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https://www.readbyqxmd.com/read/28203268/steady-state-preserving-simulation-of-genetic-regulatory-systems
#1
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
#2
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
#3
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/28181574/indispensable-role-of-mdm2-p53-interaction-during-the-embryonic-and-postnatal-inner-ear-development
#4
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
#5
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/28155209/do-mesenchymal-stem-cells-derived-from-atypical-lipomatous-tumors-have-greater-differentiation-potency-than-cells-from-normal-adipose-tissues
#6
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
#7
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
#8
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
#9
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
#10
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
https://www.readbyqxmd.com/read/28130307/p53-and-mdm2-their-yin-yang-intimacy
#11
EDITORIAL
Hua Lu
No abstract text is available yet for this article.
January 27, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/28129655/a-novel-long-noncoding-rna-pilrls-promote-proliferation-through-tcl1a-by-activing-mdm2-in-retroperitoneal-liposarcoma
#12
Yebo Shao, Yong Zhang, Yingyong Hou, Hanxing Tong, Rongyuan Zhuang, Zhengbiao Ji, Binliang Wang, Yuhong Zhou, Weiqi Lu
It is becoming evident that lncRNAs may be an important class of pervasive genes involved in carcinogenesis and metastasis. However, the biological and molecular mechanisms of lncRNAs in retroperitoneal liposarcoma have never been reported. In our study, we found a novel lncRNA PILRLS (Proliferation Interacting LncRNA in Retroperitoneal Liposarcoma), which as an oncogene significantly overexpressed in retroperitoneal liposarcoma. Functions of PILRLS on tumor progression both in vitro and in vivo have verified in this study which PILRLS knockdown significantly inhibited cell proliferation and colony formation...
January 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28126523/positive-effect-of-mdm2-on-p53-expression-explains-excitability-of-p53-in-response-to-dna-damage
#13
Ján Eliaš
Most of the existing biological models consider Mdm2 as a dominant negative regulator of p53 appearing in several negative feedback loops. However, in addition to targeting p53 for degradation, Mdm2 in tight cooperation with MdmX can control expression levels of p53 through enhanced induction of p53 synthesis in response to DNA damage. Whilst ATM-dependent phosphorylation of p53 is not observed to be important in this enhanced synthesis, ATM-dependent phosphorylation of Mdm2 (as well as MdmX) is essential for its dual role, which is accompanied with widely oscillating p53...
January 24, 2017: Journal of Theoretical Biology
https://www.readbyqxmd.com/read/28124991/mir-660-p53-mir-486-network-a-new-key-regulatory-pathway-in-lung-tumorigenesis
#14
Cristina Borzi, Linda Calzolari, Giovanni Centonze, Massimo Milione, Gabriella Sozzi, Orazio Fortunato
Lung cancer is the most frequent cause of cancer-related death worldwide, with limited therapeutic options and rapid development of drug resistance. MicroRNAs, a class of small non-coding RNAs that control different physiological processes, have been associated with cancer development, as either oncomiRNAs or tumor-suppressor miRNAs. In the present study we investigated the interaction between mir-486-5p and mir-660-5p, two independent tumor-suppressor miRNAs, to assess their possible role and synergistic effect in lung cancer treatment...
January 23, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28122227/protection-against-high-fat-diet-induced-obesity-in-mdm2-c305f-mice-due-to-reduced-p53-activity-and-enhanced-energy-expenditure
#15
Shijie Liu, Tae-Hyung Kim, Derek A Franklin, Yanping Zhang
The RPL11-MDM2 interaction constitutes a p53 signaling pathway activated by deregulated ribosomal biosynthesis in response to stress. Mice bearing an MDM2(C305F) mutation that disrupts RPL11-MDM2 binding were analyzed on a high-fat diet (HFD). The Mdm2(C305F/C305F) mice, although phenotypically indistinguishable from wild-type (WT) mice when fed normal chow, demonstrated decreased fat accumulation along with improved insulin sensitivity and glucose tolerance after prolonged HFD feeding. We found that HFD increases expression of c-MYC and RPL11 in both WT and Mdm2(C305F/C305F) mice; however, p53 was induced in WT but not in Mdm2(C305F/C305F) mice...
January 24, 2017: Cell Reports
https://www.readbyqxmd.com/read/28119089/the-p53-protein-induces-stable-mirnas-that-have-the-potential-to-modify-subsequent-p53-responses
#16
Miguel A Cabrita, Reetesh Bose, Erin J Vanzyl, Alyssa Pastic, Kristen A Marcellus, Elysia Pan, Jeff D Hamill, Bruce C McKay
The p53 tumour suppressor is a transcription factor that can increase the expression of mRNAs and microRNAs (miRNAs). HT29-tsp53 cells expressing a temperature sensitive variant of p53 have provided a useful model to rapidly and reversibly control p53 activity. In this model, the majority of p53-responsive mRNAs were upregulated rapidly but they were short-lived leading to rapid decay of the p53 response at the restrictive temperature. Here we used oligonucleotide microarrays and reverse transcriptase PCR to show that p53-induced miRNAs exhibited a distinct temporal pattern of expression...
January 21, 2017: Gene
https://www.readbyqxmd.com/read/28118981/monitoring-p53-by-mdm2-and-mdmx-is-required-for-endocrine-pancreas-development-and-function-in-a-spatio-temporal-manner
#17
Yiwei Zhang, Shelya X Zeng, Qian Hao, Hua Lu
Although p53 is not essential for normal embryonic development, it plays a pivotal role in many biological and pathological processes, including cell fate determination-dependent and independent events and diseases. The expression and activity of p53 largely depend on its two biological inhibitors, MDM2 and MDMX, which have been shown to form a complex in order to tightly control p53 to an undetectable level during early stages of embryonic development. However, more delicate studies using conditional gene-modification mouse models show that MDM2 and MDMX may function separately or synergistically on p53 regulation during later stages of embryonic development and adulthood in a cell and tissue-specific manner...
January 22, 2017: Developmental Biology
https://www.readbyqxmd.com/read/28113565/hypoxia-stress-response-pathways-modeling-and-targeted-therapy
#18
Sriram Vakulabaranam, Rajani Varghese, Jijayanagaram Venkatraj, Aniruddha Datta
Hypoxia is a consequence of the decrease in the oxygen reaching the tissues of the body. It is a prominent feature of most solid tumors and is known to promote malignant progression, metastatic capacity, resistance to chemotherapy and leads to poor patient prognosis. When a cell is under hypoxic stress, a cascade of cell signals are initiated through a family of transcription factors named as Hypoxia Inducible Factors (HIFs). During hypoxia, HIF stabilizes and enters the nucleus and binds to the DNA via the Hypoxia Response Element (HRE) and leads to the translation of downstream genes...
April 27, 2016: IEEE Journal of Biomedical and Health Informatics
https://www.readbyqxmd.com/read/28108672/stromal-interaction-molecule-1-stim1-regulates-growth-cell-cycle-and-apoptosis-of-human-tongue-squamous-carcinoma-cells
#19
Xiaobo Cui, Laixiao Song, Yunfei Bai, Yaping Wang, Boqian Wang, Wei Wang
Oral tongue squamous carcinoma (OTSCC) is the most common type of cancer of oral carcinomas. However, the molecular mechanism by which OTSCC development is not fully identified. Stromal interaction molecule 1 (STIM1) is a transmembrane protein, mainly located in the endoplasmic reticulum (ER). STIM1 is involved in several types of cancers. Here we report that STIM1 contributes to the development of human OTSCC. We knocked down STIM1 in OTSCC cell line Tca-8113 with lentivirus-mediated shRNA and found that SITM1 knockdown repressed the proliferation of Tca-8113 cells...
January 20, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/28108249/synthesis-and-biological-evaluation-of-thiazole-derivatives-as-novel-usp7-inhibitors
#20
Chao Chen, Jiemei Song, Jinzheng Wang, Chang Xu, Caiping Chen, Wei Gu, Hongbin Sun, Xiaoan Wen
Herpesvirus-associated Ubiquitin-Specific Protease (HAUSP, also called USP7) interacts with and stabilizes Mdm2, and represents one of the first examples that deubiquitinases oncogenic proteins. USP7 has been regarded as a potential drug target for cancer therapy. Inhibitors of USP7 have been recently shown to suppress tumor cell growth in vitro and in vivo. Based on leading USP7 inhibitors P5091 and P22077, we designed and synthesized a series of thiazole derivatives. The results of in vitro assays showed that the thiazole compounds exhibited low micromolar inhibition activity against both USP7 enzyme and cancer cell lines...
January 10, 2017: Bioorganic & Medicinal Chemistry Letters
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