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https://www.readbyqxmd.com/read/28226265/alterations-of-ubiquitin-related-proteins-in-the-pathology-and-development-of-schizophrenia-evidence-from-human-and-animal-studies
#1
Jessica L Andrews, Frederic J Goodfellow, Natalie Matosin, Mollie K Snelling, Kelly A Newell, Xu-Feng Huang, Francesca Fernandez-Enright
Gene expression analyses in post-mortem schizophrenia brains suggest that a number of ubiquitin proteasome system (UPS) genes are associated with schizophrenia; however the status of UPS proteins in the schizophrenia brain is largely unknown. Ubiquitin related proteins are inherently involved in memory, neuronal survival and morphology, which are processes implicated in neurodevelopmental disorders such as schizophrenia. We examined levels of five UPS proteins (Protein Inhibitor of Activated STAT2 [PIAS2], F-Box and Leucine rich repeat protein 21 [FBXL21], Mouse Double Minute 2 homolog [MDM2], Ubiquitin Carboxyl-Terminal Hydrolase-L1 [UCHL1] and Ubiquitin Conjugating Enzyme E2D1 [UBE2D1]) involved in these neuronal processes, within the dorsolateral prefrontal cortex of post-mortem schizophrenia subjects and matched controls (n = 30/group), in addition to across neurodevelopmental time-points (juvenile, adolescent and adult stages of life), utilizing a well-established neurodevelopmental phencyclidine (PCP) animal model of schizophrenia...
January 18, 2017: Journal of Psychiatric Research
https://www.readbyqxmd.com/read/28223335/cooperation-of-musashi-2-numb-mdm2-and-p53-in-drug-resistance-and-malignant-biology-of-pancreatic-cancer
#2
Weiwei Sheng, Ming Dong, Chuanping Chen, Zixin Wang, Yunwei Li, Kewei Wang, Yuji Li, Jianping Zhou
Our earlier work showed that Musashi (MSI)-2 promoted the development of pancreatic cancer (PC) by down-regulating Numb, which prevented murine double-minute (MDM)-2-mediated p53 ubiquitin degradation. Thus, we investigate the relationship among MSI2, Numb, MDM2, and p53 in PC in vitro and invivo, an association that has not been reported to our knowledge. MSI2 had no relationship with mutant p53 (mtp53) and wild-type p53 (wtp53) in normal PC cells. However, in response to gemcitabine or cisplatin treatment, MSI2 silencing simultaneously down-regulated MDM2 and up-regulated Numb and wtp53 protein levels...
February 21, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28219709/cordycepin-diminishes-thymic-stromal-lymphopoietin-induced-interleukin-13-production
#3
Myoung-Schook Yoou, Kyoung Wan Yoon, Youngjin Choi, Hyung-Min Kim, Hyun-Ja Jeong
Atopic dermatitis (AD) is known to aggravate by thymic stromal lymphopoietin (TSLP) and TSLP is also known to up-regulate mast cell proliferation via production of interleukin (IL)-13. Thus, we investigated whether cordycepin could regulate mast cell proliferation induced by TSLP in human mast cell line, HMC-1 cell. Cordycepin significantly diminished the production and mRNA of IL-13 through the down-regulation of phosphorylated-signal transducer and activation of transcription 6 in the TSLP-stimulated HMC-1 cells...
February 17, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28216878/nardostachys-jatamansi-root-extract-modulates-the-growth-of-imr-32-and-sk-n-mc-neuroblastoma-cell-lines-through-mycn-mediated-regulation-of-mdm2-and-p53
#4
Snehal Suryavanshi, Prerna Raina, Rashmi Deshpande, Ruchika Kaul-Ghanekar
AIM: The present study evaluated the effect of ethanolic extract of Nardostachys jatamansi roots (NJet) on MYCN mediated regulation of expression of MDM2 and p53 proteins in neuroblastoma cell lines, IMR-32 and SK-N-MC. MATERIALS AND METHODS: The effect of NJet on cell viability was determined by MTT; and on growth kinetics was evaluated by trypan blue dye exclusion method and soft agar assay. The expression of p53, MDM2 and MYCN proteins in response to NJet treatment was evaluated by immunoblotting...
January 2017: Pharmacognosy Magazine
https://www.readbyqxmd.com/read/28216291/ovarian-tumor-domain-containing-protein-1-deubiquitinates-and-stabilizes-p53
#5
Shudong Piao, Han Zhong Pei, Bin Huang, Suk-Hwan Baek
Ubiquitination and deubiquitination pathways play important roles in the regulation of p53 stability and activity. p53 is ubiquitinated and destabilized by E3 ubiquitin ligases and is deubiquitinated and stabilized by deubiquitinases (DUBs). We screened ovarian tumor (OTU) subfamily proteins to identify novel DUBs that stabilized p53. OTU domain-containing protein 1 (OTUD1) is a DUB belonging to the OTU family; however, its substrates and its role in cells are unknown. Here, we used an overexpression and knockdown system to show that OTUD1 is a novel regulator of p53 stability...
February 13, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28216017/usp7-inhibitor-p5091-inhibits-wnt-signaling-and-colorectal-tumor-growth
#6
An Tao, Gong Yaxiao, Li Xue, Kong Lingmei, Ma Pengcheng, Gong Liang, Zhu Huifang, Yu Chunlei, Liu Jianmei, Zhou Hongyu, Mao Bingyu, Li Yan
Aberrant activation of Wnt/β-catenin signaling is closely associated with the development of various human cancers, especially colorectal cancers (CRC). The ubiquitin proteasome system (UPS) is essential in the regulation of Wnt signaling and inhibitors targeting the UPS could have great potential in CRC therapy. Ubiquitin-specific protease 7 (USP7), a deubiquitinating enzyme, plays a significant role in neoplastic diseases due to its well-known function of regulating the MDM2-p53 complex. Inspired by our recent study identifying the positive role of USP7 in the Wnt signaling, we report here that USP7 is overexpressed in colorectal carcinoma cell lines and tissues, which is closely related with the poor prognosis...
February 16, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28212808/next-generation-repeat-free-fish-probes-for-dna-amplification-in-glioblastoma-in-vivo-improving-patient-selection-to-mdm2-targeted-inhibitors
#7
Matteo Brunelli, Albino Eccher, Luca Cima, Tobia Trippini, Serena Pedron, Marco Chilosi, Mattia Barbareschi, Aldo Scarpa, Giampietro Pinna, Giulio Cabrini, Sara Pilotto, Luisa Carbognin, Emilio Bria, Giampaolo Tortora, Adele Fioravanzo, Nicola Schiavo, Mario Meglio, Teodoro Sava, Laura Belli, Guido Martignoni, Claudio Ghimenton
A next-generation FISH probe mapping to the MDM2 locus-specific region has recently been designed. The level of MDM2 gene amplification (high versus low) may allow selection of patients for cancer treatment with MDM2 inhibitors and may predict their responsiveness. We investigated the spectrum of MDM2 gene alterations using the new probes in vivo after visualizing single neoplastic cells in situ from a series of glioblastomas. Signals from next-generation repeat-free FISH interphase probes were identified in tissue microarrays that included 3 spots for each of the 48 cases...
January 2017: Cancer Genetics
https://www.readbyqxmd.com/read/28212558/ataxin-1-regulates-epithelial-mesenchymal-transition-of-cervical-cancer-cells
#8
A-Ram Kang, Hyoung-Tae An, Jesang Ko, Seongman Kang
The mutant form of the protein ataxin-1 (ATXN1) causes the neurodegenerative disease spinocerebellar ataxia type-1. Recently, ATXN1 was reported to enhance E-cadherin expression in the breast cancer cell line MCF-7, suggesting a potential association between ATXN1 and cancer development. In the present study, we discovered a novel mechanism through which ATXN1 regulates the epithelial-mesenchymal transition (EMT) of cancer cells. Hypoxia-induced upregulation of the Notch intracellular domain expression decreased ATXN1 expression via MDM2-associated ubiquitination and degradation...
February 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28203268/steady-state-preserving-simulation-of-genetic-regulatory-systems
#9
Ruqiang Zhang, Julius Osato Ehigie, Xilin Hou, Xiong You, Chunlu Yuan
A novel family of exponential Runge-Kutta (expRK) methods are designed incorporating the stable steady-state structure of genetic regulatory systems. A natural and convenient approach to constructing new expRK methods on the base of traditional RK methods is provided. In the numerical integration of the one-gene, two-gene, and p53-mdm2 regulatory systems, the new expRK methods are shown to be more accurate than their prototype RK methods. Moreover, for nonstiff genetic regulatory systems, the expRK methods are more efficient than some traditional exponential RK integrators in the scientific literature...
2017: Computational and Mathematical Methods in Medicine
https://www.readbyqxmd.com/read/28196907/acetylation-dependent-regulation-of-mdm2-e3-ligase-activity-dictates-its-oncogenic-function
#10
Naoe T Nihira, Kohei Ogura, Kouhei Shimizu, Brian J North, Jinfang Zhang, Daming Gao, Hiroyuki Inuzuka, Wenyi Wei
Abnormal activation of the oncogenic E3 ubiquitin ligase murine double minute 2 (MDM2) is frequently observed in human cancers. By ubiquitinating the tumor suppressor p53 protein, which leads to its proteasome-mediated destruction, MDM2 limits the tumor-suppressing activity of p53. On the other hand, by ubiquitinating itself, MDM2 targets itself for destruction and promotes the p53 tumor suppressor pathway, a process that can be antagonized by the deubiquitinase herpesvirus-associated ubiquitin-specific protease (HAUSP)...
February 14, 2017: Science Signaling
https://www.readbyqxmd.com/read/28195382/contribution-of-atm-and-atr-kinase-pathways-to-p53-mediated-response-in-etoposide-and-methyl-methanesulfonate-induced-dna-damage
#11
Bin Sun, Susan M Ross, Sean Rowley, Yeyejide Adeleye, Rebecca A Clewell
p53 is a key integrator of cellular response to DNA damage, supporting post-translational repair and driving transcription-mediated responses including cell cycle arrest, apoptosis, and repair. DNA damage sensing kinases recognize different types of DNA damage and initiate specific responses through various post-translational modifications of p53. This study evaluated chemical specificity of the p53 pathway response by manipulating p53 or its upstream kinases and assessing the effect on DNA damage and cellular responses to prototype chemicals: etoposide (ETP, topoisomerase II inhibitor) and methyl methane sulfonate (MMS, alkylating agent)...
February 14, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28193096/dedifferentiated-liposarcoma-of-the-retroperitoneum-with-heterologous-osteosarcomatous-differentiation-and-a-striking-aneurysmal-bone-cyst-like-morphology
#12
Carole Van Haverbeke, Jo Van Dorpe, Evelyne Lecoutere, Uta Flucke, Liesbeth Ferdinande, David Creytens
A 69-year-old woman with a 10-year medical history of recurrent retroperitoneal dedifferentiated liposarcoma presented with a 3-cm large hemorrhagic and multicystic left-sided retroperitoneal mass. Histopathological examination of the resected specimen showed a heterogeneous, high-grade mesenchymal nonlipogenic tumor with areas of osteoblastic/osteosarcomatous differentiation and aneurysmal bone cyst-like features. Based on the clinical presentation, the morphology, and the supportive immunohistochemical and molecular findings (MDM2 overexpression and amplification of the MDM2 gene, respectively), a diagnosis of a dedifferentiated liposarcoma with heterologous osteosarcomatous differentiation and an aneurysmal bone cyst-like morphology was made...
February 1, 2017: International Journal of Surgical Pathology
https://www.readbyqxmd.com/read/28181574/indispensable-role-of-mdm2-p53-interaction-during-the-embryonic-and-postnatal-inner-ear-development
#13
M Laos, M Sulg, A Herranen, T Anttonen, U Pirvola
p53 is a key component of a signaling network that protects cells against various stresses. As excess p53 is detrimental to cells, its levels are tightly controlled by several mechanisms. The E3 ubiquitin ligase Mdm2 is a major negative regulator of p53. The significance of balanced p53 levels in normal tissues, at different stages of lifetime, is poorly understood. We have studied in vivo how the disruption of Mdm2/p53 interaction affects the early-embryonic otic progenitor cells and their descendants, the auditory supporting cells and hair cells...
February 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28166445/mdm2-splice-isoforms-regulate-the-p53-mdm2-mdm4-regulatory-circuit-via-ring-domain-mediated-ubiquitination-of-p53-and-mdm4
#14
Chuandong Fan, Xinjiang Wang
p53 is regulated by heterodimer E3 ligase Mdm2-Mdm4 via RING domain interaction. Mdm2 transcripts undergo alternative splicing, and Mdm2 splice isoforms are increased in cancer and induced by DNA damage. Although two major Mdm2 splice isoforms that do not bind to p53 were reported to impact the p53 pathway, the underlying biochemical mechanisms were not understood. Here, we show that these Mdm2 splice isoforms ubiquitinate Mdm2 and Mdm4 in vitro and regulate the activity of Mdm2-Mdm4 E3 complex in cells. The Mdm2 isoforms are capable of promoting p53 ubiquitination in the absence of Mdm2 or Mdm4...
February 6, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28158999/mdm2-promoter-polymorphism-del1518-rs3730485-and-its-impact-on-endometrial-and-ovarian-cancer-risk
#15
Liv B Gansmo, Merete Bjørnslett, Mari Kyllesø Halle, Helga B Salvesen, Pål Romundstad, Kristian Hveem, Lars Vatten, Anne Dørum, Per E Lønning, Stian Knappskog
BACKGROUND: The del1518 (rs3730485) polymorphism is an in/del variant in the MDM2 promoter P1. The variant is in complete linkage disequilibrium with MDM2 SNP309 (rs2279744) and has previously been found associated with an increased risk of colon cancer. In this study we assessed the impact of MDM2 del1518 on risk of ovarian and endometrial cancer. METHODS: Here, we genotyped del1518 in two large hospital-based series of patients diagnosed with ovarian (n = 1,385) or endometrial (n = 1,404) cancer and performed risk estimations as compared to the genotype distribution among 1,872 healthy female controls...
February 3, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28155209/do-mesenchymal-stem-cells-derived-from-atypical-lipomatous-tumors-have-greater-differentiation-potency-than-cells-from-normal-adipose-tissues
#16
Hiroyuki Inatani, Norio Yamamoto, Katsuhiro Hayashi, Hiroaki Kimura, Akihiko Takeuchi, Shinji Miwa, Takashi Higuchi, Kensaku Abe, Yuta Taniguchi, Satoshi Yamada, Kiyofumi Asai, Takanobu Otsuka, Hiroyuki Tsuchiya
BACKGROUND: The p53 protein in mesenchymal stem cells (MSCs) regulates differentiation to osteogenic or adipogenic lineage. Because p53 function is depressed in most malignancies, if MSCs in malignancy also have p53 hypofunction, differentiation therapy to osteogenic or adipogenic lineage may be an effective treatment. We therefore wished to begin to explore this idea by evaluating atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) cells, because murine double minute 2 (MDM2) gene amplification, which leads to p53 hypofunction, is found in almost all ALT/WDLs...
February 2, 2017: Clinical Orthopaedics and related Research
https://www.readbyqxmd.com/read/28153791/hdac6-deacetylates-p53-at-lysines-381-382-and-differentially-coordinates-p53-induced-apoptosis
#17
Hyun-Wook Ryu, Dong-Hee Shin, Dong Hoon Lee, Junjeong Choi, Gyoonhee Han, Kang Young Lee, So Hee Kwon
HDAC6-selective inhibitors represent promising new cancer therapeutic agents, but their precise mechanisms of action are not well understood. In particular, p53's role in HDAC6 inhibitor-induced effects has not been fully elucidated. In this study, we show that an HDAC6-selective inhibitor, A452, increased wild-type p53 levels by destabilizing MDM2, but decreased mutant p53 by inducing MDM2 and inhibiting Hsp90-mutant p53 complex formation. Interestingly, HDAC6 levels inversely correlated with p53 acetylation at lysines 381/382 associated with p53 functional activation...
January 30, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28150872/polymorphism-in-anril-is-associated-with-relapse-in-patients-with-multiple-myeloma-after-autologous-stem-cell-transplant
#18
Ming J Poi, Junan Li, Douglas W Sborov, Zachary VanGundy, Yu Kyoung Cho, Misty Lamprecht, Flavia Pichiorri, Mitch A Phelps, Craig C Hofmeister
Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells and overproduction of monoclonal immunoglobins. Treatment with melphalan is currently standard of care for younger and fit patients when followed by hematopoietic stem cell transplantation (HSCT), and in transplant ineligible patients when used in combination regimens. It has been previously shown that changes in the p53 pathway are associated with melphalan efficacy, but the regulatory role of the p14ARF-MDM2-p53 axis has yet to be fully explored...
February 2, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/28147328/autoantibody-to-mdm2-a-potential-serological-marker-of-primary-sjogren-s-syndrome
#19
Yuan Liu, Xining Liao, Ying Wang, Shiju Chen, Yuechi Sun, Qingyan Lin, Guixiu Shi
INTRODUCTION: Primary Sjogren's Syndrome (pSS) is one of the autoimmune diseases characterized by polyclonal autoantibody production. The human homologue of the mouse double minute 2 (MDM2) is an important negative regulator of p53. Our previous study indicated that autoantibody to MDM2 can be detected in systemic lupus erythematosus patients. The purpose of this study is to study anti-MDM2 autoantibody in pSS patients. METHODS: Anti-MDM2 autoantibody in sera from 100 pSS patients and 74 normal controls was investigated by ELISA...
January 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28130345/the-piddosome-activates-p53-in-response-to-supernumerary-centrosomes
#20
Luca L Fava, Fabian Schuler, Valentina Sladky, Manuel D Haschka, Claudia Soratroi, Lisa Eiterer, Egon Demetz, Guenter Weiss, Stephan Geley, Erich A Nigg, Andreas Villunger
Centrosomes, the main microtubule-organizing centers in animal cells, are replicated exactly once during the cell division cycle to form the poles of the mitotic spindle. Supernumerary centrosomes can lead to aberrant cell division and have been causally linked to chromosomal instability and cancer. Here, we report that an increase in the number of mature centrosomes, generated by disrupting cytokinesis or forcing centrosome overduplication, triggers the activation of the PIDDosome multiprotein complex, leading to Caspase-2-mediated MDM2 cleavage, p53 stabilization, and p21-dependent cell cycle arrest...
January 1, 2017: Genes & Development
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