Identification of an AP1-ZFP36 Regulatory Network Associated with Breast Cancer Prognosis.

It has been established that ZFP36 (also known as Tristetraprolin or TTP) promotes mRNA degradation of proteins involved in inflammation, proliferation and tumor invasiveness. In mammary epithelial cells ZFP36 expression is induced by STAT5 activation during lactogenesis, while in breast cancer ZFP36 expression is associated with lower grade and better prognosis. Here, we show that the AP-1 transcription factor components, i.

Bypassing ubiquitination enables LAT recycling to the cell surface and enhanced signaling in T cells.

LAT molecules defective in ubiquitination have an increased half-life and induce enhanced signaling when expressed in T cells. In this study, we have examined the role of ubiquitination in regulating LAT endocytosis, recycling, and degradation in resting and stimulated T cells. By tracking and comparing plasma membrane-labeled wild type and ubiquitination-resistant 2KR LAT, we find that ubiquitination promotes the degradation of surface LAT in T cells.

Spheroscope: A custom-made miniaturized microscope for tracking tumour spheroids in microfluidic devices.

3D cell culture models consisting of self-assembled tumour cells in suspension, commonly known as tumour spheroids, are becoming mainstream for high-throughput anticancer drug screening. A usual measurable outcome of screening studies is the growth rate of the spheroids in response to treatment. This is commonly quantified on images obtained using complex, expensive, optical microscopy systems, equipped with high-quality optics and customized electronics.

Enhanced T-cell activation and differentiation in lymphocytes from transgenic mice expressing ubiquitination-resistant 2KR LAT molecules.

Linker for activation of T cells (LAT) is critical for the propagation of T-cell signals upon T-cell receptor (TCR) activation. Previous studies demonstrated that substitution of LAT lysines with arginines (2KR LAT) resulted in decreased LAT ubiquitination and elevated T-cell signaling, indicating that LAT ubiquitination is a molecular checkpoint for attenuation of T-cell signaling. To investigate the role of LAT ubiquitination in vivo, we have generated transgenic mice expressing WT and ubiquitin-defective 2KR LAT.

Effect of angiotensin II and small GTPase Ras signaling pathway inhibition on early renal changes in a murine model of obstructive nephropathy.

Tubulointerstitial fibrosis is a major feature of chronic kidney disease. Unilateral ureteral obstruction (UUO) in rodents leads to the development of renal tubulointerstitial fibrosis consistent with histopathological changes observed in advanced chronic kidney disease in humans. The purpose of this study was to assess the effect of inhibiting angiotensin II receptors or Ras activation on early renal fibrotic changes induced by UUO.

VAV3 mediates resistance to breast cancer endocrine therapy.

Introduction: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor α (ERα) are among the most effective systemic treatments for ERα-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERα transcriptional regulatory plasticity. Herein we identify VAV3 as a critical component in this process.

Imbalance of neurotrophin receptor isoforms TrkB-FL/TrkB-T1 induces neuronal death in excitotoxicity.

A better understanding of the mechanisms underlying neuronal death in cerebral ischemia is required for the development of stroke therapies. Here we analyze the contribution of the tropomyosin-related kinase B (TrkB) neurotrophin receptor to excitotoxicity, a primary pathological mechanism in ischemia, which is induced by overstimulation of glutamate receptors of the N-methyl-D-aspartate type. We demonstrate a significant modification of TrkB expression that is strongly associated with neurodegeneration in models of ischemia and in vitro excitotoxicity.

Etiopathology of chronic tubular, glomerular and renovascular nephropathies: clinical implications.

Chronic kidney disease (CKD) comprises a group of pathologies in which the renal excretory function is chronically compromised. Most, but not all, forms of CKD are progressive and irreversible, pathological syndromes that start silently (i.e.

Common pathophysiological mechanisms of chronic kidney disease: therapeutic perspectives.

It is estimated that over 10% of the adult population in developed countries have some degree of chronic kidney disease (CKD). CKD is a progressive and irreversible deterioration of the renal excretory function that results in implementation of renal replacement therapy in the form of dialysis or renal transplant, which may also lead to death. CKD poses a growing problem to society as the incidence of the disease increases at an annual rate of 8%, and consumes up to 2% of the global health expenditure.

Kidins220/ARMS downregulation by excitotoxic activation of NMDARs reveals its involvement in neuronal survival and death pathways.

Functional and protein interactions between the N-methyl-D-aspartate type of glutamate receptor (NMDAR) and neurotrophin or ephrin receptors play essential roles in neuronal survival and differentiation. A shared downstream effector for neurotrophin- and ephrin-receptor signaling is kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS). Because this molecule is obligatory for neurotrophin-induced differentiation, we investigated whether Kidins220/ARMS and NMDAR functions were related.

Activation of Erk1/2 and Akt following unilateral ureteral obstruction.

Chronic unilateral ureteral obstruction is a well characterized model of renal injury leading to tubulointerstitial fibrosis and distinct patterns of cell proliferation and apoptosis in the obstructed kidney. In this study we assessed the contribution of the mitogen activated protein kinase (MAPK)-ERK1/2 and the phosphatidylinositol 3 kinase (PI3K)-Akt pathways to early renal changes following unilateral obstruction. Increased activation of small Ras GTPase and its downstream effectors ERK1/2 and Akt was detected in ligated kidneys.

Thyroid hormone receptor-beta (TR beta 1) impairs cell proliferation by the transcriptional inhibition of cyclins D1, E and A2.

Thyroid hormone receptor-beta1 (TRbeta1) belongs to the ligand-inducible transcription factor superfamily. We have previously described that stable TRbeta1 expression impairs fibroblast proliferation diminishing levels and activity of the main regulators of the G(1)/S transition. To unmask the underlying molecular mechanism of this action, we have investigated the expression of cyclin D1, E and A2 upon serum stimulation in TRbeta1 expressing cells, finding a strong downregulation of their mRNAs, concomitant with low protein levels.

Long-term nebivolol administration reduces renal fibrosis and prevents endothelial dysfunction in rats with hypertension induced by renal mass reduction.

Objectives: D/L-Nebivolol is a lypophilic beta1-adrenergic antagonist which is devoid of intrinsic sympathomimetic activity and can increase nitric oxide (NO) bioavailability with its subsequent vasodilating properties. The purpose of the present work was to assess the effect of long-term nebivolol administration on both renal damage and endothelial dysfunction induced by renal mass reduction (RMR) in rats. Atenolol, which does not increase NO bioavailability, was included in the study as a comparative beta-adrenoceptor antagonist.

Involvement of small Ras GTPases and their effectors in chronic renal disease.

The mechanisms involved in the development of renal fibrosis are poorly understood. Small Ras GTPases control cell proliferation, differentiation, cellular growth and apoptosis, with cell-specific expression in the kidney. Cytokines, high glucose medium or advanced glycation end-products activate Ras in different renal cells.

Excitotoxicity and focal cerebral ischemia induce truncation of the NR2A and NR2B subunits of the NMDA receptor and cleavage of the scaffolding protein PSD-95.

The N-methyl-D-aspartate receptor (NMDAR) is central to physiological and pathological functioning of neurons. Although promising results are beginning to be obtained in the treatment of dementias, clinical trials with NMDAR antagonists for stroke, trauma and neurodegenerative disorders, such as Hungtinton's disease, have failed before. In order to design effective therapies to prevent excitotoxic neuronal death, it is critical to characterize the consequences of excessive NMDAR activation on its expression and function.

Endoglin regulates renal ischaemia-reperfusion injury.

Background: Renal ischaemia-reperfusion (I-R) can cause acute tubular necrosis and chronic renal deterioration. Endoglin, an accessory receptor for Transforming Growth Factor-beta1 (TGF-beta1), is expressed on activated endothelium during macrophage maturation and implicated in the control of fibrosis, angiogenesis and inflammation.

Methods: Endoglin expression was monitored over 14 days after renal I-R in rats.

Temporal changes in renal endoglin and TGF-beta1 expression following ureteral obstruction in rats.

Chronic renal disease is characterized by the accumulation of extracellular matrix proteins in the kidney and a loss of renal function. Tubulointerstitial fibrosis has been reported to play an important role in the progression of chronic renal diseases. Transforming growth factor-beta1 (TGF-beta1) is a profibrotic cytokine playing a major contribution to fibrotic kidney disease.

Transcription of the NR1 subunit of the N-methyl-D-aspartate receptor is down-regulated by excitotoxic stimulation and cerebral ischemia.

The N-methyl-D-aspartate (NMDA) type of glutamate receptor (NMDAR) plays central roles in normal and pathological neuronal functioning. We have examined the regulation of the NR1 subunit of the NMDAR in response to excessive activation of this receptor in in vitro and in vivo models of excitotoxicity. NR1 protein expression in cultured cortical neurons was specifically reduced by stimulation with 100 microM NMDA or glutamate.

Activation of small GTPase Ras and renal fibrosis.

Although mechanisms responsible for the initiation and development of renal fibrosis have been extensively studied, the intracellular signals involved in this phenomenon are still poorly understood. Ras proteins are the prototype members of a large family of small GTPases bound to membrane that control signalling pathways implicated in cellular growth, differentiation, proliferation and apoptosis. The purpose of the present manuscript is to review Ras signalling studies focusing on the possible role of Ras activation in renal fibrosis.

What are the effects of maternal and pre-adult environments on ageing in humans, and are there lessons from animal models?

An open issue in research on ageing is the extent to which responses to the environment during development can influence variability in life span in animals, and the health profile of the elderly in human populations. Both affluence and adversity in human societies have profound impacts on survivorship curves, and some of this effect may be traceable to effects in utero or in infancy. The Barker Hypothesis that links caloric restriction in very early life to disruptions of glucose-insulin metabolism in later life has attracted much attention, as well as some controversy, in medical circles.

Effect of the long-term treatment with trandolapril on endoglin expression in rats with experimental renal fibrosis induced by renal mass reduction.

Background: Endoglin is a membrane glycoprotein that regulates TGF-beta1 signaling. Previous studies have revealed that endoglin is upregulated in several models of experimental fibrosis, and that endoglin expression can counteract the fibrogenic effects of TGF-beta1. As treatment with angiotensin converting enzyme (ACE) inhibitors reduces renal fibrosis by mechanisms that are, in part, not dependent on angiotensin II blockade, we have assessed the hypothesis that this effect could be mediated by endoglin upregulation.

Unliganded thyroid hormone receptor beta1 inhibits proliferation of murine fibroblasts by delaying the onset of the G1 cell-cycle signals.

Thyroid hormone receptors (TRs) are members of the ligand-inducible transcription factor superfamily. The two major functional TRs (alpha1 and beta1) have different spatial and temporal expression patterns and specific physiological functions for these isoforms are now starting to emerge. By expressing these TR isoforms individually in Swiss 3T3 fibroblasts, we found that TRbeta1 expression, in the absence of hormone, provokes a proliferation arrest in G0/G1, lengthening the cycling time.