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Common genetic variants in the TP53 pathway and their impact on cancer

Journal of molecular Cell Biology 2019年第7期11卷 578-585页

作者： Thibaut Barnoud Joshua L.D.Parris Maureen E.Murphy Program in Molecular and Cellular Oncogenesis The Wistar InstitutePhiladelphiaPA 19104USA Cell and Molecular Biology Program Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaPA 19104USA

The TP53 gene is well known to be the most frequently mutated gene in human *** addition to mutations,there are > 20 different coding region single-nucleotide polymorphisms (SNPs) in the TP53 gene,as well as SNPs in MDM2,the negative regulator of *** of these SNPs are known to alter p53 pathway *** makes p53 rather unique among cancer-critical genes,*** coding regions of other cancer-critical genes like Ha-Ras,RB,and PI3KCA do not have non-synonymous coding region SNPs that alter their function in *** next frontier in p53 biology will consist of probing which of these coding region SNPs are moderately or strongly pathogenic and whether they influence cancer risk and the efficacy of cancer *** challenge after that will consist of determining whether we can tailor chemotherapy to correct the defects for each ofthese *** we review the SNPs in TP53 and MDM2 that show the most significant impact on cancer and other *** also propose avenues for how this information can be used to better inform personalized medicine approaches to cancer and other diseases.

关键词： p53 Pro47Ser Pro72Arg PAS MDM2 SNP309

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Cardinal regenerative features of the mrl mouse-an update

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Gene Therapy and Regulation 2011年第1期6卷 51-70页

作者： Arthur, L. Matthew Sachadyn, Pawel Gourevitch, Dmitri Heber-Katz, Ellen Molecular and Cellular Oncogenesis Program Wistar Institute Philadelphia PA United States Microbiology Department Gdansk University of Technology Gdansk Poland

In this review, we discuss recent studies relating to major features of adult MRL mouse biology that contribute to the regenerative responses seen. These include an increased inflammatory cell profile, a unique glycolytic metabolic state typically found during embryogenesis, and a cell cycle phenotype of DNA damage and G2/M arrest. These traits have been found in other mammalian and non-mammalian regenerative systems. How these physiological systems interact with each other and bring about regeneration is explored. © 2011 World Scientific Publishing Company.

关键词： MRL mouse p21-null mouse

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Nongenetic Mechanisms of Drug Resistance in Melanoma

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Cancer Biology 1000年第1期4卷 315-330页

作者： Vito W. Rebecca Meenhard Herlyn Molecular and Cellular Oncogenesis Program and Melanoma Research Center The Wistar Institute Philadelphia Pennsylvania 19104 USA email: herlynm@***

Resistance to targeted and immune-based therapies limits cures in patients with metastatic melanoma. A growing number of reports have identified nongenetic primary resistance mechanisms including intrinsic microenvironment- and lineage plasticity–mediated processes serving critical functions in the persistence of disease throughout therapy. There is a temporally shifting spectrum of cellular identities fluidly occupied by therapy-persisting melanoma cells responsible for driving therapeutic resistance and metastasis. The key epigenetic, metabolic, and phenotypic reprogramming events requisite for the manifestation and maintenance of so-called persister melanoma populations remain poorly understood and underscore the need to comprehensively investigate actionable vulnerabilities. Here we attempt to integrate the field's observations on nongenetic mechanisms of drug resistance in melanoma. We postulate that the future design of therapeutic strategies specifically addressing therapy-persisting subpopulations of melanoma will improve the curative potential of therapy for patients with metastatic disease.

关键词： neural crest stem cell plasticity dedifferentiation therapy resistance metastasis

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Linking SOX10 to a slow-growth resistance phenotype

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细胞研究（英文版） 2014年第8期24卷 906-907页

作者： Gao Zhang Meenhard Herlyn Molecular and Cellular Oncogenesis Program The Wistar InstitutePhiladelphia PA 19104 USA Melanoma Research Center The Wistar InstitutePhiladelphia PA 19104 USA

Slow-cycling BRAFV600E melanoma cells are notoriously resistant to standard chemotherapy or targeted therapy but the underlying mechanism remains *** a new study unlocks this mystery and offers novel insights into developing more effective therapeutic ***-guided targeted therapies have been effective in shrinking the bulk of BRAFV600E tumors,particularly in patients with advanced or unresectable melanoma [1].Unfortunately,therapeutic response is not durable,which is inevitably followed by tumor relapse.

关键词： @@

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Protein Detection in Gels Using Fixation

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Current Protocols in Protein Science 2018年第1期91卷 10-10页

作者： Beer, Lynn A. Speicher, David W. Molecular and Cellular Oncogenesis Program The Wistar Institute Pennsylvania United States

The most commonly used types of gels for separating proteins are SDS gels, either in a 1-D format or as the second dimension of various 2-D separations, and the most common methods of visualizing proteins in these gels use protein binding dyes after fixing the proteins in the gel matrix. In recent years, there has been a continuing trend away from preparing staining solutions in the laboratory to using commercially available kits, which are convenient, save time, have defined shelf lives, and may provide greater reproducibility than stains formulated in research laboratories. In general, when using commercial kits, satisfactory results can be readily obtained by following the manufacturer's protocols. This unit reviews commonly used fixation-based stains and provides a number of manual formulations with staining protocols for those who prefer such staining methods. © 2018 by John Wiley & Sons, Inc. Copyright © 2018 John Wiley & Sons, Inc.

关键词： Coomassie stains MS compatible stains SDS gel stains silver stains SYPRO Ruby

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Annotation of gene promoters by integrative data-mining of ChIP-seq Pol-II enrichment data

Annotation of gene promoters by integrative data-mining of C...

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8th Asia-Pacific Bioinformatics Conference, APBC 2010

作者： Gupta, Ravi Wikramasinghe, Priyankara Bhattacharyya, Anirban Perez, Francisco A. Pal, Sharmistha Davuluri, Ramana V. Center for Systems and Computational Biology Molecular and Cellular Oncogenesis Program Wistar Institute Philadelphia PA United States Graduate Group in Genomics and Computational Biology Department of Genetics University of Pennsylvania Philadelphia PA United States

Background: Use of alternative gene promoters that drive widespread cell-type, tissue-type or developmental gene regulation in mammalian genomes is a common phenomenon. Chromatin immunoprecipitation methods coupled with DNA microarray (ChIP-chip) or massive parallel sequencing (ChIP-seq) are enabling genome-wide identification of active promoters in different cellular conditions using antibodies against Pol-II. However, these methods produce enrichment not only near the gene promoters but also inside the genes and other genomic regions due to the non-specificity of the antibodies used in ChIP. Further, the use of these methods is limited by their high cost and strong dependence on cellular type and context. Methods: We trained and tested different state-of-art ensemble and meta classification methods for identification of Pol-II enriched promoter and Pol-II enriched non-promoter sequences, each of length 500 bp. The classification models were trained and tested on a bench-mark dataset, using a set of 39 different feature variables that are based on chromatin modification signatures and various DNA sequence features. The best performing model was applied on seven published ChIP-seq Pol-II datasets to provide genome wide annotation of mouse gene promoters. Results: We present a novel algorithm based on supervised learning methods to discriminate promoter associated Pol-II enrichment from enrichment elsewhere in the genome in ChIP-chip/seq profiles. We accumulated a dataset of 11,773 promoter and 46,167 non-promoter sequences, each of length 500 bp, generated from RNA Pol-II ChIP-seq data of five tissues (Brain, Kidney, Liver, Lung and Spleen). We evaluated the classification models in building the best predictor and found that Bagging and Random Forest based approaches give the best accuracy. We implemented the algorithm on seven different published ChIP-seq datasets to provide a comprehensive set of promoter annotations for both protein-coding and non-coding genes in

关键词： Mammals

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Induction of metallothionein expression during monocyte to melanoma-associated macrophage differentiation

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Frontiers in Biology 2012年第4期7卷 359-367页

作者： Yingbin GE Rikka AZUMA Bethsebah GEKONGE Alfonso LOPEZ-CORAL Min XIAO Gao ZHANG Xiaowei XU Luis J. MONTANER Zhi WEI Meenhard HERLYN Tao WANG Russel E. KAUFMAN Molecular and Cellular Oncogenesis Program The Wistar Institute Philadelphia PA 19104 USA Department of Physiology Nanjing Medical University Nanjing 210029 China Undergraduate Program University of Pennsylvania Philadelphia PA 19104 USA Tumor Microenvironment and Metastasis Program The Wistar Institute Philadelphia PA 19104 USA Graduate Program The Catholic University of America Washington DC 20064 USA Department of Pathology and Laboratory Medicine University of Pennsylvania Philadelphia PA 19104 USA Department of Computer Science New Jersey Institute of Technology NJ 07102 USA

Tumor-associated macrophages （TAMs） play a critical role in melanoma growth and metastasis. Infiltration of TAMs correlates with the poor prognosis of melanoma. TAMs are differentiated from monocytes in response to the tumor microenvironment cue. However, the mechanism how TAMs adapt to the tumor microenvironment after differentiation from monocytes is not fully understood. In addition, specific identification of TAMs in melanoma is difficult because the expression of the most commonly used macrophage marker, CD68, is also expressed in melanoma cells. In an earlier study, we found by gene microarray analysis that seven members of the metallothionein （MTs） family were upregulated in melanoma-conditioned medium induced macrophages （MCIM-MO）. MTs have been implicated in zinc metabolism and inflammation. In the present study, we confirmed that expression of metallothionein is induced in M-CSF differentiated macrophages （M-CSF/M~） and MCIM-M~ at both the mRNA and protein levels using real-time PCR, immunofluorescence, and western blot analysis. Furthermore, we demonstrated the presence of metallothionein in melanoma tissues in vivo and that metallothionein was co-localized with TAMs markers, CD68 and CD163. Finally, we demonstrated the induction of the zinc importer gene Zip8 both in M-CSF/MO and MCIM-MO. Our study identifies metallothionein as a novel marker for TAMs and suggests that metaliothionein might play important roles in macrophage adaptation and function in the tumor microenvironment.

关键词： melanoma macrophages metallothionein

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Discovery of Regulatory Networks in Plants by Linking Promoter and Transcription Factor Databases

Discovery of Regulatory Networks in Plants by Linking Promot...

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Ohio Collaborative Conference on Bioinformatics, OCCBIO

作者： Alper Yilmaz Ramana Davuluri Saranyan Palaniswamy Erich Grotewold Department of Plant Cellular and Molecular Biology Ohio State Uinversity Columbus OH USA Molecular and Cellular Oncogenesis Program Wistar Institute Philadelphia PA USA Human Cancer Genetics Program Comprehensive Cancer Center Ohio State Uinversity Columbus OH USA

Transcription factors (TFs) control the levels as well as the sites and times of expression of a discrete set of target genes by binding to specific cis-regulatory elements in the corresponding promoter regions. They can function as master control switches for the regulation of metabolic pathways, cell differentiation and the cell cycle. Thus, the state of a living cell is the result of regulated transcription of thousands of genes in which TFs are major players. A first step in the discovering the regulatory networks is to establish the organization of cis-elements in promoters and the direct targets of TFs. Towards this goal, our lab has developed two publicly available TF and promoter databases. AGRIS (***) is dedicated to reveal regulatory networks in Arabidopsis and is currently composed of databases of putative cis-elements (AtcisDB) and TFs (AtTFDB). The regulatory network in Arabidopsis is constructed based on available data by linking cis-regulatory elements and transcription factors, interactions that are visualized by *** (***) provides regulatory information gathered from computational and experimental sources for the grasses, initially including maize, rice, sorghum and sugarcane. Promoter sequences across these grasses and cis-elements important for gene expression are gathered in GrassPROMDB. GrassTFDB contains information on TFs, their DNA-binding properties and the genes that they have been experimentally demonstrated to bind/regulate. GrassREGNET is the ultimate component of GRASSIUS, currently under development, and will provide a dynamic relationship between the contents of GrassTFDB and GrassPROMDB in the light of experimentally verified interactions, helping visualize spatio-temporal gene regulation and regulatory networks.

关键词： Joining processes Plants (biology) Visual databases DNA cellular networks Cells (biology) Sequences RNA Cancer Gene expression

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Kaposi’s sarcoma-associated herpesvirus induces mitochondrial fission to evade host immune responses and promote viral production

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Nature Microbiology 2025年 1-20页

作者： Qing Zhu Robert McElroy Janvhi Suresh Machhar Joel Cassel Zihan Zheng Behzad Mansoori Sen Guo Christian Pangilinan Jinghui Liang Dongliang Shen Lu Zhang Qin Liu Maureen E. Murphy Joseph M. Salvino Chengyu Liang Hongrui Guo Andrew V. Kossenkov Dario C. Altieri Paul M. Lieberman Shou-Jiang Gao Pinghui Feng Jikui Song Qiming Liang Jae U. Jung Program in Molecular and Cellular Oncogenesis The Wistar Institute Philadelphia PA USA Department of Molecular Microbiology and Immunology Keck School of Medicine University of Southern California Los Angeles CA USA Program in Genome Regulation and Cell Signaling The Wistar Institute Philadelphia PA USA Cancer Virology Program University of Pittsburgh Medical Center Hillman Cancer Center University of Pittsburgh School of Medicine Pittsburgh PA USA Section of Infection and Immunity Herman Ostrow School of Dentistry Norris Comprehensive Cancer Center University of Southern California Los Angeles CA USA Department of Biochemistry University of California Riverside CA USA Center for Immune-Related Diseases at Shanghai Institute of Immunology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai China Department of Cancer Biology Department of Infection Biology and Global Center for Pathogen and Human Health Research Lerner Research Institute Cleveland Clinic Cleveland OH USA

Mitochondrial dynamics are pivotal for host immune responses upon infection, yet how viruses manipulate these processes to impair host defence and enhance viral fitness remains unclear. Here we show that Kaposi’s sarcoma-associated herpesvirus (KSHV), an oncogenic virus also known as human herpesvirus 8, encodes Bcl-2 (vBcl-2), which reprogrammes mitochondrial architecture. It binds with NM23-H2, a host nucleoside diphosphate (NDP) kinase, to stimulate GTP loading of the dynamin-related protein (DRP1) GTPase, which triggers mitochondrial fission, inhibits mitochondrial antiviral signalling protein (MAVS) aggregation and impairs interferon responses in cell lines. An NM23-H2-binding-defective vBcl-2 mutant fails to evoke fission, leading to defective virion assembly due to activated MAVS–IFN signalling. Notably, we identify two key interferon-stimulated genes restricting vBcl-2-dependent virion morphogenesis. Using a high-throughput drug screening, we discover an inhibitor targeting vBcl-2–NM23-H2 interaction that blocks virion production in vitro. Our study identifies a mechanism in which KSHV manipulates mitochondrial dynamics to allow for virus assembly and shows that targeting the virus–mitochondria interface represents a potential therapeutic strategy.

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Inflammatory reflex disruption in COVID-19

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Clinical and Experimental Neuroimmunology 2022年第4期13卷 295-301页

作者： Hajiasgharzadeh, Khalil Jafarlou, Mahdi Mansoori, Behzad Dastmalchi, Narges Baradaran, Behzad Khabbazi, Alireza Immunology Research Center Tabriz University of Medical Sciences Tabriz Iran Connective Tissue Diseases Research Center Tabriz University of Medical Sciences Tabriz Iran Cellular and Molecular Oncogenesis Program The Wistar Institute Philadelphia PA United States Department of Biology University College of Nabi Akram Tabriz Iran Pharmaceutical Analysis Research Center Tabriz University of Medical Sciences Tabriz Iran

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in Wuhan, China, in late 2019 and caused coronavirus disease 2019 (COVID-19), which is still a global pandemic. In most infected people, SARS-CoV-2 only causes moderate symptoms, whereas in other patients, it leads to severe illness and eventually death. Although the main clinical manifestation of COVID-19 is often seen in the lungs, this disease affects almost all body organs. The excessive and prolonged release of inflammatory cytokines that might occur in COVID-19 patients, known as cytokine storms, stimulates undesired immune responses and can cause various tissues damage. In the current review article, we focus on the potential advantages of the intrinsic cholinergic anti-inflammatory pathway as the efferent arm of the inflammatory reflex in COVID-19 management. Considering this endogenous protective mechanism against chronic inflammation, we focused on the effects of SARS-CoV-2 in the destruction of this anti-inflammatory system. Several studies showed the interaction of SARS-CoV-2 with the alpha-7 subtype of the nicotinic acetylcholine receptor as the effector molecule of the inflammatory reflex. In contrast, neurological manifestations have increasingly been identified as significant extrapulmonary manifestations of COVID-19. The rational connection between these findings and COVID-19 pathogenesis might be an important issue in both our understanding of and dealing with this disease. COVID-19 is deeply rooted in our daily life and requires an urgent need for the establishment of effective therapeutic options, and all the possible treatments must be considered for the control of such inflammatory conditions. © 2022 Japanese Society for Neuroimmunology.

关键词： autonomic dysfunction cholinergic anti-inflammatory pathway COVID-19 inflammatory reflex SARS-CoV-2

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