signalling stimulated by the type III translocation factor YopB is counteracted by multiple effectors in epithelial cells infected with Yersinia pseudotuberculosis

Adaptations Of Skeletal Muscle To Prolonged, Intense Endurance Training

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 3 2002
John A Hawley
SUMMARY 1. Endurance exercise induces a variety of metabolic and morphological responses/adaptations in skeletal muscle that function to minimize cellular disturbances during subsequent training sessions. 2. Chronic adaptations in skeletal muscle are likely to be the result of the cumulative effect of repeated bouts of exercise, with the initial signalling responses leading to such adaptations occurring after each training session. 3. Recently, activation of the mitogen-activated protein kinase signalling cascade has been proposed as a possible mechanism involved in the regulation of many of the exercise-induced adaptations in skeletal muscle. 4. The protein targets of AMP-activated protein kinase also appear to be involved in both the regulation of acute metabolic responses and chronic adaptations to exercise. 5. Endurance training is associated with an increase in the activities of key enzymes of the mitochondrial electron transport chain and a concomitant increase in mitochondrial protein concentration. These morphological changes, along with increased capillary supply, result in a shift in trained muscle to a greater reliance on fat as a fuel with a concomitant reduction in glycolytic flux and tighter control of acid,base status. Taken collectively, these adaptations result in an enhanced performance capacity. [source]