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1. chinaXiv:201605.01809 [pdf]

BMP2-SMAD Signaling Represses the Proliferation of Embryonic Neural Stem Cells through YAP

Yao, Minghui; Wang, Yadong; Zhang, Peng; Chen, Hong; Yuan, Zengqiang; Yao, Minghui; Xu, Zhiheng; Jiao, Jianwei; Wang, Yadong
Subjects: Biology >> Biophysics >> Neurosciences

Previous studies have shown that the Hippo pathway effector yes-associated protein (YAP) plays an important role in maintaining stem cell proliferation. However, the precise molecular mechanism of YAP in regulating murine embryonic neural stem cells (NSCs) remains largely unknown. Here, we show that bone morphogenetic protein-2 (BMP2) treatment inhibited the proliferation of mouse embryonic NSCs, that YAP was critical for mouse NSC proliferation, and that BMP2 treatment-induced inhibition of mouse NSC proliferation was abrogated by YAP knockdown, indicating that the YAP protein mediates the inhibitory effect of BMP2 signaling. Additionally, we found that BMP2 treatment reduced YAP nuclear translocation, YAP-TEAD interaction, and YAP-mediated transactivation. BMP2 treatment inhibited YAP/TEAD-mediated Cyclin D1 (ccnd1) expression, and knockdown of ccnd1 abrogated the BMP2-mediated inhibition of mouse NSC proliferation. Mechanistically, we found that Smad1/4, effectors of BMP2 signaling, competed with YAP for the interaction with TAED1 and inhibited YAP's cotranscriptional activity. Our data reveal mechanistic cross talk between BMP2 signaling and the Hippo-YAP pathway in murine NSC proliferation, which may be exploited as a therapeutic target in neurodegenerative diseases and aging.

submitted time 2016-06-06 Hits3324Downloads1351 Comment 0

2. chinaXiv:201605.01362 [pdf]

Mitochondrial calcium uniporter protein MCU is involved in oxidative stress-induced cell death

Liao, Yajin; Hao, Yumin; Chen, Hong; He, Qing; Yuan, Zengqiang; Cheng, Jinbo; Liao, Yajin; He, Qing
Subjects: Biology >> Biophysics >> Cell Biology

Mitochondrial calcium uniporter (MCU) is a conserved Ca2+ transporter at mitochondrial in eukaryotic cells. However, the role of MCU protein in oxidative stress-induced cell death remains unclear. Here, we showed that ectopically expressed MCU is mitochondrial localized in both HeLa and primary cerebellar granule neurons (CGNs). Knockdown of endogenous MCU decreases mitochondrial Ca2+ uptake following histamine stimulation and attenuates cell death induced by oxidative stress in both HeLa cells and CGNs. We also found MCU interacts with VDAC1 and mediates VDAC1 overexpression-induced cell death in CGNs. This finding demonstrates that MCU-VDAC1 complex regulates mitochondrial Ca2+ uptake and oxidative stress-induced apoptosis, which might represent therapeutic targets for oxidative stress related diseases.

submitted time 2016-05-12 Hits1504Downloads748 Comment 0

3. chinaXiv:201605.01197 [pdf]

HDAC2 Selectively Regulates FOXO3a-Mediated Gene Transcription during Oxidative Stress-Induced Neuronal Cell Death

Peng, Shengyi; Zhao, Siqi; Cheng, Jinbo; Huang, Li; Chen, Hong; Yuan, Zengqiang; Yan, Feng; Liu, Qingsong; Peng, Shengyi; Yuan, Zengqiang; Peng, Shengyi
Subjects: Biology >> Biophysics >> Neurosciences

All neurodegenerative diseases are associated with oxidative stress-induced neuronal death. Forkhead box O3a (FOXO3a) is a key transcription factor involved in neuronal apoptosis. However, how FOXO3a forms complexes and functions in oxidative stress processing remains largely unknown. In the present study, we show that histone deacetylase 2 (HDAC2) forms a physical complex with FOXO3a, which plays an important role in FOXO3a-dependent gene transcription and oxidative stress-induced mouse cerebellar granule neuron (CGN) apoptosis. Interestingly, we also found that HDAC2 became selectively enriched in the promoter region of the p21 gene, but not those of other target genes, and inhibited FOXO3a-mediated p21 transcription. Furthermore, we found that oxidative stress reduced the interaction between FOXO3a and HDAC2, leading to an increased histone H4K16 acetylation level in the p21 promoter region and upregulated p21 expression in a manner independent of p53 or E2F1. Phosphorylation of HDAC2 at Ser 394 is important for the HDAC2-FOXO3a interaction, and we found that cerebral ischemia/reperfusion reduced phosphorylation of HDAC2 at Ser 394 and mitigated the HDAC2-FOXO3a interaction in mouse brain tissue. Our study reveals the novel regulation of FOXO3a-mediated selective gene transcription via epigenetic modification in the process of oxidative stress-induced cell death, which could be exploited therapeutically.

submitted time 2016-05-11 Hits1505Downloads839 Comment 0

4. chinaXiv:201605.00768 [pdf]

Amplified RLR signaling activation through an interferon-stimulated gene-endoplasmic reticulum stress-mitochondrial calcium uniporter protein loop

Cheng, Jinbo; Liao, Yajin; Zhou, Lujun; Peng, Shengyi; Chen, Hong; Yuan, Zengqiang; Liao, Yajin; Zhou, Lujun;
Subjects: Biology >> Biophysics

Type I interferon (IFN-I) is critical for a host against viral and bacterial infections via induction of hundreds of interferon-stimulated genes (ISGs), but the mechanism underlying the regulation of IFN-I remains largely unknown. In this study, we first demonstrate that ISG expression is required for optimal IFN-beta levels, an effect that is further enhanced by endoplasmic reticulum (ER) stress. Furthermore, we identify mitochondrial calcium uniporter protein (MCU) as a mitochondrial antiviral signaling protein (MAVS)-interacting protein that is important for ER stress induction and amplified MAVS signaling activation. In addition, by performing an ectopic expression assay to screen a library of 117 human ISGs for effects on IFN-beta levels, we found that tumor necrosis factor receptor 1 (TNFR1) significantly increases IFN-beta levels independent of ER stress. Altogether, our findings suggest that MCU and TNFR1 are involved in the regulation of RIG-I-like receptors (RLR) signaling.

submitted time 2016-05-05 Hits1622Downloads748 Comment 0

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