Neuronal deletion of Ca1.2 is associated with sex-specific behavioral phenotypes in mice.

The gene CACNA1C, which encodes the pore forming subunit of the L-type calcium channel Ca1.2, is associated with increased risk for neuropsychiatric disorders including schizophrenia, autism spectrum disorder, major depression, and bipolar disorder. Previous rodent work identified that loss or reduction of Ca1.

Deletion of the voltage-gated calcium channel, Ca 1.3, causes deficits in motor performance and associative learning.

L-type voltage-gated calcium channels are important regulators of neuronal activity and are widely expressed throughout the brain. One of the major L-type voltage-gated calcium channel isoforms in the brain is Ca 1.3.

Persistent increase in mitochondrial superoxide mediates cisplatin-induced chronic kidney disease.

Severe and recurrent cisplatin-induced acute kidney injury (AKI) as part of standard cancer therapy is a known risk factor for development of chronic kidney disease (CKD). The specific role of superoxide (O)-mediated disruption of mitochondrial oxidative metabolism in CKD after cisplatin treatment is unexplored. Cisplatin is typically administered in weekly or tri-weekly cycles as part of standard cancer therapy.

EGF regulation of proximal tubule cell proliferation and VEGF-A secretion.

Proximal tubule cell (PTC) proliferation is critical for tubular regeneration and recovery from acute kidney injury. Epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF-A) are important for the maintenance of tubulointerstitial integrity and can stimulate PTC proliferation. We utilized HK-2 cells, an immortalized human PTC line, to characterize the EGF-dependent regulation of VEGF-A secretion and proliferation in PTCs.

Disruption of Protein Processing in the Endoplasmic Reticulum of DYT1 Knock-in Mice Implicates Novel Pathways in Dystonia Pathogenesis.

Unlabelled: Dystonia type 1 (DYT1) is a dominantly inherited neurological disease caused by mutations in TOR1A, the gene encoding the endoplasmic reticulum (ER)-resident protein torsinA. Previous work mostly completed in cell-based systems suggests that mutant torsinA alters protein processing in the secretory pathway. We hypothesized that inducing ER stress in the mammalian brain in vivo would trigger or exacerbate mutant torsinA-induced dysfunction.

FBG1 Is the Final Arbitrator of A1AT-Z Degradation.

Alpha-1 antitrypsin deficiency is the leading cause of childhood liver failure and one of the most common lethal genetic diseases. The disease-causing mutant A1AT-Z fails to fold correctly and accumulates in the endoplasmic reticulum (ER) of the liver, resulting in hepatic fibrosis and hepatocellular carcinoma in a subset of patients. Furthermore, A1AT-Z sequestration in hepatocytes leads to a reduction in A1AT secretion into the serum, causing panacinar emphysema in adults.

Using a ubiquitin ligase as an unfolded protein sensor.

A significant fraction of all proteins are misfolded and must be degraded. The ubiquitin-proteasome pathway provides an essential protein quality control function necessary for normal cellular homeostasis. Substrate specificity is mediated by proteins called ubiquitin ligases.

FBG1 is a promiscuous ubiquitin ligase that sequesters APC2 and causes S-phase arrest.

During cell proliferation, protein degradation is strictly regulated by the cell cycle and involves two complementary ubiquitin ligase complexes, the SCF (Skp, Cullin, F-box) and APC/C (Anaphase Promoting Complex/Cyclosome) ubiquitin ligases. SCF ligases are constitutively active and generally target only proteins after they have been selected for degradation, usually by phosphorylation. In contrast, APC/C complexes are themselves activated by phosphorylation and their substrates contain a targeting signal known as degron, a consensus amino acid sequence such as a D-Box.

Diversity in tissue expression, substrate binding, and SCF complex formation for a lectin family of ubiquitin ligases.

Post-translational modification of proteins regulates many cellular processes. Some modifications, including N-linked glycosylation, serve multiple functions. For example, the attachment of N-linked glycans to nascent proteins in the endoplasmic reticulum facilitates proper folding, whereas retention of high mannose glycans on misfolded glycoproteins serves as a signal for retrotranslocation and ubiquitin-mediated proteasomal degradation.

Selective cochlear degeneration in mice lacking the F-box protein, Fbx2, a glycoprotein-specific ubiquitin ligase subunit.

Little is known about the role of protein quality control in the inner ear. We now report selective cochlear degeneration in mice deficient in Fbx2, a ubiquitin ligase F-box protein with specificity for high-mannose glycoproteins (Yoshida et al., 2002).

A novel route for F-box protein-mediated ubiquitination links CHIP to glycoprotein quality control.

In SCF (Skp1/Cullin/F-box protein) ubiquitin ligases, substrate specificity is conferred by a diverse array of F-box proteins. Only in fully assembled SCF complexes, it is believed, can substrates bound to F-box proteins become ubiquitinated. Here we show that Fbx2, a brain-enriched F-box protein implicated in the ubiquitination of glycoproteins discarded from the endoplasmic reticulum, binds the co-chaperone/ubiquitin ligase CHIP (C terminus of Hsc-70-interacting protein) through a unique N-terminal PEST domain in Fbx2.