Cell Signalling Pathways. Xanya Sofra Weiss

Cells use a large number of clearly defined signalling pathways to regulate their activity. In this module, attention is focused on the ON mechanisms responsible for transmitting information into the cell. These signalling pathways fall into two main groups depending on how they are activated. Most of them are activated by external stimuli and function to transfer information from the cell surface to internal effector systems. However, some of the signalling systems respond to information generated from within the cell, usually in the form of metabolic messengers. For all of these signalling pathways, information is conveyed either through protein–protein interactions or it is transmitted by diffusible elements usually referred to as second messengers. Cells often employ a number of these signalling pathways, and cross-talk between them is an important feature. In this section, attention is focused on the
properties of the major intracellular signalling pathways operating in cells to regulate their cellular activity.
During the processes of development, specific cell types select out those signalling systems that are suitable to control their particular functions. One of the aims of this website is to understand how these unique cell-specific signalsomes function to regulate different mammalian cell types.

Xanya Sofra Weiss

Xanya Sofra Weiss

Phosphorylation meets nuclear import: a review. Xanya Sofra Weiss

Phosphorylation is the most common and pleiotropic modification in biology, which plays a vital role in regulating and finely tuning a multitude of biological pathways. Transport across the nuclear envelope is also an essential cellular function and is intimately linked to many degeneration processes that lead to disease. It is therefore not surprising that phosphorylation of cargos trafficking between the cytoplasm and nucleus is emerging as an important step to regulate nuclear availability, which directly affects gene expression, cell growth and proliferation. However, the literature on phosphorylation of nucleocytoplasmic trafficking cargos is often confusing. Phosphorylation, and its mirror process dephosphorylation, has been shown to have opposite and often contradictory effects on the ability of cargos to be transported across the nuclear envelope. Without a clear connection between attachment of a phosphate moiety and biological response, it is difficult to fully understand and predict how phosphorylation regulates nucleocytoplasmic trafficking. In this review, we will recapitulate clue findings in the field and provide some general rules on how reversible phosphorylation can affect the nuclear-cytoplasmic localization of substrates. This is only now beginning to emerge as a key regulatory step in biology.

Xanya Sofra Weiss

Xanya Sofra Weiss

Nuclear Shp-2 keeps telomerase reverse transcriptase in the nucleus – new potential anti-aging target

Vascular diseases are associated with cellular aging, which is accompanied by telomere shortening counteracted in the nucleus by telomerase reverse transcriptase (TERT). Under conditions of oxidative stress TERT is exported from the nucleus and this export is mediated by Src-kinases via tyrosine phosphorylation of TERT. Nuclear export of TERT resulted in accelerated aging of endothelial cells. Therefore, the aim of this study was to determine a counterplayer for nuclear export of TERT.
In embryonic fibroblasts deficient in Src, Fyn and Yes, TERT nuclear export induced by oxidative stress is abolished. Fyn does not seem to play a role, because unlike Src and Yes it is not found in the nucleus. A putative regulator of this export is the tyrosine phosphatase Shp-2, which can regulate the activity of the Src-kinase family. We demonstrated that Shp-2 is localized in the nucleus and associated with TERT in endothelial cells. Overexpression of Shp-2 inhibited oxidative stress induced nuclear export of TERT and ablation of Shp-2 by siRNA reduced nuclear telomerase activity. This inhibition was dependent on the enzymatic activity of Shp-2 and on tyrosine 707 in TERT because overexpression of the dominant negative Shp-2 mutant (C459S) led to a reduction of TERT protein and telomerase activity, whereas telomerase activity in TERTY707F overexpressing cells was not altered by Shp-2. Thus, tyrosine 707 seems to be a critical target for regulation of TERT localization by Shp-2 mediated dephosphorylation. To establish a causal link between Shp-2, nuclear TERT and oxidative stress, we determined reactive oxygen species (ROS) formation in endothelial cells. Overexpression of Shp-2(C459S) (2.45 fold +/- 0.34 of Shp-2 wt) or ablation of Shp-2 by siRNA increased ROS levels (2.23 fold +/- 0.54 of scrambled siRNA). In contrast, keeping TERT in the nucleus by mutating tyrosine 707 or overexpressing Shp-2 wt reduced ROS formation (0.73 and 0.75 fold, respectively).
In summary, these data indicate that TERT is associated with nuclear Shp-2, Shp-2 acts as a negative regulator for nuclear export of TERT probably via regulating tyrosine 707 dephosphorylation of TERT and reducing ROS formation.
Thus, increasing nuclear Shp-2 activity could be a useful tool to delay vascular aging processes.

Xanya Sofra Weiss

Xanya Sofra Weiss

Causal Protein-Signaling Networks Derived from Multiparame Single-Cell Data. Xanya Sofra Weiss

Machine learning was applied for the automated derivation of causal influences in cellular networks. This derivation relied on the simultaneous measurement of multiple phosphoryl protein and phospholipid components in thousands of individual primary human immune cells. Perturbing these cells with molecular interventions drove the ordering of connection between pathway components, wherein Bayesian network computational methods automat elucidated most of the traditionally reported signaling relationships and predicted novel interpathway network causalities, which we verified experimentally. Reconstruction of netw models from physiologically relevant primary single cells might be applied to understandi native-state tissue signaling biology, complex drug actions, and dysfunctional signaling in diseased cells.

Xanya Sofra Weiss

Xanya Sofra Weiss

Attenuation of age-related declines in glucagon-mediated signal transduction in rat liver by exercise training. Xanya Sofra Weiss

This study investigated alterations in glucagon receptor-mediated signal transduction in rat livers from 7- to 25-mo-old animals and examined the effects of exercise training on ameliorating these changes. Sixty-six young (4 mo), middle-aged (12 mo), and old (22 mo) male Fischer 344 rats were divided into sedentary and trained (treadmill running) groups. Isolated hepatic membranes were combined with [ I-Tyr ]monoiodoglucagon and nine concentrations of glucagon to determine maximal binding capacity (B ) and dissociation constant (K d). No alterations were found in B among groups; however, middle-aged trained animals had significantly higher glucagon affinity (lowerK d; 21.1 ± 1.8 nM) than did their untrained counterparts (50.2 ± 7.1 nM). Second messenger studies were performed by measuring adenylyl cyclase (AC) specific activity under basal conditions and with four pharmacological stimulations to assess changes in receptor-dependent, G protein- dependent, and AC catalyst-dependent cAMP production. Age-related declines were observed in the old animals under all five conditions. Training resulted in increased cAMP production in the old animals when AC was directly stimulated by forskolin. Stimulatory G protein (Gs) content was reduced with age in the sedentary group; however, training offset this decline. We conclude that age-related declines in glucagon signaling capacity and responsiveness may be attributed, in part, to declines in intrinsic AC activity and changes in G protein [inhibitory G protein (Gi)/Gs] ratios. These age-related changes occur in the absence of alterations in glucagon receptor content and appear to involve both G protein- and AC-related changes. Endurance training was able to significantly offset these declines through restoration of the Gi/Gs ratio and AC activity.

Xanya Sofra Weiss

Xanya Sofra Weiss

Synthesis and anti-bacterial, anti-fungal activity of some novel chalcone derivatives. Xanya Sofra Weiss

S.S.Turkar, A.H. Rodge, G.D.Hatnapure, A.P.Keche, G.S.Gaikwad

Department of Chemistry, J.L.Charturvedi College of Engineering, Nagpur- India

Chalcone have displayed an impressive array of biological importance.
A new series of chalcone have been synthesized by reacting 1-(4-isobutylphenyl) ethanone with different substituted aldehyde in turn clasien-schimidt condensation.
All synthesized compounds have been evaluated for anti-bacterial and anti-fungal studies.
Compound 11 showed promising anti-bacterial activities against staphylococcus aureus having MIC50 value of 2.10ug/ml and compound 2 also showed good anti-fungal activity against Candida krusei having MIC50 value of 2.12ug/ml.

Xanya Sofra Weiss

Xanya Sofra Weiss

Age-related enhancement of a protein synthesis-depende induced by low frequency paired-pulse stimulation. Xanya Sofra Weiss

Protein synthesis-dependent late phase of LTP (L-LTP) is typically induced by repeated high-frequency stimulation (H and is positively correlated with age-related memory loss.Here we report a novel form of protein synthesis-dependen induced by a brief 1-Hz paired-pulse stimulation (PP-1 Hz, 1 min). In contrast to L-LTP induced by HFS, the late animals. Rather, it emerges and becomes enhanced in an age-related way. Thus, in 1.5- to 2-mo-old mice, a brief decaying to baseline in about 90 min. By contrast, PP-1 Hz stimulation induces an enduring and protein synthesis Hz-induced L-LTP is dependent on NMDA receptor activation, requires voltage-dependent calcium channels, and i memory ability declines with aging, the age-related enhancement of L-LTP induced by PP-1 Hz stimulation indic correlated with memory ability.

Xanya Sofra Weiss

Xanya Sofra Weiss