Hyaluronan- and RNA-binding deubiquitinating enzymes of USP17 family members associated with cell viability

BACKGROUND: Protein degradation by the ubiquitin system plays a crucial role in numerous cellular signaling pathways. Deubiquitination, a reversal of ubiquitination, has been recognized as an important regulatory step in the ubiquitin-dependent degradation pathway. RESULTS: While identifying putative ubiquitin specific protease (USP) enzymes that contain a conserved Asp (I) domain in humans, 4 USP17 subfamily members, highly homologous to DUB-3, have been found (USP17K, USP17L, USP17M, and USP17N), from human chorionic villi. Expression analysis showed that USP17 transcripts are highly expressed in the heart, liver, and pancreas and are expressed moderately in various human cancerous cell lines. Amino acid sequence analysis revealed that they contain the highly conserved Cys, His, and Asp domains which are responsible for the deubiquitinating activity. Biochemical enzyme assays indicated that they have deubiquitinating activity. Interestingly, the sequence analysis showed that these proteins, with exception of USP17N, contain the putative hyaluronan/RNA binding motifs, and cetylpyridinium chloride (CPC)-precipitation analysis confirmed the association between these proteins and intracellular hyaluronan and RNA. CONCLUSION: Here, we report that the overexpression of these proteins, with exception of USP17N, leads to apoptosis, suggesting that the hyaluronan and RNA binding motifs in these enzymes play an important role in regulating signal transduction involved in cell death

Transcriptional Regulator TonEBP Mediates Oxidative Damages in Ischemic Kidney Injury

TonEBP (tonicity-responsive enhancer binding protein) is a transcriptional regulator whose expression is elevated in response to various forms of stress including hyperglycemia, inflammation, and hypoxia. Here we investigated the role of TonEBP in acute kidney injury (AKI) using a line of TonEBP haplo-deficient mice subjected to bilateral renal ischemia followed by reperfusion (I/R). In the TonEBP haplo-deficient animals, induction of TonEBP, oxidative stress, inflammation, cell death, and functional injury in the kidney in response to I/R were all reduced. Analyses of renal transcriptome revealed that genes in several cellular pathways including peroxisome and mitochondrial inner membrane were suppressed in response to I/R, and the suppression was relieved in the TonEBP deficiency. Production of reactive oxygen species (ROS) and the cellular injury was reproduced in a renal epithelial cell line in response to hypoxia, ATP depletion, or hydrogen peroxide. The knockdown of TonEBP reduced ROS production and cellular injury in correlation with increased expression of the suppressed genes. The cellular injury was also blocked by inhibitors of necrosis. These results demonstrate that ischemic insult suppresses many genes involved in cellular metabolism leading to local oxidative stress by way of TonEBP induction. Thus, TonEBP is a promising target to prevent AKI

Short-Term Effects of Combined Serial Casting and Botulinum Toxin Injection for Spastic Equinus in Ambulatory Children with Cerebral Palsy

PURPOSE: The purpose of this paper is to test the hypothesis that combination therapy of serial cast and botulinum toxin type A (BTX-A) injection can further enhance the effects of a BTX-A injection in ambulant children with cerebral palsy (CP) who have an equinus foot. MATERIALS AND METHODS: Children in group A (30 legs of 21 children) received a serial casting application after an injection of BTX-A, and children in group B (25 legs of 17 children) received only a BTX-A injection. Assessments were performed before the intervention and 1 month after the intervention. RESULTS: After the intervention, there were significant improvements in tone, dynamic spasticity, and passive range of motion (ROM) in both groups. However, the changes were greater in group A than in group B. Dimension D (standing) in Gross Motor Function Measure (GMFM)-66 was significantly improved in group A but not in group B. On the other hand, there were no significant changes in dimension E (walking, running, jumping) in GMFM-66 in either group. CONCLUSION: The results of our study suggest that a serial casting application after BTX-A injection can enhance the benefits of BTX-A injection in children with cerebral palsy.ope

The First Korean Case of KCNQ2 Mutation in a Family with Benign Familial Neonatal Convulsions

Neonatal seizures represent a heterogeneous group of disorders with vastly different etiologies and outcomes. Benign familial neonatal convulsions (BFNC) are a distinctive epileptic syndrome of autosomal dominant inheritance with a favorable prognosis, characterized by the occurrence of unprovoked partial or generalized clonic seizures in the neonatal period or early infancy. Recently, mutations in two potassium channel genes, KCNQ2 and KCNQ3, have been described in this disorder. In this report, we describe a family with BFNC due to a KCNQ2 mutation, the first such family to be described in the Korean population. The diagnosis of BFNC can be made based on clinical suspicion and careful history taking with special emphasis on the familial nature of the disorder. KCNQ2 mutations may be associated with BFNC in a number of different races, as has been reported in other ethnic groups