Direct interaction of menin leads to ubiquitin-proteasomal degradation of ß-catenin.

Menin, encoded by the multiple endocrine neoplasia type 1 (MEN1) gene, is a tumor suppressor and transcription regulator. Menin interacts with various proteins as a scaffold protein and is proposed to play important roles in multiple physiological and pathological processes by controlling gene expression, proliferation, and apoptosis. The mechanisms underlying menin's suppression of tumorigenesis are largely elusive. In this study, we showed that menin was essential for the regulation of canonical Wnt/ß-catenin signaling in cultured cells. The C-terminal domain of menin was able to directly interact with and promote ubiquitin-mediated degradation of ß-catenin. We further revealed that overexpression of menin down-regulated the transcriptional activity of ß-catenin and target gene expression. Moreover, menin efficiently inhibited ß-catenin protein levels, transcriptional activity, and proliferation of human renal carcinoma cells with an activated ß-catenin pathway. Taken together, our results provide novel molecular insights into the tumor suppressor activity of menin, which is partly mediated by proteasomal degradation of ß-catenin and inhibition of Wnt/ß-catenin signaling.

A Pediatric Case of Severe Fever with Thrombocytopenia Syndrome in Korea.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease and elderly people living in rural areas have the greatest risk of infection. We report the first pediatric case of SFTS in Korea and the clinical characteristics and disease progression in children. A 10-year-old child from Chonnam province visited the hospital with myalgia and a history of fever over the previous 8 days. Her father noticed a tick on her head and removed it before fever developed. Because the symptoms continued, her father consulted the community health center and SFTS virus was detected both from the tick (Haemaphysalis longicornis) and the patient's blood. On hospitalization, fever and severe myalgia were improved and no gastrointestinal and hemorrhagic symptoms were observed. The patient was successfully treated with a combination of steroids, IVIG, and ribavirin. In this report, a pediatric case of SFTS presents a mild clinical course but close attention must be paid to the screening of children with mild symptoms consisting of SFTS.

The role of tumor suppressor menin in IL-6 regulation in mouse islet tumor cells.

Menin is a gene product of multiple endocrine neoplasia type1 (Men1), an inherited familial cancer syndrome characterized by tumors of endocrine tissues. To gain insight about how menin performs an endocrine cell-specific tumor suppressor function, we investigated the possibility that menin was integrated in a cancer-associated inflammatory pathway in a cell type-specific manner. Here, we showed that the expression of IL-6, a proinflammatory cytokine, was specifically elevated in mouse islet tumor cells upon depletion of menin and Men(-/-) MEF cells, but not in hepatocellular carcinoma cells. Histone H3 lysine (K) 9 methylation, but not H3 K27 or K4 methylation, was involved in menin-dependent IL-6 regulation. Menin occupied the IL-6 promoter and recruited SUV39H1 to induce H3 K9 methylation. Our findings provide a molecular insight that menin-dependent induction of H3 K9 methylation in the cancer-associated interleukin gene might be linked to preventing endocrine-specific tumorigenesis.

The role of histone chaperones in osteoblastic differentiation of C2C12 myoblasts.

Cellular differentiation is a process in which the cells gain a more specialized shape, metabolism, and function. These cellular changes are accompanied by dynamic changes in gene expression programs. In most cases, DNA methylation, histone modification, and variant histones drive the epigenetic transition that reprograms the gene expression. Histone chaperones, HIRA and Asf1a, have a role for cellular differentiation by deposition of one of variant histones, H3.3, during myogenesis of murine C2C12 cells. In this study, we accessed the roles of histone chaperones and histone H3.3 in osteoblastic conversion of C2C12 myoblasts and compared their roles with those for myogenic differentiation. The unbiased analysis of the expression pattern of histone chaperones and variant histones proposed their uncommon contribution to each pathway. HIRA and Asf1a decreased to ∼50% and further diminished during differentiation into osteoblasts, while they were maintained during differentiation into myotubes. HIRA, Asf1a, and H3.3 were indispensable for expression of cell type-specific genes during conversion into osteoblasts or myotubes. RNA interference analysis indicated that histone chaperones and H3.3 were required for early steps of osteoblastic differentiation. Our results suggest that histone chaperones and variant histones might be differentially required for the distinct phases of differentiation pathway.

Improvement of treatment outcome over 2 decades in children with acute myeloid leukemia.

BACKGROUND: The prognosis of pediatric acute myeloid leukemia (AML) has recently improved. This study aimed to describe the epidemiology, changes in treatment strategies, and improvement of outcomes in Gwangju-Chonnam children with AML over 2 decades. METHODS: Medical records of 116 children with newly diagnosed AML were retrospectively reviewed for demographic characteristics, prognostic groups including cytogenetic risks, treatment protocols, and survival rates over the periods between 1996 and 2005 (Period I, N=53), and 2006 and 2015 (Period II, N=38). RESULTS: The annual incidence of AML has decreased with reduced pediatric population. The 5-year Kaplan-Meier (K-M) estimated overall survival (OS) and event-free survival (EFS) rates in 110 AML patients were 53.2±5.1% and 43.8±5.1%, respectively. The 5-year OS rate significantly improved during period II (70.3±7.0%) as compared to that during period I (40.0±6.8%) (P =0.001). The 5-year OS was not significantly different among cytogenetic risk groups (P =0.11). Fifty-eight patients underwent hematopoietic stem cell transplantation (HSCT). The K-M 5-year estimated survival for transplanted patients was 53.7±7.0%, while that for chemotherapy-only patients was 30.1±9.1% (P =0.014). Among the prognostic factors, treatment modality was the only independent factor. The chemotherapy-only group had a relative risk of 2.06 for death compared with the transplantation group (P=0.015). CONCLUSION: The survival of Korean children with AML has improved to a level comparable with that of developed countries over 2 decades, owing to a change in induction strategy, better supportive care with economic growth, refinement of HSCT techniques including a better selection of patients based on prognostic groups, and stem cell donor selection.

The structural shift of a DNA template between a hairpin and a dimer tunes the emission color of DNA-templated AgNCs.

The scaffolding DNA sequence and the size of silver nanoclusters (AgNCs), confined in a DNA template are the key parameters in determining the fluorescent properties of DNA-stabilized silver nanoclusters (DNA/AgNCs). In addition, we suggest here that the structural shift of a DNA hairpin-dimer is as important as the DNA sequence in determining the emission wavelength of DNA/AgNCs. Furthermore, we show that the structural shift post AgNC formation can be triggered by incubation time and pre-AgNC formation under salt conditions. As an important factor in predicting the emission properties of DNA/AgNCs, the modulation of DNA secondary structures with either sequence changes or ionic conditions can be applied for the dual-color detection system of a target molecule. Particularly, the dual-color detection method may increase the reliability of DNA/AgNC sensors for miRNAs.

Differential regulation of the histone chaperone HIRA during muscle cell differentiation by a phosphorylation switch.

Replication-independent incorporation of variant histone H3.3 has a profound impact on chromatin function and numerous cellular processes, including the differentiation of muscle cells. The histone chaperone HIRA and H3.3 have essential roles in MyoD regulation during myoblast differentiation. However, the precise mechanism that determines the onset of H3.3 deposition in response to differentiation signals is unclear. Here we show that HIRA is phosphorylated by Akt kinase, an important signaling modulator in muscle cells. By generating a phosphospecific antibody, we found that a significant amount of HIRA was phosphorylated in myoblasts. The phosphorylation level of HIRA and the occupancy of phosphorylated protein on muscle genes gradually decreased during cellular differentiation. Remarkably, the forced expression of the phosphomimic form of HIRA resulted in reduced H3.3 deposition and suppressed the activation of muscle genes in myotubes. Our data show that HIRA phosphorylation limits the expression of myogenic genes, while the dephosphorylation of HIRA is required for proficient H3.3 deposition and gene activation, demonstrating that the phosphorylation switch is exploited to modulate HIRA/H3.3-mediated muscle gene regulation during myogenesis.

Identification of small molecules that inhibit the histone chaperone Asf1 and its chromatin function.

The eukaryotic genome is packed into chromatin, which is important for the genomic integrity and gene regulation. Chromatin structures are maintained through assembly and disassembly of nucleosomes catalyzed by histone chaperones. Asf1 (anti-silencing function 1) is a highly conserved histone chaperone that mediates histone transfer on/off DNA and promotes histone H3 lysine 56 acetylation at globular core domain of histone H3. To elucidate the role of Asf1 in the modulation of chromatin structure, we screened and identified small molecules that inhibit Asf1 and H3K56 acetylation without affecting other histone modification. These pyrimidine-2,4,6-trione derivative molecules inhibited the nucleosome assembly mediated by Asf1 in vitro, and reduced the H3K56 acetylation in HeLa cells. Furthermore, production of HSV viral particles was reduced by these compounds. As Asf1 is implicated in genome integrity, cell proliferation, and cancer, current Asf1 inhibitor molecules may offer an opportunity for the therapeutic development for treatment of diseases.