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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 Hits1870Downloads630 Comment 0

2. chinaXiv:201605.01499 [pdf]

YAP Enhances Autophagic Flux to Promote Breast Cancer Cell Survival in Response to Nutrient Deprivation

Song, Qinghe; Mao, Beibei; Cheng, Jinbo; Gao, Yuhao; Yuan, Zengqiang; Song, Qinghe; Gao, Yuhao; Yuan, Zengqiang; Jiang, Ke; Meng, Songshu; Chen, Jun
Subjects: Biology >> Biophysics

The Yes-associated protein (YAP), a transcriptional coactivator inactivated by the Hippo tumor suppressor pathway, functions as an oncoprotein in a variety of cancers. However, its contribution to breast cancer remains controversial. This study investigated the role of YAP in breast cancer cells under nutrient deprivation (ND). Here, we show that YAP knockdown sensitized MCF7 breast cancer cells to nutrient deprivation-induced apoptosis. Furthermore, in response to ND, YAP increased the autolysosome degradation, thereby enhancing the cellular autophagic flux in breast cancer cells. Of note, autophagy is crucial for YAP to protect MCF7 cells from apoptosis under ND conditions. In addition, the TEA domain (TEAD) family of growth-promoting transcription factors was indispensable for YAP-mediated regulation of autophagy. Collectively, our data reveal a role for YAP in promoting breast cancer cell survival upon ND stress and uncover an unappreciated function of YAP/TEAD in the regulation of autophagy.

submitted time 2016-05-12 Hits527Downloads359 Comment 0

3. chinaXiv:201605.01470 [pdf]

Brahma regulates the Hippo pathway activity through forming complex with Yki-Sd and regulating the transcription of Crumbs

Zhu, Ye; Wang, Yadong; Pei, Chunli; Yuan, Zengqiang; Zhang, Peng; Li, Dong; Liu, Song; Zhang, Lei
Subjects: Biology >> Biophysics >> Cell Biology

The Hippo signaling pathway restricts organ size by inactivating the Yorkie (Yki)/Yes-associated protein (YAP) family proteins. The oncogenic Yki/YAP transcriptional coactivator family promotes tissue growth by activating target gene transcription, but the regulation of Yki/YAP activation remains elusive. In mammalian cells, we identified Brg1, a major subunit of chromatin-remodeling SWI/SNF family proteins, which interacts with YAP. This finding led us to investigate the in vivo functional interaction of Yki and Brahma (Brm), the Drosophila homolog of Brg1. We found that Brm functions at the downstream of Hippo pathway and interacts with Yki and Scalloped (Sd) to promotes Yki-dependent transcription and tissue growth. Furthermore, we demonstrated that Brm is required for the Crumbs (Crb) dysregulation-induced Yki activation. Interestingly, we also found that crb is a downstream target of Yki-Brm complex. Brm physically binds to the promoter of crb and regulates its transcription through Yki. Together, we showed that Brm functions as a critical regulator of Hippo signaling during tissue growth and plays an important role in the feedback loop between Crb and Yki. (C) 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.

submitted time 2016-05-12 Hits727Downloads410 Comment 0

4. chinaXiv:201605.01469 [pdf]

Dynamic Phosphorylation of CENP-A at Ser68 Orchestrates Its Cell-Cycle-Dependent Deposition at Centromeres

Yu, Zhouliang; Zhou, Xiang; Wang, Wenjing; Deng, Wenqiang; Fang, Junnan; Hu, Hao; Wang, Zichen; Cui, Lei; Shen, Jing; Ou, Guangshuo; Yang, Na; Chen, Ping; Xu, Rui-Ming; Li, Guohong; Yu, Zhouliang; Deng, Wenqiang; Fang, Junnan; Hu, Hao; Peng, Shengyi; Li, Shangze
Subjects: Biology >> Biophysics >> Cell Biology

The H3 histone variant CENP-A is an epigenetic marker critical for the centromere identity and function. However, the precise regulation of the spatiotemporal deposition and propagation of CENP-A at centromeres during the cell cycle is still poorly understood. Here, we show that CENP-A is phosphorylated at Ser68 during early mitosis by Cdk1. Our results demonstrate that phosphorylation of Ser68 eliminates the binding of CENP-A to the assembly factor HJURP, thus preventing the premature loading of CENP-A to the centromere prior to mitotic exit. Because Cdk1 activity is at its minimum at the mitotic exit, the ratio of Cdk1/PP1 alpha activity changes in favor of Ser68 dephosphorylation, thus making CENP-A available for centromeric deposition by HJURP. Thus, we reveal that dynamic phosphorylation of CENP-A Ser68 orchestrates the spatiotemporal assembly of newly synthesized CENP-A at active centromeres during the cell cycle.

submitted time 2016-05-12 Hits715Downloads465 Comment 0

5. chinaXiv:201605.01450 [pdf]

Interdomain interface-mediated target recognition by the Scribble PDZ34 supramodule

Ren, Jinqi; Feng, Lei; Bai, Yujie; Pei, Haohong; Feng, Wei; Ren, Jinqi; Bai, Yujie; Yuan, Zengqiang
Subjects: Biology >> Biophysics >> Biochemistry & Molecular Biology

Tandem-arranged PDZ [PSD-95 (postsynaptic density-95), Dlg (discs large homologue) and ZO-1 (zonula occludens-1)] domains often form structural and functional supramodules with distinct target-binding properties. In the present study, we found that the two PDZ domains within the PDZ34 tandem of Scribble, a cell polarity regulator, tightly pack in a 'front-to-back' mode to form a compact supramodule. Although PDZ4 contains a distorted alpha B/beta B pocket, the attachment of PDZ4 to PDZ3 generates an unexpected interdomain pocket that is adjacent to and integrates with the canonical aB/aB pocket of PDZ3 to form an expanded target-binding groove. The structure of the PDZ34-target peptide complex further demonstrated that the peptide binds to this expanded target-binding groove with its upstream residues anchoring into the interdomain pocket directly. Mutations of the interdomain pocket and disruptions of the PDZ34 supramodule both interfere with its target-binding capacity. Therefore, the interdomain interface between the PDZ34 supramodule is intrinsically required for its target recognition and determines its target-binding specificity. This interdomain interface-mediated specific recognition may represent a novel mode of target recognition and would broaden the target-binding versatility for PDZ supramodules. The supramodular nature and target recognitionmode of the PDZ34 tandem found in the present study would also help to identify the new binding partners of Scribble and thus may direct further research on the PDZ domain-mediated assembly of Scribble polarity complexes.

submitted time 2016-05-12 Hits353Downloads191 Comment 0

6. 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 Hits378Downloads238 Comment 0

7. chinaXiv:201605.01247 [pdf]

CHD2 is Required for Embryonic Neurogenesis in the Developing Cerebral Cortex

Shen, Tianjin; Ji, Fen; Jiao, Jianwei; Yuan, Zengqiang; Shen, Tianjin
Subjects: Biology >> Biophysics

Chromodomain helicase DNA-binding protein 2 (CHD2) has been associated with a broad spectrum of neurodevelopmental disorders, such as autism spectrum disorders and intellectual disability. However, it is largely unknown whether and how CHD2 is involved in brain development. Here, we demonstrate that CHD2 is predominantly expressed in Pax6(+) radial glial cells (RGs) but rarely expressed in Tbr2(+) intermediate progenitors (IPs). Importantly, the suppression of CHD2 expression inhibits the self-renewal of RGs and increases the generation of IPs and the production of neurons. CHD2 mediates these functions by directly binding to the genomic region of repressor element 1-silencing transcription factor (REST), thereby regulating the expression of REST. Furthermore, the overexpression of REST rescues the defect in neurogenesis caused by CHD2 knockdown. Taken together, these findings demonstrate an essential role of CHD2 in the maintenance of the RGs self-renewal levels, the subsequent generation of IPs, and neuronal output during neurogenesis in cerebral cortical development, suggesting that inactivation of CHD2 during neurogenesis might contribute to abnormal neurodevelopment. Stem Cells2015;33:1794-1806

submitted time 2016-05-11 Hits379Downloads213 Comment 0

8. 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 Hits464Downloads256 Comment 0

9. 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 Hits420Downloads247 Comment 0

10. chinaXiv:201605.00755 [pdf]

Dysfunction of Wntless triggers the retrograde Golgi-to-ER transport of Wingless and induces ER stress

Zhang, Peng; Zhou, Lujun; Pei, Chunli; Yuan, Zengqiang; Lin, Xinhua; Lin, Xinhua;
Subjects: Biology >> Biophysics

Secreted Wnts play diverse roles in a non-cell-autonomous fashion. However, the cell-autonomous effect of unsecreted Wnts remains unknown. Endoplasmic reticulum (ER) stress is observed in specialized secretory cells and participates in pathophysiological processes. The correlation between Wnt secretion and ER stress remains poorly understood. Here, we demonstrated that Drosophila miR-307a initiates ER stress specifically in wingless (wg)-expressing cells through targeting wntless (wls/evi). This phenotype could be mimicked by retromer loss-of-function or porcupine (porc) depletion, and rescued by wg knockdown, arguing that unsecreted Wg triggers ER stress. Consistently, we found that disrupting the secretion of human Wnt5a also induced ER stress in mammalian cells. Furthermore, we showed that a C-terminal KKVY-motif of Wg is required for its retrograde Golgi-to-ER transport, thus inducing ER stress. Next, we investigated if COPI, the regulator of retrograde transport, is responsible for unsecreted Wg to induce ER stress. To our surprise, we found that COPI acts as a novel regulator of Wg secretion. Taken together, this study reveals a previously unknown Golgi-to-ER retrograde route of Wg, and elucidates a correlation between Wnt secretion and ER stress during development.

submitted time 2016-05-05 Hits385Downloads227 Comment 0

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