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Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis
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Chris D Madsen Jesper T Pedersen Freja A Venning Lukram Babloo Singh Emad Moeendarbary Guillaume Charras Thomas R Cox Erik Sahai Janine T Erler 《EMBO reports》2015,16(10):1394-1408
Cancer‐associated fibroblasts (CAFs) interact with tumour cells and promote growth and metastasis. Here, we show that CAF activation is reversible: chronic hypoxia deactivates CAFs, resulting in the loss of contractile force, reduced remodelling of the surrounding extracellular matrix and, ultimately, impaired CAF‐mediated cancer cell invasion. Hypoxia inhibits prolyl hydroxylase domain protein 2 (PHD2), leading to hypoxia‐inducible factor (HIF)‐1α stabilisation, reduced expression of αSMA and periostin, and reduced myosin II activity. Loss of PHD2 in CAFs phenocopies the effects of hypoxia, which can be prevented by simultaneous depletion of HIF‐1α. Treatment with the PHD inhibitor DMOG in an orthotopic breast cancer model significantly decreases spontaneous metastases to the lungs and liver, associated with decreased tumour stiffness and fibroblast activation. PHD2 depletion in CAFs co‐injected with tumour cells similarly prevents CAF‐induced metastasis to lungs and liver. Our data argue that reversion of CAFs towards a less active state is possible and could have important clinical implications. 相似文献
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miR‐9‐5p suppresses pro‐fibrogenic transformation of fibroblasts and prevents organ fibrosis by targeting NOX4 and TGFBR2
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Marta Fierro‐Fernández óscar Busnadiego Pilar Sandoval Cristina Espinosa‐Díez Eva Blanco‐Ruiz Macarena Rodríguez Héctor Pian Ricardo Ramos Manuel López‐Cabrera Maria Laura García‐Bermejo Santiago Lamas 《EMBO reports》2015,16(10):1358-1377
Uncontrolled extracellular matrix (ECM) production by fibroblasts in response to injury contributes to fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Reactive oxygen species (ROS) generation is involved in the pathogenesis of IPF. Transforming growth factor‐β1 (TGF‐β1) stimulates the production of NADPH oxidase 4 (NOX4)‐dependent ROS, promoting lung fibrosis (LF). Dysregulation of microRNAs (miRNAs) has been shown to contribute to LF. To identify miRNAs involved in redox regulation relevant for IPF, we performed arrays in human lung fibroblasts exposed to ROS. miR‐9‐5p was selected as the best candidate and we demonstrate its inhibitory effect on TGF‐β receptor type II (TGFBR2) and NOX4 expression. Increased expression of miR‐9‐5p abrogates TGF‐β1‐dependent myofibroblast phenotypic transformation. In the mouse model of bleomycin‐induced LF, miR‐9‐5p dramatically reduces fibrogenesis and inhibition of miR‐9‐5p and prevents its anti‐fibrotic effect both in vitro and in vivo. In lung specimens from patients with IPF, high levels of miR‐9‐5p are found. In omentum‐derived mesothelial cells (MCs) from patients subjected to peritoneal dialysis (PD), miR‐9‐5p also inhibits mesothelial to myofibroblast transformation. We propose that TGF‐β1 induces miR‐9‐5p expression as a self‐limiting homeostatic response. 相似文献
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Integrative genomics positions MKRN1 as a novel ribonucleoprotein within the embryonic stem cell gene regulatory network
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Paul A Cassar Richard L Carpenedo Payman Samavarchi‐Tehrani Jonathan B Olsen Chang Jun Park Wing Y Chang Zhaoyi Chen Chandarong Choey Sean Delaney Huishan Guo Hongbo Guo R Matthew Tanner Theodore J Perkins Scott A Tenenbaum Andrew Emili Jeffrey L Wrana Derrick Gibbings William L Stanford 《EMBO reports》2015,16(10):1334-1357
In embryonic stem cells (ESCs), gene regulatory networks (GRNs) coordinate gene expression to maintain ESC identity; however, the complete repertoire of factors regulating the ESC state is not fully understood. Our previous temporal microarray analysis of ESC commitment identified the E3 ubiquitin ligase protein Makorin‐1 (MKRN1) as a potential novel component of the ESC GRN. Here, using multilayered systems‐level analyses, we compiled a MKRN1‐centered interactome in undifferentiated ESCs at the proteomic and ribonomic level. Proteomic analyses in undifferentiated ESCs revealed that MKRN1 associates with RNA‐binding proteins, and ensuing RIP‐chip analysis determined that MKRN1 associates with mRNAs encoding functionally related proteins including proteins that function during cellular stress. Subsequent biological validation identified MKRN1 as a novel stress granule‐resident protein, although MKRN1 is not required for stress granule formation, or survival of unstressed ESCs. Thus, our unbiased systems‐level analyses support a role for the E3 ligase MKRN1 as a ribonucleoprotein within the ESC GRN. 相似文献
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Abo1, a conserved bromodomain AAA‐ATPase,maintains global nucleosome occupancy and organisation
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Lakxmi Subramanian Alex J Whale Karen M Moore Konrad Paszkiewicz Sandra Codlin Jürg Bähler Kevin M Creamer Janet F Partridge Robin C Allshire Nicholas A Kent Simon K Whitehall 《EMBO reports》2016,17(1):79-93
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The balance of Id3 and E47 determines neural stem/precursor cell differentiation into astrocytes
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Christian Bohrer Sabrina Pfurr Könül Mammadzada Sebastian Schildge Leandra Plappert Miriam Hils Lauriane Pous Katharina S Rauch Verónica I Dumit Dietmar Pfeifer Jörn Dengjel Matthias Kirsch Kristina Schachtrup Christian Schachtrup 《The EMBO journal》2015,34(22):2804-2819
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Marc D Tambini Marta Pera Ellen Kanter Hua Yang Cristina Guardia‐Laguarta David Holtzman David Sulzer Estela Area‐Gomez Eric A Schon 《EMBO reports》2016,17(1):27-36
In addition to the appearance of senile plaques and neurofibrillary tangles, Alzheimer''s disease (AD) is characterized by aberrant lipid metabolism and early mitochondrial dysfunction. We recently showed that there was increased functionality of mitochondria‐associated endoplasmic reticulum (ER) membranes (MAM), a subdomain of the ER involved in lipid and cholesterol homeostasis, in presenilin‐deficient cells and in fibroblasts from familial and sporadic AD patients. Individuals carrying the ε4 allele of apolipoprotein E (ApoE4) are at increased risk for developing AD compared to those carrying ApoE3. While the reason for this increased risk is unknown, we hypothesized that it might be associated with elevated MAM function. Using an astrocyte‐conditioned media (ACM) model, we now show that ER–mitochondrial communication and MAM function—as measured by the synthesis of phospholipids and of cholesteryl esters, respectively—are increased significantly in cells treated with ApoE4‐containing ACM as compared to those treated with ApoE3‐containing ACM. Notably, this effect was seen with lipoprotein‐enriched preparations, but not with lipid‐free ApoE protein. These data are consistent with a role of upregulated MAM function in the pathogenesis of AD and may help explain, in part, the contribution of ApoE4 as a risk factor in the disease. 相似文献
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Reversible HuR‐microRNA binding controls extracellular export of miR‐122 and augments stress response
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Kamalika Mukherjee Bartika Ghoshal Souvik Ghosh Yogaditya Chakrabarty Shivaprasad Shwetha Saumitra Das Suvendra N Bhattacharyya 《EMBO reports》2016,17(8):1184-1203
microRNAs (miRNAs), the tiny but stable regulatory RNAs in metazoan cells, can undergo selective turnover in presence of specific internal and external cues to control cellular response against the changing environment. We have observed reduction in cellular miR‐122 content, due to their accelerated extracellular export in human hepatic cells starved for small metabolites including amino acids. In this context, a new role of human ELAV protein HuR has been identified. HuR, a negative regulator of miRNA function, accelerates extracellular vesicle (EV)‐mediated export of miRNAs in human cells. In stressed cells, HuR replaces miRNPs from target messages and is both necessary and sufficient for the extracellular export of corresponding miRNAs. HuR could reversibly bind miRNAs to replace them from Ago2 and subsequently itself gets freed from bound miRNAs upon ubiquitination. The ubiquitinated form of HuR is predominantly associated with multivesicular bodies (MVB) where HuR‐unbound miRNAs also reside. These MVB‐associated pool of miRNAs get exported out via EVs thereby delimiting cellular miR‐122 level during starvation. Therefore, by modulating extracellular export of miR‐122, HuR could control stress response in starved human hepatic cells. 相似文献
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Cytokine‐induced megakaryocytic differentiation is regulated by genome‐wide loss of a uSTAT transcriptional program
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Hyun Jung Park Juan Li Rebecca Hannah Simon Biddie Ana I Leal‐Cervantes Kristina Kirschner David Flores Santa Cruz Veronika Sexl Berthold Göttgens Anthony R Green 《The EMBO journal》2016,35(6):580-594
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Sara Planamente Osman Salih Eleni Manoli David Albesa‐Jové Paul S Freemont Alain Filloux 《The EMBO journal》2016,35(15):1613-1627
The type VI secretion system (T6SS) is a supra‐molecular bacterial complex that resembles phage tails. It is a killing machine which fires toxins into target cells upon contraction of its TssBC sheath. Here, we show that TssA1 is a T6SS component forming dodecameric ring structures whose dimensions match those of the TssBC sheath and which can accommodate the inner Hcp tube. The TssA1 ring complex binds the T6SS sheath and impacts its behaviour in vivo. In the phage, the first disc of the gp18 sheath sits on a baseplate wherein gp6 is a dodecameric ring. We found remarkable sequence and structural similarities between TssA1 and gp6 C‐termini, and propose that TssA1 could be a baseplate component of the T6SS. Furthermore, we identified similarities between TssK1 and gp8, the former interacting with TssA1 while the latter is found in the outer radius of the gp6 ring. These observations, combined with similarities between TssF and gp6N‐terminus or TssG and gp53, lead us to propose a comparative model between the phage baseplate and the T6SS. 相似文献
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Elke Gabriel Arpit Wason Anand Ramani Li Ming Gooi Patrick Keller Andrei Pozniakovsky Ina Poser Florian Noack Narasimha Swamy Telugu Federico Calegari Tomo Šarić Jürgen Hescheler Anthony A Hyman Marco Gottardo Giuliano Callaini Fowzan Sami Alkuraya Jay Gopalakrishnan 《The EMBO journal》2016,35(8):803-819
A mutation in the centrosomal‐P4.1‐associated protein (CPAP) causes Seckel syndrome with microcephaly, which is suggested to arise from a decline in neural progenitor cells (NPCs) during development. However, mechanisms of NPCs maintenance remain unclear. Here, we report an unexpected role for the cilium in NPCs maintenance and identify CPAP as a negative regulator of ciliary length independent of its role in centrosome biogenesis. At the onset of cilium disassembly, CPAP provides a scaffold for the cilium disassembly complex (CDC), which includes Nde1, Aurora A, and OFD1, recruited to the ciliary base for timely cilium disassembly. In contrast, mutated CPAP fails to localize at the ciliary base associated with inefficient CDC recruitment, long cilia, retarded cilium disassembly, and delayed cell cycle re‐entry leading to premature differentiation of patient iPS‐derived NPCs. Aberrant CDC function also promotes premature differentiation of NPCs in Seckel iPS‐derived organoids. Thus, our results suggest a role for cilia in microcephaly and its involvement during neurogenesis and brain size control. 相似文献
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Rene Ladurner Emanuel Kreidl Miroslav P Ivanov Heinz Ekker Maria Helena Idarraga‐Amado Georg A Busslinger Gordana Wutz David A Cisneros Jan‐Michael Peters 《The EMBO journal》2016,35(6):635-653
Cohesion between sister chromatids is established during DNA replication but needs to be maintained to enable proper chromosome–spindle attachments in mitosis or meiosis. Cohesion is mediated by cohesin, but also depends on cohesin acetylation and sororin. Sororin contributes to cohesion by stabilizing cohesin on DNA. Sororin achieves this by inhibiting WAPL, which otherwise releases cohesin from DNA and destroys cohesion. Here we describe mouse models which enable the controlled depletion of sororin by gene deletion or auxin‐induced degradation. We show that sororin is essential for embryonic development, cohesion maintenance, and proper chromosome segregation. We further show that the acetyltransferases ESCO1 and ESCO2 are essential for stabilizing cohesin on chromatin, that their only function in this process is to acetylate cohesin''s SMC3 subunit, and that DNA replication is also required for stable cohesin–chromatin interactions. Unexpectedly, we find that sororin interacts dynamically with the cohesin complexes it stabilizes. This implies that sororin recruitment to cohesin does not depend on the DNA replication machinery or process itself, but on a property that cohesin acquires during cohesion establishment. 相似文献
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Structure and function of the N‐terminal domain of the human mitochondrial calcium uniporter
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Youngjin Lee Choon Kee Min Tae Gyun Kim Hong Ki Song Yunki Lim Dongwook Kim Kahee Shin Moonkyung Kang Jung Youn Kang Hyung‐Seop Youn Jung‐Gyu Lee Jun Yop An Kyoung Ryoung Park Jia Jia Lim Ji Hun Kim Ji Hye Kim Zee Yong Park Yeon‐Soo Kim Jimin Wang Do Han Kim Soo Hyun Eom 《EMBO reports》2015,16(10):1318-1333
The mitochondrial calcium uniporter (MCU) is responsible for mitochondrial calcium uptake and homeostasis. It is also a target for the regulation of cellular anti‐/pro‐apoptosis and necrosis by several oncogenes and tumour suppressors. Herein, we report the crystal structure of the MCU N‐terminal domain (NTD) at a resolution of 1.50 Å in a novel fold and the S92A MCU mutant at 2.75 Å resolution; the residue S92 is a predicted CaMKII phosphorylation site. The assembly of the mitochondrial calcium uniporter complex (uniplex) and the interaction with the MCU regulators such as the mitochondrial calcium uptake‐1 and mitochondrial calcium uptake‐2 proteins (MICU1 and MICU2) are not affected by the deletion of MCU NTD. However, the expression of the S92A mutant or a NTD deletion mutant failed to restore mitochondrial Ca2+ uptake in a stable MCU knockdown HeLa cell line and exerted dominant‐negative effects in the wild‐type MCU‐expressing cell line. These results suggest that the NTD of MCU is essential for the modulation of MCU function, although it does not affect the uniplex formation. 相似文献
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Hongbin Zhang Meiping Guan Kristy L Townsend Tian Lian Huang Ding An Xu Yan Ruidan Xue Tim J Schulz Jonathon Winnay Marcelo Mori Michael F Hirshman Karsten Kristiansen John S Tsang Andrew P White Aaron M Cypess Laurie J Goodyear Yu‐Hua Tseng 《EMBO reports》2015,16(10):1378-1393
Brown adipose tissue (BAT) dissipates chemical energy as heat and can counteract obesity. MicroRNAs are emerging as key regulators in development and disease. Combining microRNA and mRNA microarray profiling followed by bioinformatic analyses, we identified miR‐455 as a new regulator of brown adipogenesis. miR‐455 exhibits a BAT‐specific expression pattern and is induced by cold and the browning inducer BMP7. In vitro gain‐ and loss‐of‐function studies show that miR‐455 regulates brown adipocyte differentiation and thermogenesis. Adipose‐specific miR‐455 transgenic mice display marked browning of subcutaneous white fat upon cold exposure. miR‐455 activates AMPKα1 by targeting HIF1an, and AMPK promotes the brown adipogenic program and mitochondrial biogenesis. Concomitantly, miR‐455 also targets the adipogenic suppressors Runx1t1 and Necdin, initiating adipogenic differentiation. Taken together, the data reveal a novel microRNA‐regulated signaling network that controls brown adipogenesis and may be a potential therapeutic target for human metabolic disorders. 相似文献