Dual role of the adhesion G-protein coupled receptor ADRGE5/CD97 in glioblastoma invasion and proliferation.

CD97, an adhesion G-protein coupled receptor highly expressed in glioblastoma (GBM), consists of two noncovalently bound domains: the N-terminal fragment (NTF) and C-terminal fragment. The C-terminal fragment contains a GPCR domain that couples to Gα, while the NTF interacts with extracellular matrix components and other receptors. We investigated the effects of changing CD97 levels and its function on primary patient-derived GBM stem cells (pdGSCs) in vitro and in vivo.

Targeting extracellular matrix remodeling sensitizes glioblastoma to ionizing radiation.

Background: The median survival of Glioblastoma multiforme (GBM) patients is 14+ months due to poor responses to surgery and chemoradiation. Means to counteract radiation resistance are therefore highly desirable. We demonstrate the membrane bound matrix metalloproteinase MT1-MMP promotes resistance of GBM to radiation, and that using a selective and brain permeable MT1-MMP inhibitor, -ND336, improved tumor control can be achieved in preclinical studies.

Identification of miRNAs involved in DRG neurite outgrowth and their putative targets.

Peripheral neurons regenerate their axons after injury. Transcriptional regulation by microRNAs (miRNAs) is one possible mechanism controlling regeneration. We profiled miRNA expression in mouse dorsal root ganglion neurons after a sciatic nerve crush, and identified 49 differentially expressed miRNAs.

The mTOR Substrate S6 Kinase 1 (S6K1) Is a Negative Regulator of Axon Regeneration and a Potential Drug Target for Central Nervous System Injury.

The mammalian target of rapamycin (mTOR) positively regulates axon growth in the mammalian central nervous system (CNS). Although axon regeneration and functional recovery from CNS injuries are typically limited, knockdown or deletion of PTEN, a negative regulator of mTOR, increases mTOR activity and induces robust axon growth and regeneration. It has been suggested that inhibition of S6 kinase 1 (S6K1, gene symbol: RPS6KB1), a prominent mTOR target, would blunt mTOR's positive effect on axon growth.

Dyrk kinases regulate phosphorylation of doublecortin, cytoskeletal organization, and neuronal morphology.

In a neuronal overexpression screen focused on kinases and phosphatases, one "hit" was the dual specificity tyrosine phosphorylation-regulated kinase (Dyrk4), which increased the number of dendritic branches in hippocampal neurons. Overexpression of various Dyrk family members in primary neurons significantly changed neuronal morphology. Dyrk1A decreased axon growth, Dyrk3 and Dyrk4 increased dendritic branching, and Dyrk2 decreased both axon and dendrite growth and branching.

Kinase/phosphatase overexpression reveals pathways regulating hippocampal neuron morphology.

Development and regeneration of the nervous system requires the precise formation of axons and dendrites. Kinases and phosphatases are pervasive regulators of cellular function and have been implicated in controlling axodendritic development and regeneration. We undertook a gain-of-function analysis to determine the functions of kinases and phosphatases in the regulation of neuron morphology.

Quantitative control of adaptive cardiac hypertrophy by acetyltransferase p300.

Background: Acetyltransferase p300 is essential for cardiac development and is thought to be involved in cardiac myocyte growth through MEF2- and GATA4-dependent transcription. However, the importance of p300 in the modulation of cardiac growth in vivo is unknown.

Methods And Results: Pressure overload induced by transverse aortic coarctation, postnatal physiological growth, and human heart failure were associated with large increases in p300.

Involvement of endoplasmic reticulum stress in a novel Classic Galactosemia model.

Inherited deficiency of galactose-1-phosphate uridyltransferase (GALT) activity in humans leads to a potentially lethal disorder called Classic Galactosemia. It is well known that patients often accumulate high levels of galactose metabolites such as galactose-1-phosphate (gal-1-p) in their tissues. However, specific targets of gal-1-p and other accumulated metabolites remain uncertain.

Prevention of a molecular misdiagnosis in galactosemia.

Purpose: The polymerase chain reaction is generally used for mutational analysis of the galactose-1-phosphate uridyl transferase (GALT) gene in the diagnosis of galactosemia. This method is problematic when used in families of Ashkenazi Jewish descent.

Methods: We amplified the GALT gene from leukocyte DNA followed by allele specific oligonucleotide hybridization, DNA sequencing and Southern Blot analysis to determine the mutant alleles causing galactosemia in a representative Jewish family.

Intracellular galactose-1-phosphate accumulation leads to environmental stress response in yeast model.

In humans, deficiency of galactose-1-phosphate uridyltransferase (GALT) can lead a metabolic disorder Classic Galactosemia. Although the biochemical abnormalities associated with this disease have been described in detail, few attempts have been made to characterize the pathogenic mechanisms of this disorder at the molecular level. Here we report the use of high-throughput DNA microarray to examine how galactose affects gene expression in isogenic yeast models that are deficient in either galactokinase (GALK) or GALT, two enzymes which are essential for normal galactose metabolism.