Histone variant H3.5 in testicular cell differentiation and its interactions with histone chaperones.

Testicular cell differentiation is a highly regulated process, essential for male reproductive health. The histone variant H3.5 is apparently a critical player in this intricate orchestra of cell types, but its regulation and function remains poorly understood.

Iodinated PSMA Ligands as XFI Tracers for Targeted Cell Imaging and Characterization of Nanoparticles.

Prostate cancer is the second most commonly diagnosed cancer in men worldwide. Despite this, current diagnostic tools are still not satisfactory, lacking sensitivity for early-stage or single-cell diagnosis. This study describes the development of small-molecule tracers for the well-known tumor marker prostate-specific membrane antigen (PSMA).

Regulation of the Activity of the Dual Leucine Zipper Kinase by Distinct Mechanisms.

The dual leucine zipper kinase (DLK) alias mitogen-activated protein 3 kinase 12 (MAP3K12) has gained much attention in recent years. DLK belongs to the mixed lineage kinases, characterized by homology to serine/threonine and tyrosine kinase, but exerts serine/threonine kinase activity. DLK has been implicated in many diseases, including several neurodegenerative diseases, glaucoma, and diabetes mellitus.

Regulation of dual leucine zipper kinase activity through its interaction with calcineurin.

Hyperglycemia enhancing the intracellular levels of reactive oxygen species (ROS) contributes to dysfunction and progressive loss of beta cells and thereby to diabetes mellitus. The oxidation sensitive calcium/calmodulin dependent phosphatase calcineurin promotes pancreatic beta cell function and survival whereas the dual leucine zipper kinase (DLK) induces apoptosis. Therefore, it was studied whether calcineurin interferes with DLK action.

Mechanistic role of the CREB-regulated transcription coactivator 1 in cardiac hypertrophy.

The sympathetic nervous system is the main stimulator of cardiac function. While acute activation of the β-adrenoceptors exerts positive inotropic and lusitropic effects by increasing cAMP and Ca, chronically enhanced sympathetic tone with changed β-adrenergic signaling leads to alterations of gene expression and remodeling. The CREB-regulated transcription coactivator 1 (CRTC1) is activated by cAMP and Ca.

TNFα-induced DLK activation contributes to apoptosis in the beta-cell line HIT.

Reduction in beta-cell mass and function contributes to the pathogenesis of diabetes mellitus type 2. The proinflammatory cytokines tumor necrosis factor (TNF)α and interleukin (IL)-1β have been implicated in the pathogenesis of this disease. Overexpression of the dual leucine zipper kinase (DLK) inhibits beta-cell function and induces apoptosis in the beta-cell line HIT.

Endothelial cells regulate β-catenin activity in adrenocortical cells via secretion of basic fibroblast growth factor.

Endothelial cell-derived products influence the synthesis of aldosterone and cortisol in human adrenocortical cells by modulating proteins such as steroidogenic acute-regulatory (StAR) protein, steroidogenic factor (SF)-1 and CITED2. However, the potential endothelial cell-derived factors that mediate this effect are still unknown. The current study was perfomed to look into the control of β-catenin activity by endothelial cell-derived factors and to identify a mechanism by which they affect β-catenin activity in adrenocortical NCIH295R cells.

Regulation of Beta-Cell Function and Mass by the Dual Leucine Zipper Kinase.

Diabetes mellitus is one of the most rapidly increasing diseases worldwide, whereby approximately 90-95% of patients suffer from type 2 diabetes. Considering its micro- and macrovascular complications like blindness and myocardial infarction, a reliable anti-diabetic treatment is needed. Maintaining the function and the mass of the insulin producing beta-cells despite elevated levels of beta-cell-toxic prediabetic signals represents a desirable mechanism of action of anti-diabetic drugs.

Dual leucine zipper kinase (MAP3K12) modulators: a patent review (2010-2015).

Introduction: The dual leucine zipper kinase (DLK, MAP3K12) is essential for neuronal development and has been shown to mediate axon regeneration. On the other hand, DLK is involved in the pathogenesis of neurodegenerative disease and diabetes mellitus. Several patents have been published claiming to modulate or inhibit DLK by various approaches including ATP competitive inhibitors.

Distinct functions of the dual leucine zipper kinase depending on its subcellular localization.

The dual leucine zipper kinase DLK induces β-cell apoptosis by inhibiting the transcriptional activity conferred by the β-cell protective transcription factor cAMP response element binding protein CREB. This action might contribute to β-cell loss and ultimately diabetes. Within its kinase domain DLK shares high homology with the mixed lineage kinase (MLK) 3, which is activated by tumor necrosis factor (TNF) α and interleukin (IL)-1β, known prediabetic signals.

Inhibition of human insulin gene transcription and MafA transcriptional activity by the dual leucine zipper kinase.

Insulin biosynthesis is an essential β-cell function and inappropriate insulin secretion and biosynthesis contribute to the pathogenesis of diabetes mellitus type 2. Previous studies showed that the dual leucine zipper kinase (DLK) induces β-cell apoptosis. Since β-cell dysfunction precedes β-cell loss, in the present study the effect of DLK on insulin gene transcription was investigated in the HIT-T15 β-cell line.

Something old, something new and something very old: drugs for treating type 2 diabetes.

Diabetes mellitus belongs to the most rapidly increasing diseases worldwide. Approximately 90-95% of these patients suffer from type 2 diabetes mellitus, which is characterized by peripheral insulin resistance and the progressive loss of beta-cell function and mass. Considering the complications of this chronic disease, a reliable anti-diabetic treatment is indispensable.

Lithium enhances CRTC oligomer formation and the interaction between the CREB coactivators CRTC and CBP--implications for CREB-dependent gene transcription.

Lithium salts are important drugs to treat bipolar disorder. Previous work showed that lithium by enforcing the interaction between the transcription factor CREB and its coactivator CRTC1 enhanced cAMP-stimulated CREB-dependent gene transcription. Both CREB and CRTC have been implicated in neuronal adaptation, which might underlie lithium's therapeutic action.

Cyclosporin A, but not everolimus, inhibits DNA repair mediated by calcineurin: implications for tumorigenesis under immunosuppression.

Unlike other immunosuppressive drugs including everolimus, cyclosporin A causes a dramatic increase of UV-induced skin cancer, a feature that is reminiscent of xeroderma pigmentosum (XP), where defective nucleotide excision repair (NER) of UV-induced DNA damage results in cutaneous carcinogenesis. The molecular basis of the clinically important differential activities of cyclosporin A and everolimus is still unclear. We measured post-UV cell survival of cyclosporin A- and everolimus-treated human fibroblasts and lymphoblasts using a cell proliferation assay (MTT).

Regulation of the CREB coactivator TORC by the dual leucine zipper kinase at different levels.

CREB is a ubiquitously expressed transcription factor regulating gene expression via binding to a CRE DNA element. Previous work showed that the dual leucine zipper kinase (DLK) reduced CREB-dependent gene transcription at least in part via inhibition of the coactivator CBP. Here we demonstrate that DLK also inhibits CREB activity by affecting the interaction of CREB with its second coactivator TORC.

Inhibition of human insulin gene transcription by peroxisome proliferator-activated receptor gamma and thiazolidinedione oral antidiabetic drugs.

Background And Purpose: The transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for glucose homeostasis. PPARgamma ligands reducing insulin levels in vivo are used as drugs to treat type 2 diabetes mellitus. Genes regulated by PPARgamma have been found in several tissues including insulin-producing pancreatic islet beta-cells.

Loss of insulin-induced inhibition of glucagon gene transcription in hamster pancreatic islet alpha cells by long-term insulin exposure.

Aims/hypothesis: Diabetes mellitus type 2 is characterised by hyperglucagonaemia, resulting in hepatic glucose production and hyperglycaemia. Considering that insulin inhibits glucagon secretion and gene transcription, hyperglucagonaemia in the face of hyperinsulinaemia in diabetes mellitus type 2 suggests that there is insulin resistance also at the glucagon-producing pancreatic islet alpha cells. However, the molecular mechanism of alpha cell insulin resistance is unknown.

Stimulation by lithium of the interaction between the transcription factor CREB and its co-activator TORC.

Lithium salts are clinically important drugs used to treat bipolar mood disorder. The mechanisms accounting for the clinical efficacy are not completely understood. Chronic treatment with lithium is required to establish mood stabilization, suggesting the involvement of neuronal plasticity processes.

Functional characterization of a -100_-102delAAG deletion-insertion polymorphism in the promoter region of the HTR3B gene.

Objective: The HTR3B gene encodes the B-subunit of the type 3 serotonin receptor (5-HT3). A -100_-102delAAG deletion in the promoter region has been associated with poor response to antiemetic medication and susceptibility to bipolar affective disorders. The molecular mechanisms underlying these associations, however, remained unclear.

Activation of the dual-leucine-zipper-bearing kinase and induction of beta-cell apoptosis by the immunosuppressive drug cyclosporin A.

Post-transplant diabetes is an untoward effect often observed under immunosuppressive therapy with cyclosporin A. Besides the development of peripheral insulin resistance and a decrease in insulin gene transcription, a beta-cell toxic effect has been described. However, its molecular mechanism remains unknown.

A peroxisome proliferator-activated receptor gamma-retinoid X receptor heterodimer physically interacts with the transcriptional activator PAX6 to inhibit glucagon gene transcription.

The peptide hormone glucagon stimulates hepatic glucose output, and its levels in the blood are elevated in type 2 diabetes mellitus. The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) has essential roles in glucose homeostasis, and thiazolidinedione PPARgamma agonists are clinically important antidiabetic drugs. As part of their antidiabetic effect, thiazolidinediones such as rosiglitazone have been shown to inhibit glucagon gene transcription through binding to PPARgamma and inhibition of the transcriptional activity of PAX6 that is required for cell-specific activation of the glucagon gene.

Inhibition of MafA transcriptional activity and human insulin gene transcription by interleukin-1beta and mitogen-activated protein kinase kinase kinase in pancreatic islet beta cells.

Aims/hypothesis: Inappropriate insulin secretion and biosynthesis are hallmarks of beta cell dysfunction and contribute to the progression from a prediabetic state to overt diabetes mellitus. During the prediabetic state, beta cells are exposed to elevated levels of proinflammatory cytokines. In the present study the effect of these cytokines and mitogen-activated protein kinase kinase kinase 1 (MEKK1), which is known to be activated by these cytokines, on human insulin gene (INS) transcription was investigated.

Tissue-specific alternative promoters of the serotonin receptor gene HTR3B in human brain and intestine.

The serotonin receptor type 3 is a pentameric ligand-gated ion channel regulating intestinal motility, nausea, and vomiting in humans. The HTR3B gene codes for the subunit B of this receptor. The HTR3B transcription start site is not unequivocally identified.

The role of prostaglandin E receptor-dependent signaling via cAMP in Mdr1b gene activation in primary rat hepatocyte cultures.

Multidrug resistance (mdr) proteins of the mdr1 type function as multispecific xenobiotic transporters in hepatocytes. In the liver, mdr1 overexpression occurs during regeneration, cirrhosis, and hepatocarcinogenesis and may contribute to primary chemotherapy resistance. Cultured rat hepatocytes exhibit a time-dependent "intrinsic" increase in functional mdr1b expression, which depends on cyclooxygenase-catalyzed prostaglandin E(2) release.