GH and GH receptors are expressed throughout life, and GH elicits a diverse range of responses, including growth and altered metabolism. It is therefore important to understand the full spectrum of GH signaling pathways and cellular responses. We applied mass spectrometry-based phosphoproteomics combined with stable isotope labeling with amino acids ...

PF-03814735 is a novel, reversible inhibitor of Aurora kinases A and B that finished a phase I clinical trial for the treatment of advanced solid tumors. To find predictive biomarkers, we screened a diverse panel of 87 cancer cell lines for growth inhibition upon PF-03814735 treatment. Small cell lung cancer ...

Neurofibromatosis type 2 (NF2) is an inherited predisposition cancer syndrome characterized by the development of multiple benign tumors in the nervous system including schwannomas, meningiomas, and ependymomas. Using a disease model comprising primary human schwannoma cells, we previously demonstrated that adherens junctions (AJs) are impaired in schwannoma cells because of ...

Suppressing the activity of Gsk3β is critical for maintenance of murine pluripotent stem cells. In murine embryonic stem cells (mESCs), Gsk3β is inhibited by multiple mechanisms including its inhibitory phosphorylation on serine 9 by protein kinase B (Akt), a major effector of the canonical PI3K pathway. A second PI3K/Akt-regulated mechanism ...

Upregulation of PIM kinase expression has been reported in many malignancies, suggesting that inhibition of PIM kinase activity may be an attractive therapeutic strategy. We hypothesised that inhibition of PIM kinase activity with SGI-1776, a novel small molecule inhibitor of PIM kinase activity, would reduce the viability of renal cell ...

ABSTRACT: BACKGROUND: Genetic studies in Drosophila melanogaster reveal an important role for Myc in controlling growth. Similar studies have also shown how components of the insulin and target of rapamycin (TOR) pathways are key regulators of growth. Despite few suggestions that Myc transcriptional activity lies downstream of these pathways, a ...

The transcription factor c-Myc has been previously shown to be phosphorylated and stabilized by NEMO through direct interaction in the nucleus. Here, we show that NEMO induces up-regulation of the c-Myc target protein, γ-glutamyl-cysteine synthetase (γ-GCS), leading to an increase of intracellular glutathione (GSH) levels and simultaneous enhancement of redox-controlling ...

Because constitutive activation of STAT3 has been linked with cellular transformation, survival, proliferation, chemoresistance, and angiogenesis of various tumor cells, agents that can suppress STAT3 activation have potential as cancer therapeutics. In the present report, we identified a flavone from the leaves of a Thai plant, Gardenia obtusifolia, 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone (PMF) ...

Glycogen synthase kinase 3β (GSK3β) regulates diverse physiological processes, including metabolism, development, oncogenesis and neuroprotection. GSK3β kinase activity has been reported to be critical for various types of cancer cells, but the mechanism remained elusive. In this study we examined the mechanism by which GSK3β regulates the survival of leukemia ...

The mammalian genome encodes four members of the NDR/LATS kinase family: NDR1 (STK38), NDR2 (STK38L), LATS1 and LATS2, which are highly conserved from yeast to man. Members of the NDR/LATS kinase family have been implicated in a variety of biological processes ranging from cell division and morphology to apoptosis and ...

The Pim kinases are weak oncogenes. However, when co-expressed with a strong oncogene, such as c-Myc, Pim kinases potentiate the oncogenic effect resulting in an acceleration of tumorigenesis. In this study we show that the least studied Pim kinase, Pim-3, is encoded by a gene directly regulated by c-Myc via ...

The Fbw7 tumor suppressor gene encodes the substrate recognition subunit of the SCF ubiquitin ligase, which targets for degradation a range of oncogenic proteins in a phosphorylation-dependent manner. Substrate phosphorylation is thought to be the main mechanism that ensures timely destruction of Fbw7 substrates. We show here that PI3K dependent ...

Bovine papillomavirus types 1 or 2 (BPV-1/2) are involved in the aetiopathogenesis of bovine urinary bladder cancer. BPV-1/2 E5 activates the platelet-derived growth factor β receptor (PDGFβR). The aim of this study was to analyse the Ras/mitogen-activated protein kinase (MAPK) pathway in relation to activation of PDGFβR in natural bovine ...

PURPOSE: Basic fibroblast growth factor is a candidate causative factor of detrusor overactivity in bladder outlet obstruction cases through up-regulation of the gap junction protein connexin 43. We addressed the transcriptional and behavioral implications of this axis. MATERIALS AND METHODS: Cx43 and Cx45 mRNA expression was assessed by real-time reverse ...

It has been demonstrated that increases in poly(ADP-ribose) polymerase (PARP) activity causes damage to several organs under ischemia/reperfusion (I/R) conditions. The aims of this study were to investigate whether inhibition of PARP could suppress apoptosis in the bladder following acute urinary retention (AUR) and subsequent bladder emptying. Twelve-week-old male Sprague ...

5-Hydroxyindole-3-acetic acid (5-HIAA), an indole derivative, is the main metabolite of serotonin in the human body. We determined whether or not ultraviolet B (UVB)-activated 5-HIAA (5-HIAA(UVB)) affects the viability of human prostate (LnCaP and PC-3) and bladder cancer cells (TCCSUP). While 5-HIAA alone had no cytotoxic effect at <1mM, 5-HIAA(UVB) ...

The clinical data on the use of the orally active phosphodiesterase (PDE) type 5 inhibitors sildenafil (VIAGRA™), vardenafil (LEVITRA™), and tadalafil (CIALIS™) for the treatment of male erectile dysfunction have boosted research activities on the physiology and pharmacology of the organs of the lower urinary tract (LUT). This includes both ...

Normal urinary bladder function is based on the proper contraction and relaxation of smooth muscle (SM), which constitutes the majority of the bladder wall. The contraction and relaxation of all SM involves a phosphorylation-dephosphorylation pathway involving the enzymes smooth muscle myosin light chain kinase (SMMLCK) and smooth muscle myosin light ...

Evidence is presented for the nuclear presence of a functional heteromeric complex of epidermal growth factor (EGFR), Src and the Signal Transducer and Activator of Transcription (Stat)3 proteins in pancreatic cancer cells. Stat3 remains nuclear and associated with Src or EGFR, respectively, upon the siRNA knockdown of EGFR or Src, ...

The ability of the intestinal epithelial barrier to respond to various injurious insults is an essential component of intestinal homeostasis. However, the molecular mechanisms responsible for wound-healing and repair in the intestine are poorly understood. The glycogen synthase kinase 3ß (GSK3ß) has been implicated in various biological processes such as ...

Changes in airway smooth muscle (ASM) phenotype may contribute to the pathogenesis of airway disease. Platelet-derived growth factor (PDGF) switches ASM from a contractile to a proliferative, hypo-contractile phenotype, a process requiring activation of extracellular signal-regulated kinase (ERK) and p70(S6) Kinase (p70(S6K) ). The effects of cAMP-elevating agents on these ...

The purpose of this study was to assess the effects of gadolinium (Gd3+), provided as gadolinium chloride, on fibroblast function. Human dermal fibroblasts in monolayer culture and intact skin in organ culture were exposed to the lanthanide metal (1-20 μM). Increased proliferation was observed, in association with upregulation of matrix ...

Treatment of aortic smooth muscle cells with PDGF induces the upregulation of protein tyrosine phosphatase 1B (PTP1B). PTP1B, in turn, decreases the function of several growth factor receptors, thus completing a negative feedback loop. Studies have reported that PDGF induces the downregulation of PKG as part of a repertoire of ...

During the course of liver fibrogenesis, hepatic stellate cell (HSC) proliferation as well as subsequent synthesis of excessive extracellular matrix components is known to be the central events. Thus, factors that could limit HSC proliferation are potential anti-fibrotic agents. The aim of this study was to investigate the effects of ...

We have previously reported that fenofibrate displayed a potent antithrombotic effect by the inhibition of platelet aggregation. The present study was designed to investigate the effects of fenofibrate on the neointimal hyperplasia and its possible molecular mechanism. Neointimal hyperplasia was measured in balloon-inflated-induced vascular injury model of male Sprague-Dawley rats ...

We earlier showed that vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) exhibit increased expression of Gi proteins. Since the levels of endothelin-1 (ET-1) are enhanced in VSMC from SHR, we undertook the present study to examine the implication of endogenous ET-1 and the underlying mechanisms in the ...

Dexamethasone has been shown to inhibit vascular smooth muscle cell (VSMC) migration, which is required for preventing restenosis. However, the mechanism underlying effect of dexamethasone remains unknown. We have previously demonstrated that peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1 alpha (PGC-1α) can inhibit VSMC migration and proliferation. Here, we investigated the ...

The biological outcome of Erk1/2 activation is specified by the duration and magnitude of its phosphorylation, as well as its subcellular localization. In the present study, we investigated how the cross-talk between signaling pathways induced by platelet-derived growth factor receptor β (PDGFRβ) regulates the temporal pattern of Erk1/2 activation. We ...

Our goal was to examine the influence of indirubin-3'-monoxime (I3MO), a natural product-derived cyclin-dependent kinase inhibitor, on vascular smooth muscle cell (VSMC) proliferation in vitro, experimentally induced neointima formation in vivo, and related cell signaling pathways. I3MO dose-dependently inhibited platelet-derived growth factor (PDGF)-BB-induced VSMC proliferation by arresting cells in the ...

BACKGROUND: ε protein kinase C (εPKC) is involved in vascular smooth muscle cell (VSMC) activation, but little is known about its function in vascular pathology. We aimed at assessing the role of εPKC in the development of restenosis. METHODS AND RESULTS: Rat models of aortic balloon injury with or without ...

A temporal framework linking circadian rhythms and clocks to aging rates identifies a specific window of target of rapamycin (TOR) signaling associated with growth hormone (GH) and insulin-like growth factor (IGF-1) (largely exclusive of insulin) in early sleep. IGF-1 signaling is released by growth hormone secretory peaks and downregulation of ...

Extracellular signals play essential roles in controlling the proliferation and differentiation of oligodendrocyte progenitor cells in the developing central nervous system. However, the intracellular pathways that transduce these extrinsic signals remain to be elucidated. In this study, we showed that conditional ablation of the nonreceptor tyrosine phosphatase Shp2 in Olig1-expressing ...

The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial walls is an important pathogenic factor of vascular disorders such as atherosclerosis and restenosis after angioplasty. During atherogenesis or in response to vessel injury, VSMC proliferation is induced by a number of peptide growth factors released from platelets and ...

Vascular smooth muscle cell (VSMC) proliferation and migration and vascular endothelial cell (VEC) dysfunction are closely associated with the development of atherosclerosis. We previously demonstrated that protein tyrosine phosphatase ε M (PTPεM) promotes VEC survival and migration. The present study investigates the biological functions of PTPεM in VSMCs and determines ...

The increased proliferation and migration of vascular smooth muscle cells (VSMCs) are key events in the development of atherosclerotic lesions. Baicalin, an herb-derived flavonoid compound, has been previously shown to induce apoptosis and growth inhibition in cancer cells through multiple pathways. However, the potential role of baicalin in regulation of ...

The initiation of atherosclerosis involves the subendothelial retention of lipoproteins by proteoglycans (PGs). Structural characteristics of glycosaminoglycan (GAG) chains on PGs influence lipoprotein binding and are altered adversely by platelet-derived growth factor (PDGF). The signaling pathway for PDGF-mediated GAG elongation via the PDGF receptor (PDGFR) was investigated. In human vascular ...

PDGF is known to be critically implicated in skeletal muscle repair; however its molecular mechanism of action has been only marginally investigated. In this study we show that in mouse myoblasts PDGF transactivates S1P(1) receptor via sphingosine kinase (SK)-1 activation and that this molecular event exerts a negative regulation of ...

Gambogic acid (GA) is the major active compound of Gamboge, a brownish or orange resin exuded from Garcinia hanburryi tree in Southeast Asia. Previous studies have demonstrated that GA exhibits potent anticancer effects by inducing cell cycle arrest or apoptosis in many types of cancer cell lines and blocking angiogenesis ...

Binding of the platelet-derived growth factor (PDGF)-B to its receptor PDGFRbeta promotes proliferation, migration, and recruitment of pericytes and smooth muscle cells to endothelial cells, serving to stabilize developing blood vessels. The main goals of this study were to determine whether the extracellular domain of the PDGFRbeta can be proteolytically ...

We previously identified that overexpression of the platelet-derived growth factor receptor (PDGFR) is associated with metastatic medulloblastoma (MB) and showed that PDGF treatment increases ERK activity and promotes MB cell migration. In this study, we investigated whether ERK regulates Rac1/Pak1 signaling and is critically linked to MB cell migration. Herein ...

Activated receptor tyrosine kinases recruit many signaling proteins to activate downstream cell proliferation and survival pathways, including phosphatidylinositol 3-kinase (PI3K) consisting of a p85 regulatory protein and a p110 catalytic protein. We have recently shown the p85alpha protein also has in vitro GTPase activating protein (GAP) activity towards Rab5 and ...

Recent reports have described several cellular phenotypes that appear to be mediated by Endosialin/TEM-1/CD248 (TEM-1), including tubule formation on matrigel, migration and proliferation. It has been shown that siRNA knock-down of TEM-1 in primary human fibroblasts resulted in reduced proliferation. However, the downstream signaling events that mediate TEM-1 function(s) currently ...

Activation of platelet-derived growth factor (PDGF) receptors occurs through ligand-induced dimerization and autophosphorylation. In this study, we investigated the effects of mutation of tyrosine residue 857 (Y857) in the activation loop of the PDGF beta-receptor (PDGFRbeta) to phenylalanine (Y857F). In agreement with previous observations, we found that PDGFRbeta(Y857F) had a ...

Like many other receptor tyrosine kinases (RTKs), platelet-derived growth factor (PDGF) receptor beta (PDGFR-beta) is internalized and degraded in lysosomes in response to PDGF stimulation, which regulates many aspects of cell signalling. However, little is known about the regulation of PDGFR-beta endocytosis. Given that ligand binding is essential for the ...

Platelet-derived growth factor (PDGF) is a pleiotropic protein with critical roles in both developmental as well as pathogenic processes. In the central nervous system specifically, PDGF is critical for neuronal proliferation and differentiation and has also been implicated as a neuroprotective agent. Whether PDGF also plays a role in synaptic ...

It is becoming increasingly clear that voltage-operated Ca(2+) channels (VOCCs) play a fundamental role in the development of oligodendrocyte progenitor cells (OPCs). Because direct phosphorylation by different kinases is one of the most important mechanisms involved in VOCC modulation, the aim of this study was to evaluate the participation of ...

PURPOSE: Posterior capsular opacification (PCO) is caused partially by the migration of lens epithelial cells. To date, the mechanism of the migration is largely unknown. The purpose of this study was to investigate the effect of platelet-derived growth factor (PDGF)-triggered signaling pathways and its downstream effectors in the migration of ...

The neuroprotective effects of platelet-derived growth factor (PDGF) and the major signaling pathways involved in these were examined using primary cultured mouse cortical neurons subjected to H(2)O(2)-induced oxidative stress. The specific function of the PDGF beta-receptor (PDGFR-beta) was examined by the selective deletion of the corresponding gene using the Cre-loxP ...

The transcription factor CREB is diminished in smooth muscle cells (SMCs) in remodeled, hypertensive pulmonary arteries (PAs) in animals exposed to chronic hypoxia. Forced depletion of cyclic adenosine monophosphate response element binding protein (CREB) in PA SMCs stimulates their proliferation and migration in vitro. Platelet-derived growth factor (PDGF) produced in ...

Vascular smooth muscle cells (VSMCs) are the main cellular component in the arterial wall, and abnormal proliferation of VSMCs plays a central role in the pathogenesis of atherosclerosis and restenosis after angioplasty, and possibly in the development of hypertension. Pterostilbene, a natural dimethylated analog of resveratrol, is known to have ...