Educational Forum with Clinical Studies Current Science and Research

June 17, 2011

Abl Protein-Tyrosine Kinase Inhibitor STI571 Inhibits In Vitro Signal Transduction Mediated by c-Kit and Platelet-Derived Growth Factor Receptors. Xanya Sofra Weiss

Filed under: Xanya Sofra Weiss — Tags: — Dr. Xanya @ 6:17 am

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STI571 (formerly known as CGP 57148B) is a protein-tyrosine kinase inhibitor that is currently in clinical trials for the treatment of chronic myelogenous leukemia. STI571 selectively inhibits the Abl and platelet-derived growth factor (PDGF) receptor tyrosine kinases in vitro and blocks cellular proliferation and tumor growth of Bcr-abl– or v-abl-expressing cells. We have further investigated the profile of STI571 against related recep- tor tyrosine kinases. STI571 was found to potently inhibit the kinase activity of the

Global landscape of protein complexes in the yeast Saccharomyces cerevisiae. Xanya Sofra Weiss

Filed under: Xanya Sofra Weiss — Tags: — Dr. Xanya @ 6:15 am

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Identification of protein–protein interactions often provides insight into protein function, and many cellular processes are performed by stable protein complexes. We used tandem affinity purification to process 4,562 different tagged proteins of the yeast Saccharomyces cerevisiae. Each preparation was analysed by both matrix-assisted laser desorption/ ionization–time of flight mass spectrometry and liquid chromatography tandem mass spectrometry to increase coverage and accuracy. Machine learning was used to integrate the mass spectrometry scores and assign probabilities to the protein–protein interactions. Among 4,087 different proteins identified with high confidence by mass spectrometry from 2,357 successful purifications, our core data set (median precision of 0.69) comprises 7,123 protein–protein interactions involving 2,708 proteins. A Markov clustering algorithm organized these interactions into 547 protein complexes averaging 4.9 subunits per complex, about half of them absent from the MIPS database, as well as 429 additional interactions between pairs of complexes. The data (all of which are available online) will help future studies on individual proteins as well as functional genomics and systems biology.

Xanya Sofra Weiss

Xanya Sofra Weiss

June 10, 2011

Protein turnover plays a key role in aging. Xanya Sofra Weiss

Filed under: Xanya Sofra Weiss — Tags: — Dr. Xanya @ 3:46 am

Although the molecular mechanism of aging is unknown, a progressive increase with age in the concentration of damaged macromolecules,

especially proteins, is likely to play a central role in senescent decline. In this paper, we discuss evidence that the progressive decrease in protein

synthesis and turnover can be the primary cause of the increase in the concentration of damaged proteins with age. Conversely, protein damage itself

is likely to be the cause of the decrease in protein turnover. This could establish a positive feedback loop where the increase in protein damage decreases

the protein turnover rate, leading to a further increase in the concentration of damaged proteins. The establishment of such a feedback loop should result in

an exponential increase in the amount of protein damage—a protein damage catastrophe—that could be the basis of the general deterioration observed in senescent organisms.

© 2002 Published by Elsevier Science Ireland Ltd.

Xanya Sofra Weiss

Xanya Sofra Weiss

Parasympathetic nerve-evoked protein synthesis, mitotic activity and salivary secretion in the rat parotid gland and the dependence on NO-generation. Xanya Sofra Weiss

Filed under: Xanya Sofra Weiss — Tags: — Dr. Xanya @ 3:44 am

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Incorporation of radiolabelled leucine and thymidine into trichloroacetic acid-insoluble material of the parotid gland was used as indices of protein synthesis and mitotic activity, respectively, following electrical stimulation of the parasympathetic auriculo-temporal nerve for 30 min in pentobarbitone-anaesthetized rats under adrenoceptor blockade (phentolamine and propranolol, 2 mg/kg intravenous of each) in the absence or presence of atropine (2 mg/kg intravenous) and without or with nitric oxide synthase inhibitors. In atropinized rats, the parasympathetic non-adrenergic, non-cholinergic (NANC) nerve-evoked mean increases in protein synthesis at a frequency of 10 Hz (142%) and 40 Hz (200%) were not affected in a statistically significant way (124 and 275%, respectively) by the neuronal type NO-synthase inhibitor Nwpropyl-L-arginine (N-PLA) (30 mg/kg intravenous). Neither were the increase (175%) in protein synthesis at 10 Hz in non-atropinized animals affected by N-PLA (180%). The increase (65%) in mitotic activity, 19 h after the end of stimulation at 40 Hz, in the presence of atropine, was not affected by N-PLA (55%). Neither were the increase (95%) in gland content of amylase at this point of observation statistically significant affected by N-PLA (144%). The secretion of fluid and output of amylase from the parotid gland upon nerve stimulation was not affected by N-PLA. When examining the non-selective NO-synthase inhibitor L-NAME (30 mg/kg intravenous) in atropinized rats subjected to stimulation at 10 Hz, neither the increase in protein synthesis nor the evoked fluid response or amylase outputs were affected. Hence, in contrast to an NO-dependent sympathetic-induced protein synthesis and mitosis in the parotid gland, involving the activity of the neuronal type NO-synthase, no support for a parasympathetic-induced protein synthesis (and gain in gland amylase) and mitosis, depending on NO-generation, was found.

Xanya Sofra Weiss

Xanya Sofra Weiss

Non-neuronal cholinergic system and signal transduction pathways mediated by band 3 in red blood cells. Xanya Sofra Weiss

Filed under: Xanya Sofra Weiss — Tags: — Dr. Xanya @ 3:41 am

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BACKGROUND: Non-neuronal acetylcholine (ACh) and acetylcholinesterase (AChE) have been recognized in t Vascular ACh has been associated by us with the regulation of microcirculatory flow by modulating nitric oxide ( intracellular mobilization, metabolism (NOx) and release from erythrocytes, as well as the glycolytic flux. Velnacri maleate is a well-known AChE inhibitor which plays a competitive role by decreasing NO-mediated erythrocyte responses. A plausible hypothesis to explain the mechanisms underlying those events hinges on the NO translo among nitrosylated molecules and phosphorylated/dephosphorylated states of band 3 protein, processed by maj tyrosine-kinases (PTK: p72syk, p53/56lyn and p59/61hck) and phosphotyrosine-phosphatases (PTP).

METHODS: To assess this hypothesis under the influence of AChE effectors (acetylcholine/velnacrine), blood sa from healthy donors were harvested and Western blot analysis was subsequently used to determine the degree phosphorylation, in the presence and absence of PTK/PTP inhibitors. NO and nitrites/nitrates were quantified usi amperometric method and the Griess Reaction, respectively, in erythrocyte suspensions. Measurements of eryth metabolites (2,3-bisphosphoglycerate; glyceraldehyde 3-phosphate dehydrogenase; glucose-6-phosphodehydro lactate), hemoglobin and cyclic nucleotides were conducted afterwards.

RESULTS: Increased levels of phosphorylated-band 3 obtained upon p72syk inhibition suggest p59/61hck and as secondary involved kinases. As to NO/NOx quantification, in the presence of PTKi we reported higher levels velnacrine-AChE, as opposed to acetylcholine-AChE. Calpeptin, a PTP inhibitor which triggers full band 3-phosphorylation, led to the opposite NO mobilization, being reinforced by ACh. Oxy-hemoglobin, glyceraldehy 3-phosphate dehydrogenase and glucose-6-phosphodehydrogenase were found to decrease with ACh, whereas lactate and both cGMP/cAMP happened to increase.

CONCLUSION: Changes on human erythrocyte NOx mobilization and metabolic fluxes occur under influence of non-neuronal ACh/AChE, in turn dependent on the degree of band 3-phosphorylation. Since these vascular eve potentially change under pathological conditions, coadjuvant drugs could become accessible in the setting of microcirculation disease.

Xanya Sofra Weiss

Xanya Sofra Weiss

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