Deleterious c-Cbl Exon Skipping Contributes to Human Glioma.

c-Cbl, a RING-type ubiquitin E3 ligase, downregulates various receptor tyrosine kinases (e.g., epidermal growth factor receptor (EGFR)), leading to inhibition of cell proliferation. Moreover, patients with myeloid neoplasm frequently harbor c-Cbl mutations, implicating the role of c-Cbl as a tumor suppressor. Recently, we have shown that c-Cbl downregulates αPix-mediated cell migration and invasion, and the lack of c-Cbl in the rat C6 and human A172 glioma cells is responsible for their malignant behavior. Here, we showed that c-Cbl exon skipping occurs in the glioma cells and the brain tissues from glioblastoma patients lacking c-Cbl. This exon skipping resulted in generation of two types of c-Cbl isoforms: type I lacking exon-9 and type II lacking exon-9 and exon-10. However, the c-Cbl isoforms in the cells and tissues could not be detected as they were rapidly degraded by proteasome. Consequently, C6 and A172 cells showed sustained EGFR activation. However, no splice site mutation was found in the region from exon-7 to exon-11 of the c-Cbl gene in C6 cells and a glioblastoma tissue lacking c-Cbl. In addition, c-Cbl exon skipping could be induced when cells transfected with a c-Cbl mini-gene were grown to high density or under hypoxic stress. These results suggest that unknown alternations (e.g., mutation) of splicing machinery in C6 and A172 cells and the glioblastoma brain tissues are responsible for the deleterious exon skipping. Collectively, these findings indicate that the c-Cbl exon skipping contributes to human glioma and its malignant behavior.

c-Cbl regulates αPix-mediated cell migration and invasion.

c-Cbl, a RING-type ubiquitin E3 ligase, down-regulates receptor tyrosine kinases, including EGF receptor, and inhibits cell proliferation. Moreover, c-Cbl mutations are frequently found in patients with myeloid neoplasm. Therefore, c-Cbl is known as a tumor suppressor. αPix is expressed only in highly proliferative and mobile cells, including immune cells, and up-regulated in certain invasive tumors, such as glioblastoma multiforme. Here, we showed that c-Cbl serves as an ubiquitin E3 ligase for proteasome-mediated degradation of αPix, but not ßPix. Remarkably, the rat C6 and human A172 glioma cells were unable to express c-Cbl, which leads to a dramatic accumulation of αPix. Depletion of αPix by shRNA markedly reduced the ability of the glioma cells to migrate and invade, whereas complementation of shRNA-insensitive αPix promoted it. These results indicate that c-Cbl negatively regulates αPix-mediated cell migration and invasion and the lack of c-Cbl in the C6 and A172 glioma cells is responsible for their malignant behavior.

Modification of DBC1 by SUMO2/3 is crucial for p53-mediated apoptosis in response to DNA damage.

DBC1 is a major inhibitor of SIRT1, which plays critical roles in the control of diverse cellular processes, including stress response and energy metabolism. Therefore, the DBC1-SIRT1 interaction should finely be regulated. Here we report that DBC1 modification by Small Ubiquitin-like Modifier 2/3 (SUMO 2/3), but not by SUMO1, is crucial for p53 transactivation under genotoxic stress. Whereas etoposide treatment reduced the interaction of DBC1 with SENP1, it promoted that with PIAS3, resulting in an increase in DBC1 sumoylation. Remarkably, the switching from SENP1 to PIAS3 for DBC1 binding was achieved by ATM/ATR-mediated phosphorylation of DBC1. Furthermore, DBC1 sumoylation caused an increase in the DBC1-SIRT1 interaction, leading to the release of p53 from SIRT1 for transcriptional activation. Consistently, SENP1 knockdown promoted etoposide-induced apoptosis, whereas knockdown of PIAS3 or SUMO2/3 and overexpression of sumoylation-deficient DBC1 mutant inhibited it. These results establish the role of DBC1 sumoylation in the promotion of p53-mediated apoptosis in response to genotoxic stress.

Modification of ASC1 by UFM1 is crucial for ERα transactivation and breast cancer development.

Biological roles for UFM1, a ubiquitin-like protein, are largely unknown, and therefore we screened for targets of ufmylation. Here we show that ufmylation of the nuclear receptor coactivator ASC1 is a key step for ERα transactivation in response to 17ß-estradiol (E2). In the absence of E2, the UFM1-specific protease UfSP2 was bound to ASC1, which maintains ASC1 in a nonufmylated state. In the presence of E2, ERα bound ASC1 and displaced UfSP2, leading to ASC1 ufmylation. Polyufmylation of ASC1 enhanced association of p300, SRC1, and ASC1 at promoters of ERα target genes. ASC1 overexpression or UfSP2 knockdown promoted ERα-mediated tumor formation in vivo, which could be abrogated by treatment with the anti-breast cancer drug tamoxifen. In contrast, expression of ufmylation-deficient ASC1 mutant or knockdown of the UFM1-activating E1 enzyme UBA5 prevented tumor growth. These findings establish a role for ASC1 ufmylation in breast cancer development by promoting ERα transactivation.

Quality of Life in Korean Patients with Obstructive Sleep Apnea

BACKGROUND: Obstructive sleep apnea (OSA) is a common disease, but there are few studies about the quality of life (QOL) of Korean patients with OSA. The aims of the present study were compare the QOL of patients with OSA and healthy controls, and to determine the factors that influence the QOL in these patients. METHODS: This was a casecontrol study comparing the QOL of 136 OSA patients and 126 healthy controls. For all of the subjects, QOL and the severity of subjective symptoms were evaluated using various questionnaires, including the Korean versions of the Medical Outcome Study Short Form-36 (SF-36), the Pittsburg Sleep Quality Index (PSQI-K), the Epworth Sleepiness Scale (KESS), the Insomnia Severity Index (ISI), the Beck Depression Inventory (KBDI)-2, and the Hospital Anxiety Scale (HAS). RESULTS: The QOL was worse in patients with OSA than in the controls, but there was no association between the severity of OSA and the degree of worsening of QOL. Multiple stepwise regression analysis revealed that the strongest associations were found between QOL and HAS, ISI and BDI-2 scoring in OSA patients. CONCLUSIONS: These findings demonstrate that OSA represents a considerable burden on the QOL of Koreans, and suggest that the impairment in QOL of Koreans with OSA is related to the degree of anxiety, insomnia and depression that they suffer.

USP47 and C terminus of Hsp70-interacting protein (CHIP) antagonistically regulate katanin-p60-mediated axonal growth.

Katanin is a heterodimeric enzyme that severs and disassembles microtubules. While the p60 subunit has the enzyme activity, the p80 subunit regulates the p60 activity. The microtubule-severing activity of katanin plays an essential role in axonal growth. However, the mechanisms by which neuronal cells regulate the expression of katanin-p60 remains unknown. Here we showed that USP47 and C terminus of Hsp70-interacting protein (CHIP) antagonistically regulate the stability of katanin-p60 and thereby axonal growth. USP47 was identified as a katanin-p60-specific deubiquitinating enzyme for its stabilization. We also identified CHIP as a ubiquitin E3 ligase that promotes proteasome-mediated degradation of katanin-p60. Moreover, USP47 promoted axonal growth of cultured rat hippocampal neurons, whereas CHIP inhibited it. Significantly, treatment with basic fibroblast growth factor (bFGF), an inducer of axonal growth, increased the levels of USP47 and katanin-p60, but not CHIP. Consistently, bFGF treatment resulted in a marked decrease in the level of ubiquitinated katanin-p60 and thereby in the promotion of axonal growth. On the other hand, the level of USP47, but not CHIP, decreased concurrently with that of katanin-p60 as axons reached their target cells. These results indicate that USP47 plays a crucial role in the control of axonal growth during neuronal development by antagonizing CHIP-mediated katanin-p60 degradation.

Hypoxic-Ischemic Encephalopathy Following Carotid Endarterectomy

No abstract available.

Tentorial Dural Arteriovenous Fistula Presenting With Progressive Encephalomyelopathy

A 68-year-old man developed mild quadriparesis 1 month prior to presentation. At 4 days before presentation, he developed dysarthria and more severe quadriparesis, predominantly on the left side of the body. MRI revealed edematous lesions in the medulla and throughout the spinal cord. Angiography showed a right tentorial dural arteriovenous fistula (DAVF). Despite successful treatment achieved by endovascular embolization, there was no improvement in the weakness of either leg. Early diagnosis of tentorial DAVF is important to prevent neurological complications such as encephalomyelopathy and hemorrhage.