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Cell Death and Differentiation

Philipp J Jost, Ulrike Höckendorf
The hematopoietic system represents an organ system with an exceptional capacity for the production of mature blood cells from a small and mostly quiescent pool of hematopoietic stem cells (HSCs). This extraordinary capacity includes self-renewal but also the propensity to rapidly respond to extrinsic needs, such as acute infections, severe inflammation, and wound healing. In recent years, it became clear that inflammatory signals such as cytokines, chemokine and danger signals from pathogens (PAMPs) or dying cells (DAMPs) impact on HSCs, shaping their proliferation status, lineage bias, and repopulating ability and subsequently increasing the output of mature effector cells...
September 21, 2018: Cell Death and Differentiation
Lin-Gao Ju, Yuan Zhu, Qiao-Yun Long, Xue-Jing Li, Xiang Lin, Shan-Bo Tang, Lei Yin, Yu Xiao, Xing-Huan Wang, Lianyun Li, Lei Zhang, Min Wu
SPOP is one of the important subunits for CUL3/SPOP/RBX1 complex tightly connected with tumorigenesis. However, its exact roles in different cancers remain debatable. Here, we identify CYCLIN E1, as a novel substrate for SPOP. SPOP directly interacts with CYCLIN E1 and specific regulates its stability in prostate cancer cell lines. SPOP/CUL3/RBX1 complex regulates CYCLIN E1 stability through poly-ubiquitination. CDK2 competes with SPOP for CYCLIN E1 interaction, suggesting that SPOP probably regulates the stability of CDK2-free CYCLIN E1...
September 20, 2018: Cell Death and Differentiation
Ming-Yu Chen, Wei-Chan Hsu, Shu-Ching Hsu, Yu-Shao Yang, Tsung-Hsien Chuang, Wen-Jye Lin, Tse-Hua Tan, Yu-Wen Su
The serine/threonine phosphatase PP4 has been implicated in DNA damage repair and cell cycle regulation through its dephosphorylation of specific substrates. We previously showed that PP4 is required for mouse B cell development, germinal center (GC) formation and immunoglobulin (Ig) class switch recombination (CSR). Here, we investigate the mechanisms underlying this requirement and demonstrate that murine PP4-deficient B lymphocytes have a defect in cell proliferation. Strikingly, the DNA damage response pathway that involves ATM/p53 and is linked to cell cycle arrest and impaired cell survival is strongly induced in these mutant B cells...
September 20, 2018: Cell Death and Differentiation
Astrid Fauster, Manuele Rebsamen, Katharina L Willmann, Adrian César-Razquin, Enrico Girardi, Johannes W Bigenzahn, Fiorella Schischlik, Stefania Scorzoni, Manuela Bruckner, Justyna Konecka, Katrin Hörmann, Leonhard X Heinz, Kaan Boztug, Giulio Superti-Furga
Regulation of cell and tissue homeostasis by programmed cell death is a fundamental process with wide physiological and pathological implications. The advent of scalable somatic cell genetic technologies creates the opportunity to functionally map such essential pathways, thereby identifying potential disease-relevant components. We investigated the genetic basis underlying necroptotic cell death by performing a complementary set of loss-of-function and gain-of-function genetic screens. To this end, we established FADD-deficient haploid human KBM7 cells, which specifically and efficiently undergo necroptosis after a single treatment with either TNFα or the SMAC mimetic compound birinapant...
September 20, 2018: Cell Death and Differentiation
Gaia Gherardi, Leonardo Nogara, Stefano Ciciliot, Gian Paolo Fadini, Bert Blaauw, Paola Braghetta, Paolo Bonaldo, Diego De Stefani, Rosario Rizzuto, Cristina Mammucari
Skeletal muscle mitochondria readily accumulate Ca2+ in response to SR store-releasing stimuli thanks to the activity of the mitochondrial calcium uniporter (MCU), the highly selective channel responsible for mitochondrial Ca2+ uptake. MCU positively regulates myofiber size in physiological conditions and counteracts pathological loss of muscle mass. Here we show that skeletal muscle-specific MCU deletion inhibits myofiber mitochondrial Ca2+ uptake, impairs muscle force and exercise performance, and determines a slow to fast switch in MHC expression...
September 19, 2018: Cell Death and Differentiation
Wulf Tonnus, Florian Gembardt, Markus Latk, Simon Parmentier, Christian Hugo, Stefan R Bornstein, Andreas Linkermann
Necroinflammation is defined as the inflammatory response to necrotic cell death. Different necrotic cell death pathways exhibit different immune reponses, despite a comparable level of intracellular content release (referred to as damage associated molecular patterns or DAMPs). In addition to DAMP release, which is inevitably associated with necrotic cell death, the active production of pro/anti-inflammatory cytokines characterizes certain necrotic pathways. Necroptosis, ferroptosis and pyroptosis, therefore, are immunogenic to a different extent...
September 17, 2018: Cell Death and Differentiation
Roberto Bravo-Sagua, Valentina Parra, Carolina Ortiz-Sandoval, Mario Navarro-Marquez, Andrea E Rodríguez, Natalia Diaz-Valdivia, Carlos Sanhueza, Camila Lopez-Crisosto, Nasser Tahbaz, Beverly A Rothermel, Joseph A Hill, Mariana Cifuentes, Thomas Simmen, Andrew F G Quest, Sergio Lavandero
Close contacts between endoplasmic reticulum and mitochondria enable reciprocal Ca2+ exchange, a key mechanism in the regulation of mitochondrial bioenergetics. During the early phase of endoplasmic reticulum stress, this inter-organellar communication increases as an adaptive mechanism to ensure cell survival. The signalling pathways governing this response, however, have not been characterized. Here we show that caveolin-1 localizes to the endoplasmic reticulum-mitochondria interface, where it impairs the remodelling of endoplasmic reticulum-mitochondria contacts, quenching Ca2+ transfer and rendering mitochondrial bioenergetics unresponsive to endoplasmic reticulum stress...
September 12, 2018: Cell Death and Differentiation
Hyun Ho Park
The assembly of death-inducing signaling complex (DISC) for activation of initiator caspase is a key step for the receptor-mediated apoptosis signaling. Many death effector domain (DED)-containing proteins are involved in DISC assembly and controlling. One of the main DISC component, caspase-8, contains DED and DED-mediated dimerization and oligomerization in the DISC is critical for the activation of this initiator caspase. There have been intensive studies to understand DED-mediated dimerization and oligomerization for the DISC assembly but no clear answer has been provided and there are many controversial arguments...
September 11, 2018: Cell Death and Differentiation
Hyang-Hee Seo, Seahyoung Lee, Chang Youn Lee, Jiyun Lee, Sunhye Shin, Byeong-Wook Song, Il-Kwon Kim, Jung-Won Choi, Soyeon Lim, Sang Woo Kim, Ki-Chul Hwang
Cardiac fibrosis is a common precursor to ventricular dysfunction and eventual heart failure, and cardiac fibrosis begins with cardiac fibroblast activation. Here we have demonstrated that the TGF-β signaling pathway and Wnt signaling pathway formed a transactivation circuit during cardiac fibroblast activation and that miR-384-5p is a key regulator of the transactivation circuit. The results of in vitro study indicated that TGF-β activated an auto-positive feedback loop by increasing Wnt production in cardiac fibroblasts, and Wnt neutralizing antibodies disrupted the feedback loop...
September 11, 2018: Cell Death and Differentiation
Tom Vanden Berghe, Eric Hoste
Current clinical diagnosis is typically based on a combination of approaches including clinical examination of the patient, clinical experience, physiologic and/or genetic parameters, high-tech diagnostic medical imaging, and an extended list of laboratory values mostly determined in biofluids such as blood and urine. One could consider this as precision medicine v1.0. However, recent advances in technology and better understanding of molecular mechanisms underlying disease will allow us to better characterize patients in the future...
September 10, 2018: Cell Death and Differentiation
Stephanie Bleicken, Tufa E Assafa, Carolin Stegmueller, Alice Wittig, Ana J Garcia-Saez, Enrica Bordignon
Bax is a Bcl-2 protein critical for apoptosis induction. In healthy cells, Bax is mostly a monomeric, cytosolic protein, while upon apoptosis initiation it inserts into the outer mitochondrial membrane, oligomerizes, and forms pores that release proapoptotic factors like Cytochrome c into the cytosol. The structures of active Bax and its homolog Bak are only partially understood and the topology of the proteins with respect to the membrane bilayer is controversially described in the literature. Here, we systematically review and examine the protein-membrane, protein-water, and protein-protein contacts of the nine helices of active Bax and Bak, and add a new set of topology data obtained by fluorescence and EPR methods...
September 5, 2018: Cell Death and Differentiation
Georgia Greaves, Mateus Milani, Michael Butterworth, Rachel J Carter, Dominic P Byrne, Patrick A Eyers, Xu Luo, Gerald M Cohen, Shankar Varadarajan
The impressive selectivity and efficacy of BH3 mimetics for treating cancer has largely been limited to BCL-2 dependent hematological malignancies. Most solid tumors depend on other anti-apoptotic proteins, including MCL-1, for survival. The recent description of S63845 as the first specific and potent MCL-1 inhibitor represents an important therapeutic advance, since MCL-1 is not targeted by the currently available BH3 mimetics, Navitoclax or Venetoclax, and is commonly associated with chemoresistance. In this study, we confirm a high binding affinity and selectivity of S63845 to induce apoptosis in MCL-1-dependent cancer cell lines...
September 5, 2018: Cell Death and Differentiation
Holly Anderton, Esther Bandala-Sanchez, Daniel S Simpson, James A Rickard, Ashley P Ng, Ladina Di Rago, Cathrine Hall, James E Vince, John Silke, Gianmaria Liccardi, Rebecca Feltham
RIPK1 is an essential downstream component of many pattern recognition and death receptors. RIPK1 can promote the activation of caspase-8 induced apoptosis and RIPK3-MLKL-mediated necroptosis, however, during development RIPK1 limits both forms of cell death. Accordingly, Ripk1-/- mice present with systemic cell death and consequent multi-organ inflammation, which is driven through the activation of both FADD-caspase-8 and RIPK3-MLKL signaling pathways causing perinatal lethality. TRADD is a death domain (DD) containing molecule that mediates signaling downstream of TNFR1 and the TLRs...
September 5, 2018: Cell Death and Differentiation
C-C Chang, M-H Yang, B-R Lin, S-T Chen, S-H Pan, M Hsiao, T-C Lai, S-K Lin, Y-M Jeng, C-Y Chu, R-H Chen, P-C Yang, Y Eugene Chin, M-L Kuo
Following publication of their article "CCN2 inhibits lung cancer metastasis through promoting DAPK-dependent anoikis and inducing EGFR degradation", the authors reported an error in Fig.6b. α-Tubulin image of rCCN2 treatment  (upper panel in CL1-5) only showed eight lanes, when there should be nine.
September 5, 2018: Cell Death and Differentiation
Daniela Kramer, Nadine Stark, Ramona Schulz-Heddergott, Norman Erytch, Shelley Edmunds, Laura Roßmann, Holger Bastians, Nicole Concin, Ute M Moll, Matthias Dobbelstein
Since publication of this article, the authors reported that the online version is missing the links to most of the Supplementary data, specifically, Supplementary Figures S1-S9; Supplementary Table S1; all legends to Supplementary Material.
September 3, 2018: Cell Death and Differentiation
Cecilia Battistelli, Giovanna Sabarese, Laura Santangelo, Claudia Montaldo, Frank J Gonzalez, Marco Tripodi, Carla Cicchini
The expression of the long noncoding RNA HOTAIR (HOX Transcript Antisense Intergenic RNA) is largely deregulated in epithelial cancers and positively correlates with poor prognosis and progression of hepatocellular carcinoma and gastrointestinal cancers. Furthermore, functional studies revealed a pivotal role for HOTAIR in the epithelial-to-mesenchymal transition, as this RNA is causal for the repressive activity of the master factor SNAIL on epithelial genes. Despite the proven oncogenic role of HOTAIR, its transcriptional regulation is still poorly understood...
August 28, 2018: Cell Death and Differentiation
He Liu, Zhaoyue He, Simon Leonhard April, Marcel Philipp Trefny, Jean-Sébastien Rougier, Souzan Salemi, Radu Olariu, Hans Rudolf Widmer, Hans-Uwe Simon
Stem cells are generally believed to contain a small number of mitochondria, thus accounting for their glycolytic phenotype. We demonstrate here, however, that despite an indispensable glucose dependency, human dermal stem cells (hDSCs) contain very numerous mitochondria. Interestingly, these stem cells segregate into two distinct subpopulations. One exhibits high, the other low-mitochondrial membrane potentials (Δ ψm ). We have made the same observations with mouse neural stem cells (mNSCs) which serve here as a complementary model to hDSCs...
August 28, 2018: Cell Death and Differentiation
Ranja Salvamoser, Kerstin Brinkmann, Lorraine A O'Reilly, Lachlan Whitehead, Andreas Strasser, Marco J Herold
Caspases exert critical functions in diverse cell death pathways, including apoptosis and pyroptosis, but some caspases also have roles in the processing of cytokines into their functional forms during inflammation. The roles of many caspases have been unravelled by the generation of knockout mice, but still very little is known about the overlapping functions of caspases as only a few studies report on double or triple caspase knockout mice. For example, the functions of caspase-12 in cell death and inflammation, on its own or overlapping with the functions of caspase-1 and caspase-11, are only poorly understood...
August 28, 2018: Cell Death and Differentiation
Yasir Mohamud, Junyan Qu, Yuan Chao Xue, Huitao Liu, Haoyu Deng, Honglin Luo
Cell autonomous immunity is the ability of individual cells to initiate a first line of host defense against invading microbes, such as viruses. Autophagy receptors, a diverse family of multivalent proteins, play a key role in this host response by detecting, sequestering, and eliminating virus in a process termed virophagy. To counteract this, positive-stranded RNA viruses, such as enteroviruses, have evolved strategies to circumvent the host autophagic machinery in an effort to promote viral propagation; however, the underlying mechanisms remain largely unclear...
August 28, 2018: Cell Death and Differentiation
Lin Huang, Tie-Gang Meng, Xue-Shan Ma, Zhen-Bo Wang, Shu-Tao Qi, Qi Chen, Qing-Hua Zhang, Qiu-Xia Liang, Zhong-Wei Wang, Meng-Wen Hu, Lei Guo, Ying-Chun Ouyang, Yi Hou, Yong Zhao, Qing-Yuan Sun
Zygotic chromatin undergoes extensive reprogramming immediately after fertilization. It is generally accepted that maternal factors control this process. However, little is known about the underlying mechanisms. Here we report that maternal RAD9A, a key protein in DNA damage response pathway, is involved in post-zygotic embryo development, via a mouse model with conditional depletion of Rad9a alleles in oocytes of primordial follicles. Post-zygotic losses originate from delayed zygotic chromatin decondensation after depletion of maternal RAD9A...
August 28, 2018: Cell Death and Differentiation
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