V-ATPase Disassembly at the Yeast Lysosome-Like Vacuole Is a Phenotypic Driver of Lysosome Dysfunction in Replicative Aging.

Declines in lysosomal acidification and function with aging are observed in organisms ranging from yeast to humans. V-ATPases play a central role in organelle acidification, and V-ATPase activity is regulated by reversible disassembly in many different settings. Using the yeast Saccharomyces cerevisiae as a replicative aging model, we demonstrate that V-ATPases disassemble into their V and V subcomplexes in aging cells, with release of V subunit C (Vma5) from the lysosome-like vacuole into the cytosol.

V-ATPase Disassembly at the Yeast Lysosome-Like Vacuole Is a Phenotypic Driver of Lysosome Dysfunction in Replicative Aging.

Declines in lysosomal acidification and function with aging are observed in organisms ranging from yeast to humans. V-ATPases play a central role in organelle acidification and V-ATPase activity is regulated by reversible disassembly in many different settings. Using the yeast as a replicative aging model, we demonstrate that V-ATPases disassemble into their V and V subcomplexes in aging cells, with release of V subunit C (Vma5) from the lysosome-like vacuole into the cytosol.

MMPs, tyrosine kinase signaling and extracellular matrix proteolysis in kidney cancer.

Patients diagnosed with metastatic renal cell carcinoma (RCC) have ∼12% chance for 5-year survival. The integrity of the extracellular matrix (ECM) that surrounds tumor cells influences their behavior and, when disturbed, it could facilitate local invasion and spread of tumor cells to distant sites. The interplay between von Hippel-Lindau/hypoxia inducible factor signaling axis and activated kinase networks results in aberrant ECM and tumor progression.

Co-chaperones TIMP2 and AHA1 Competitively Regulate Extracellular HSP90:Client MMP2 Activity and Matrix Proteolysis.

The extracellular molecular chaperone heat shock protein 90 (eHSP90) stabilizes protease client the matrix metalloproteinase 2 (MMP2), leading to tumor cell invasion. Although co-chaperones are critical modulators of intracellular HSP90:client function, how the eHSP90:MMP2 complex is regulated remains speculative. Here, we report that the tissue inhibitor of metalloproteinases-2 (TIMP2) is a stress-inducible extracellular co-chaperone that binds to eHSP90, increases eHSP90 binding to ATP, and inhibits its ATPase activity.

Regulation of transient receptor potential cation channel subfamily V1 protein synthesis by the phosphoinositide 3-kinase/Akt pathway in colonic hypersensitivity.

The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor or vanilloid receptor 1 (VR1), is expressed in nociceptive neurons in the dorsal root ganglia (DRG) and participates in the transmission of pain. The present study investigated the underlying molecular mechanisms by which TRPV1 was regulated by nerve growth factor (NGF) signaling pathways in colonic hypersensitivity in response to colitis. We found that during colitis TRPV1 protein levels were significantly increased in specifically labeled colonic afferent neurons in both L1 and S1 DRGs.

Colitis-induced bladder afferent neuronal activation is regulated by BDNF through PLCγ pathway.

Patients with inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS) often experience increased sensory responsiveness in the urinary bladder reflecting neurogenic bladder overactivity. Here we demonstrate that colitis-induced up-regulation of the phospholipase C gamma (PLCγ) pathway downstream of brain-derived neurotrophic factor (BDNF) in bladder afferent neurons in the dorsal root ganglia (DRG) plays essential roles in activating these neurons thereby leading to bladder hyperactivity. Upon induction of colitis with 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats, we found that the phosphorylation (activation) level of cAMP responsive element-binding (p-CREB) protein, a molecular switch of neuronal plasticity, was increased in specifically labeled bladder afferent neurons in the thoracolumbar and lumbosacral DRGs.

EXPRESS: Phospholipase C gamma mediates endogenous brain-derived neurotrophic factor - regulated calcitonin gene-related peptide expression in colitis - induced visceral pain.

Background: Visceral hypersensitivity is a complex pathophysiological paradigm with unclear mechanisms. Primary afferent neuronal plasticity marked by alterations in neuroactive compounds such as calcitonin gene-related peptide is suggested to underlie the heightened sensory responses. Signal transduction that leads to calcitonin gene-related peptide expression thereby sensory neuroplasticity during colitis remains to be elucidated.

Impact of V-ets Erythroblastosis Virus E26 Oncogene Homolog 1 Gene Polymorphisms Upon Susceptibility to Autoimmune Diseases: A Meta-Analysis.

V-ets erythroblastosis virus E26 oncogene homolog 1 (ETS1) is recognized as a gene of risk to autoimmune diseases (ADs). Two single nucleotide polymorphisms (SNPs) in ETS1 (rs1128334 G>A and rs10893872 T>C) were considered associated with ADs risk. However, the results remain conflicting.