Leveraging Gene Redundancy to Find New Histone Drivers in Cancer.

Histones play a critical role in chromatin function but are susceptible to mutagenesis. In fact, numerous mutations have been observed in several cancer types, and a few of them have been associated with carcinogenesis. Histones are peculiar, as they are encoded by a large number of genes, and the majority of them are clustered in three regions of the human genome.

Molecular Mechanisms of Oncogenesis through the Lens of Nucleosomes and Histones.

At the cellular level, cancer is the disease of both the genome and the epigenome, and the interplay between genetic mutations and epigenetic states may occur at the level of elementary chromatin units, the nucleosomes. They are formed by a segment of DNA wrapped around an octamer of histone proteins. In this review, we survey various mechanisms of cancer etiology and progression mediated by histones and nucleosomes.

Transcatheter Mitral Valve Repair Therapies: Evolution, Status and Challenges.

Mitral regurgitation is a common cardiac valve lesion, developing from primary lesions of the mitral valve or secondary to cardiomyopathies. Moderate or higher severity of mitral regurgitation imposes significant volume overload on the left ventricle, causing permanent structural and functional deterioration of the myocardium and heart failure. Timely correction of regurgitation is essential to preserve cardiac function, but surgical mitral valve repair is often delayed due to the risks of open heart surgery.

BMP2 rescues deficient cell migration in Tgfbr3(-/-) epicardial cells and requires Src kinase.

During embryogenesis, the epicardium undergoes proliferation, migration, and differentiation into several cardiac cell types which contribute to the coronary vessels. The type III transforming growth factor-β receptor (TGFβR3) is required for epicardial cell invasion and development of coronary vasculature in vivo. Bone Morphogenic Protein-2 (BMP2) is a driver of epicardial cell migration.

Type III TGFβ receptor and Src direct hyaluronan-mediated invasive cell motility.

During embryogenesis, the epicardium undergoes proliferation, migration, and differentiation into several cardiac cell types which contribute to the coronary vessels. This process requires epithelial to mesenchymal transition (EMT) and directed cellular invasion. The Type III Transforming Growth Factor-beta Receptor (TGFβR3) is required for epicardial cell invasion and coronary vessel development.

Adipose tissue depot-specific differences in adipocyte apolipoprotein E expression.

Important differences in gene expression have been documented in adipocytes derived from specific adipose tissue depots. We have previously documented an important role for adipocyte apolipoprotein E (apoE) in modulating adipocyte and adipose tissue triglyceride and lipoprotein metabolism. We now evaluate the endogenous expression of apoE in adipocytes isolated from unique adipose tissue depots in 4 different species.

Hyperglycemia and advanced glycosylation end products suppress adipocyte apoE expression: implications for adipocyte triglyceride metabolism.

Endogenous adipocyte apolipoprotein E (apoE) plays an important role in adipocyte lipoprotein metabolism and lipid flux. A potential role for hyperglycemia in regulating adipocyte apoE expression and triglyceride metabolism was examined. Exposure of adipocytes to high glucose or advanced glycosylation end product-BSA significantly suppressed apoE mRNA and protein levels.

Oxidative stress regulates adipocyte apolipoprotein e and suppresses its expression in obesity.

Objective: Endogenous expression of apolipoprotein E (apoE) has a significant impact on adipocyte lipid metabolism and is markedly suppressed in obesity. Adipose tissue oxidant stress is emerging as an important mediator of adipocyte dysfunction. These studies were undertaken to evaluate the role of oxidant stress for regulation of adipocyte apoE.

The sodium bicarbonate cotransporter: structure, function, and regulation.

The role of the Na(+)-coupled HCO(3)(-) transporter (NBC) family is indispensable in acid-base homeostasis. Almost all tissues express a member of the NBC family. NBC has been studied extensively in the kidney and plays a role in proximal tubule HCO(3)(-) reabsorption.

Regulation of renal Na+/HCO3- cotransporter stimulation by CO2: role of phosphorylation, exocytosis and protein synthesis.

The sodium bicarbonate cotransporter (NBC1) mediates bicarbonate reabsorption in the renal proximal tubule. NBC1 activity is stimulated by 10% CO2, however, the mechanism is poorly understood. Here, we examined the mechanism of NBC1 regulation by 10% CO2 using an immortalized human proximal tubule cell line (HK2).

The role of phosphatidylinositol 3-kinase (PI3K) in CO2 stimulation of the Na+/HCO3- cotransporter (NBC).

The basolateral Na+/HCO3- cotransporter (NBC) is the major pathway for bicarbonate reabsorption in the renal proximal tubule cells. The cotransporter activity is enhanced by 10% CO2. Phosphatidylinositol 3-kinase (PI3K) has been shown to regulate the function and trafficking of cellular proteins by promoting their translocation to the plasma membrane.

A central role for Pyk2-Src interaction in coupling diverse stimuli to increased epithelial NBC activity.

Regulation of renal Na-HCO cotransporter (NBC1) activity by cholinergic agonists, ANG II, and acute acidosis (CO(2)) requires both Src family kinase (SFK) and classic MAPK pathway activation. The nonreceptor tyrosine kinase proline-rich tyrosine kinase 2 (Pyk2) couples discrete G protein-coupled receptor and growth factor receptor signaling to SFK activation. We examined the role of Pyk2-SFK interaction in coupling these stimuli to increased NBC1 activity in opossum kidney cells.

Angiotensin II stimulation of renal epithelial cell Na/HCO3 cotransport activity: a central role for Src family kinase/classic MAPK pathway coupling.

Angiotensin II (AII) plays an important role in renal proximal tubular acidification via the costimulation of basolateral Na/HCO3 cotransporter (NBC) and apical Na/H exchanger (NHE) activities. These effects are mediated by specific G protein-coupled AII receptors, but their corresponding downstream effectors are incompletely defined. Src family tyrosine kinases (SFKs) contribute to the regulation of both transport activities by a variety of stimuli and are coupled to classic mitogen-activated protein kinase (MAPK) pathway activation in this cell type.

Depression, cognitive impairment and function in Alzheimer's disease.

Depression is very common in patients with dementia but the relationship is very complex. Depression is regarded as a cause of excess disability in persons with dementia and contributes to their functional decline. The assessment of depression in dementia patients, however, has been difficult in that the validity of self-reported depression in patients with dementia has been questioned.

Venomous cone snails: molecular phylogeny and the generation of toxin diversity.

In order to investigate the generation of conotoxin diversity, delta-conotoxin sequences from nine Conus species were analyzed in the context of their phylogeny. Using a standard molecular marker, mitochondrial 16S RNA, we determined that the delta-conotoxins were derived from three distinct species clades based on the phylogenetic reconstruction of a large set (>80) of Conus species and other toxoglossate molluscs. Four different mechanisms appear to have contributed to the diversity of the delta-conotoxins analyzed: (1) Speciation: Delta-conotoxins in different species diverge from each other (the prepro regions of orthologous genes somewhat more slowly than the reference rRNA rate, the mature toxin regions significantly faster).

SFKs, Ras, and the classic MAPK pathway couple muscarinic receptor activation to increased Na-HCO(3) cotransport activity in renal epithelial cells.

Cholinergic agents are known to affect the epithelial transport of H2O and electrolytes in the kidney. In proximal tubule cells, cholinergic agonists increase basolateral Na-HCO(3) cotransport activity via M(1) muscarinic receptor activation. The signaling intermediates that couple these G protein-coupled receptors to cotransporter activation, however, are not well defined.