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Articles 1 - 30 of 324

Full-Text Articles in Biochemistry, Biophysics, and Structural Biology

Extraction, Purification And Evaluation Of Prmt5-Inhibitory Phytochemical Compounds For The Treatment Of Prostate Adenocarcinoma, Oliver H. Richmond Iii May 2019

Extraction, Purification And Evaluation Of Prmt5-Inhibitory Phytochemical Compounds For The Treatment Of Prostate Adenocarcinoma, Oliver H. Richmond Iii

Electronic Theses & Dissertations Collection for Atlanta University & Clark Atlanta University

The development and advancement of prostate cancer is supported by a plethora of genetic and proteomic abnormalities, including events of post-translational modifications. The protein arginine methyltransferase 5 (PRMT5) enzyme regulates epigenetic events of histone modifications and protein post-translational modifications within protein signaling pathways. PRMT5 functions by catalyzing the symmetric dimethylation of terminal arginine residues on target protein substrates. Under abnormal conditions of overexpression and upregulation, PRMT5 methyltransferase activity constitutively drives the growth and proliferation of dysregulated cells. Overexpression or upregulation of PRMT5 correlates with disease progression as observed among numerous cancer types, including breast, colorectal, leukemia, lung, melanoma and prostate ...


Targeting Sec61Α By Ipomoeassin F Leads To Highly Cytotoxic Effect, Zhijian Hu May 2019

Targeting Sec61Α By Ipomoeassin F Leads To Highly Cytotoxic Effect, Zhijian Hu

Theses and Dissertations

Ipomoeassin F is a flagship congener of a resin glycoside family that inhibits growth of many tumor cell lines with only single-digital nanomolar IC50 values. However, biological and pharmacological mechanisms of ipomoeassin F have been undefined. To facilitate exploration of the biological and pharmacological properties, we performed sophisticate SAR (Structure–activity relationship) studies of ipomoeassin F to understand its pharmacophore and structure properties so that we can design favorable probes for further biological investigation. By applying appropriate deviates that possess fluorescent groups and similar bio-activity, the target protein was found to be localized in endoplasmic reticulum (ER). Through biotin affinity ...


Crispr-Sonic: Targeted Somatic Oncogene Knock-In Enables Rapid In Vivo Cancer Modeling, Haiwei Mou, Deniz M. Ozata, Jordan L. Smith, Ankur Sheel, Suet-Yan Kwan, Soren Hough, Alper Kucukural, Zachary Kennedy, Yueying Cao, Wen Xue Apr 2019

Crispr-Sonic: Targeted Somatic Oncogene Knock-In Enables Rapid In Vivo Cancer Modeling, Haiwei Mou, Deniz M. Ozata, Jordan L. Smith, Ankur Sheel, Suet-Yan Kwan, Soren Hough, Alper Kucukural, Zachary Kennedy, Yueying Cao, Wen Xue

RNA Therapeutics Institute Publications

CRISPR/Cas9 has revolutionized cancer mouse models. Although loss-of-function genetics by CRISPR/Cas9 is well-established, generating gain-of-function alleles in somatic cancer models is still challenging because of the low efficiency of gene knock-in. Here we developed CRISPR-based Somatic Oncogene kNock-In for Cancer Modeling (CRISPR-SONIC), a method for rapid in vivo cancer modeling using homology-independent repair to integrate oncogenes at a targeted genomic locus. Using a dual guide RNA strategy, we integrated a plasmid donor in the 3'-UTR of mouse beta-actin, allowing co-expression of reporter genes or oncogenes from the beta-actin promoter. We showed that knock-in of oncogenic Ras and ...


Unified Methods For Feature Selection In Large-Scale Genomic Studies With Censored Survival Outcomes, Lauren Spirko-Burns, Karthik Devarajan Mar 2019

Unified Methods For Feature Selection In Large-Scale Genomic Studies With Censored Survival Outcomes, Lauren Spirko-Burns, Karthik Devarajan

COBRA Preprint Series

One of the major goals in large-scale genomic studies is to identify genes with a prognostic impact on time-to-event outcomes which provide insight into the disease's process. With rapid developments in high-throughput genomic technologies in the past two decades, the scientific community is able to monitor the expression levels of tens of thousands of genes and proteins resulting in enormous data sets where the number of genomic features is far greater than the number of subjects. Methods based on univariate Cox regression are often used to select genomic features related to survival outcome; however, the Cox model assumes proportional ...


Supervised Dimension Reduction For Large-Scale "Omics" Data With Censored Survival Outcomes Under Possible Non-Proportional Hazards, Lauren Spirko-Burns, Karthik Devarajan Mar 2019

Supervised Dimension Reduction For Large-Scale "Omics" Data With Censored Survival Outcomes Under Possible Non-Proportional Hazards, Lauren Spirko-Burns, Karthik Devarajan

COBRA Preprint Series

The past two decades have witnessed significant advances in high-throughput ``omics" technologies such as genomics, proteomics, metabolomics, transcriptomics and radiomics. These technologies have enabled simultaneous measurement of the expression levels of tens of thousands of features from individual patient samples and have generated enormous amounts of data that require analysis and interpretation. One specific area of interest has been in studying the relationship between these features and patient outcomes, such as overall and recurrence-free survival, with the goal of developing a predictive ``omics" profile. Large-scale studies often suffer from the presence of a large fraction of censored observations and potential ...


Regulation Of The Long Non-Coding Rna Fam83h-As1 By Human Papillomavirus In Cervical Cancer, Jamie Ann Barr Ph.D. Jan 2019

Regulation Of The Long Non-Coding Rna Fam83h-As1 By Human Papillomavirus In Cervical Cancer, Jamie Ann Barr Ph.D.

Graduate Theses, Dissertations, and Problem Reports

Non-coding RNAs (NcRNAs), such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have been found to be involved in a variety of critical biological processes, and dysregulation of ncRNAs have been involved with several human diseases including cancer.

High-risk human papillomavirus (HPV) infection is one of the first events in the process of carcinogenesis in cervical and a subset of head and neck cancers. The expression of the viral oncoproteins E6 and E7 is essential in this process by inactivating the tumor suppressor proteins p53 and Rb, respectively, in addition to their interactions with other host proteins and regulation of ...


Role Of P300 Zz Domain In Chromatin Association And Histone Acetylation, Yongming Xue Dec 2018

Role Of P300 Zz Domain In Chromatin Association And Histone Acetylation, Yongming Xue

UT GSBS Dissertations and Theses (Open Access)

Transcription is strictly regulated by numerous factors including transcription coactivators. The p300 protein and its close paralogue CREB-binding protein (CREBBP, aka CBP) are well-known transcriptional coactivators that have intrinsic lysine acetyltransferase activity. The functions of p300/CBP largely rely on their capabilities to bind to chromatin and to acetylate the histone substrates. However, the molecular mechanisms underlying the regulation of these processes are not fully understood.

Through combination of various biochemical, biophysical and molecular approaches, we show that the ZZ-type zinc finger (ZZ) domain of p300 functions as a histone reader that specifically binds the N-terminal tail of histone H3 ...


A Crispr Platform For Rapid And Inducible Genome Editing In Human Non-Small Cell Lung Cancer Cells, Lloyd Bartley Nov 2018

A Crispr Platform For Rapid And Inducible Genome Editing In Human Non-Small Cell Lung Cancer Cells, Lloyd Bartley

Posters-at-the-Capitol

Non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancer, which is the leading cause of cancer death in the world. High mortality rate associated with NSCLC is partially attributed to the limited understanding of NSCLC as well as ineffective therapeutic treatments. The initiation and progression of NSCLC involves genetic changes leading to alterations in the control of tissue development and homeostatic maintenance. Better knowledge about these genetic abnormalities is imperative for developing new chemotherapeutic drugs for NSCLC. Recent research demonstrates that the expression of paraoxonase 2 (PON2), a lactonase/arylesterase with anti-oxidant properties, are markedly enhanced in ...


Colorectal Cancer Liver Metastatic Growth Depends On Pad4-Driven Citrullination Of The Extracellular Matrix, A. E. Yuzhalin, A. N. Gordon-Weeks, M. L. Tognoli, K. Jones, B. Markelc, R. Konietzny, R. Fischer, Aaron Muth, E. O'Neill, Paul R. Thompson, P. J. Venables, B. M. Kessler, S. Y. Lim, R. J. Muschel Nov 2018

Colorectal Cancer Liver Metastatic Growth Depends On Pad4-Driven Citrullination Of The Extracellular Matrix, A. E. Yuzhalin, A. N. Gordon-Weeks, M. L. Tognoli, K. Jones, B. Markelc, R. Konietzny, R. Fischer, Aaron Muth, E. O'Neill, Paul R. Thompson, P. J. Venables, B. M. Kessler, S. Y. Lim, R. J. Muschel

Open Access Articles

Citrullination of proteins, a post-translational conversion of arginine residues to citrulline, is recognized in rheumatoid arthritis, but largely undocumented in cancer. Here we show that citrullination of the extracellular matrix by cancer cell derived peptidylarginine deiminase 4 (PAD4) is essential for the growth of liver metastases from colorectal cancer (CRC). Using proteomics, we demonstrate that liver metastases exhibit higher levels of citrullination and PAD4 than unaffected liver, primary CRC or adjacent colonic mucosa. Functional significance for citrullination in metastatic growth is evident in murine models where inhibition of citrullination substantially reduces liver metastatic burden. Additionally, citrullination of a key matrix ...


Development Of A Pd-L1 Pet Imaging Biomarker, Caleb Jack Bridgwater Nov 2018

Development Of A Pd-L1 Pet Imaging Biomarker, Caleb Jack Bridgwater

Posters-at-the-Capitol

Immunotherapy strategies are very promising treatments for cancer patients. Specifically, Immune checkpoint inhibitor therapy focusing on the PD-1/PD-L1 pathway shows long-lasting positive results in many cancer patients. Unfortunately, not all the patients can benefit from this highly effective treatment. Hence, there is a great need for predictive biomarkers. Immunohistochemical (IHC) staining has been used as a way of predicting patient response, yet shows many problems. For example, IHC utilizes an invasive biopsy and sample fixing, which creates an incomplete and delayed picture of the patient’s biochemistry and the tumor microenvironment, consequently ignoring metastases.

The purpose of this study ...


Combined High-Speed Single Particle Tracking Of Membrane Proteins And Super-Resolution Of Membrane-Associated Structures, Hanieh Mazloom Farsibaf, Keith A. Lidke Nov 2018

Combined High-Speed Single Particle Tracking Of Membrane Proteins And Super-Resolution Of Membrane-Associated Structures, Hanieh Mazloom Farsibaf, Keith A. Lidke

Shared Knowledge Conference

Many experiments have shown that the diffusive motion of lipids and membrane proteins are slower on the cell surface than those in artificial lipid bilayers or blebs. One hypothesis that may partially explain this mystery is the effect of the cytoskeleton structures on the protein dynamics. A model proposed by Kusumi [1] is the Fence-Picket Model which describes the cell membrane as a set of compartment regions, each ~ 10 to 200 nm in size, created by direct or indirect interaction of lipids and proteins with actin filaments just below the membrane. To test this hypothesis, we have assembled a high-speed ...


Signaling Pathways Induced By Leptin During Epithelial(-)Mesenchymal Transition In Breast Cancer, Monserrat Olea-Flores, Juan Carlos Juarez-Cruz, Miguel A. Mendoza-Catalan, Teresita Padilla-Benavides, Napoleon Navarro-Tito Nov 2018

Signaling Pathways Induced By Leptin During Epithelial(-)Mesenchymal Transition In Breast Cancer, Monserrat Olea-Flores, Juan Carlos Juarez-Cruz, Miguel A. Mendoza-Catalan, Teresita Padilla-Benavides, Napoleon Navarro-Tito

Open Access Articles

Leptin is an adipokine that is overexpressed in obese and overweight people. Interestingly, women with breast cancer present high levels of leptin and of its receptor ObR. Leptin plays an important role in breast cancer progression due to the biological processes it participates in, such as epithelial(-)mesenchymal transition (EMT). EMT consists of a series of orchestrated events in which cell(-)cell and cell(-)extracellular matrix interactions are altered and lead to the release of epithelial cells from the surrounding tissue. The cytoskeleton is also re-arranged, allowing the three-dimensional movement of epithelial cells into the extracellular matrix. This transition provides ...


Synthesis And Biological Evaluation Of Phaeosphaeride A Derivatives As Antitumor Agents, Victoria Abzianidze, Petr Beltyukov, Sofya Zakharenkova, Natalia Moiseeva, Jennifer Mejia, Alvin Holder, Yuri Trishin, Alexander Berestetskiy, Victor Kuznetsov Nov 2018

Synthesis And Biological Evaluation Of Phaeosphaeride A Derivatives As Antitumor Agents, Victoria Abzianidze, Petr Beltyukov, Sofya Zakharenkova, Natalia Moiseeva, Jennifer Mejia, Alvin Holder, Yuri Trishin, Alexander Berestetskiy, Victor Kuznetsov

Chemistry & Biochemistry Faculty Publications

New derivatives of phaeosphaeride A (PPA) were synthesized and characterized. Anti-tumor activity studies were carried out on the HCT-116, PC3, MCF-7, A549, К562, NCI-Н929, Jurkat, THP-1, RPMI8228 tumor cell lines, and on the HEF cell line. All of the compounds synthesized were found to have better efficacy than PPA towards the tumor cell lines mentioned. Compound 6 was potent against six cancer cell lines, HCT-116, PC-3, K562, NCI-H929, Jurkat, and RPMI8226, showing a 47, 13.5, 16, 4, 1.5, and 7-fold increase in anticancer activity comparative to those of etoposide, respectively. Compound 1 possessed selectivity toward the NCI-H929 cell ...


Rare Gene Fusion Rearrangement Sptnb1-Pdgfrb In An Atypical Myeloproliferative Neoplasm, Vanessa Fiorini Furtado, Neeraj Y. Saini, William V. Walsh, Venu G. Bathini, Patricia M. Miron Oct 2018

Rare Gene Fusion Rearrangement Sptnb1-Pdgfrb In An Atypical Myeloproliferative Neoplasm, Vanessa Fiorini Furtado, Neeraj Y. Saini, William V. Walsh, Venu G. Bathini, Patricia M. Miron

Open Access Articles

The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia recognizes a distinct class of myeloid and lymphoid tumors with eosinophilia-related proliferations associated with specific gene rearrangements, one of which involves rearrangements of platelet-derived growth factor receptor B (PDGFRB) gene. We report a case of a rare PDGFRB rearrangement with SPTNB1 (spectrin beta, nonerythrocytic 1) that presented as atypical myeloproliferative neoplasm.


8th Annual Postdoctoral Science Symposium, University Of Texas Md Anderson Cancer Center Postdoctoral Association Oct 2018

8th Annual Postdoctoral Science Symposium, University Of Texas Md Anderson Cancer Center Postdoctoral Association

MD Anderson Cancer Center Postdoctoral Association Annual Postdoctoral Science Symposium Abstracts

The mission of the Annual Postdoctoral Science Symposium (APSS) is to provide a platform for talented postdoctoral fellows throughout the Texas Medical Center to present their work to a wider audience. The MD Anderson Postdoctoral Association convened its inaugural Annual Postdoctoral Science Symposium (APSS) on August 4, 2011.

The APSS provides a professional venue for postdoctoral scientists to develop, clarify, and refine their research as a result of formal reviews and critiques of faculty and other postdoctoral scientists. Additionally, attendees discuss current research on a broad range of subjects while promoting academic interactions and enrichment and developing new collaborations.


Synthetic Approaches Towards Novel Isoform Selective Pi3k Inhibitors And Their Biological Activities Against Prostate Cancer Cells, Idris Wazeerud-Din Aug 2018

Synthetic Approaches Towards Novel Isoform Selective Pi3k Inhibitors And Their Biological Activities Against Prostate Cancer Cells, Idris Wazeerud-Din

Electronic Theses & Dissertations Collection for Atlanta University & Clark Atlanta University

The development of novel imidazopyridines, which includes both tetrahydroimidazo[1,5-a]pyridine (rIMP) and imidazo[1,5-a]pyridine (IMP) was investigated using conventional and microwave induced procedures that afforded compounds at high yield of 88-96%. rIMP was synthesized using a two-step procedure that involved the microwave synthesis of IMP, then the reduction of the pyridine moiety of the fused imidazopyridine rings using 10% Pd/C and hydrazine monohydrate. The microwave synthesis of imidazopyridines involved the one pot reaction of 2-benzoylpyridine, substituted benzaldehyde and ammonium formate in acetic acid under open vessel microwave conditions, which resulted in products within 40 minutes ...


Tumor-Stroma Interactions Differentially Alter Drug Sensitivity Based On The Origin Of Stromal Cells, Benjamin D. Landry, Thomas Leete, Ryan Richards, Peter Cruz-Gordillo, Hannah R. Schwartz, Megan E. Honeywell, Gary Ren, Alyssa D. Schwartz, Shelly R. Peyton, Michael J. Lee Aug 2018

Tumor-Stroma Interactions Differentially Alter Drug Sensitivity Based On The Origin Of Stromal Cells, Benjamin D. Landry, Thomas Leete, Ryan Richards, Peter Cruz-Gordillo, Hannah R. Schwartz, Megan E. Honeywell, Gary Ren, Alyssa D. Schwartz, Shelly R. Peyton, Michael J. Lee

Program in Systems Biology Publications and Presentations

Due to tumor heterogeneity, most believe that effective treatments should be tailored to the features of an individual tumor or tumor subclass. It is still unclear, however, what information should be considered for optimal disease stratification, and most prior work focuses on tumor genomics. Here, we focus on the tumor microenvironment. Using a large-scale coculture assay optimized to measure drug-induced cell death, we identify tumor-stroma interactions that modulate drug sensitivity. Our data show that the chemo-insensitivity typically associated with aggressive subtypes of breast cancer is not observed if these cells are grown in 2D or 3D monoculture, but is manifested ...


Fluorescently Labeled Sirnas And Their Theranostic Applications In Cancer Gene Therapy, Stephen David Kozuch Aug 2018

Fluorescently Labeled Sirnas And Their Theranostic Applications In Cancer Gene Therapy, Stephen David Kozuch

Seton Hall University Dissertations and Theses (ETDs)

Gene therapy has emerged as a promising precision nano-medicine strategy in the treatment of numerous diseases including cancer. At the forefront of its utility are the applications of short-interfering RNA (siRNA), that silence oncogenic mRNA expression leading to cancer cell death through the RNA interference (RNAi) pathway. Despite the therapeutic potential, siRNAs are limited by poor pharmacological properties, which has hindered their translation into the clinic. Recent studies, however, have highlighted the applications of modified siRNAs, including the use of fluorescent probes and siRNA nanostructures in cancer detection and treatment. The siRNAs reported in this thesis are designed to target ...


Deciphering The Role Of Human Arylamine N-Acetyltransferase 1 (Nat1) In Breast Cancer Cell Metabolism Using A Systems Biology Approach., Samantha Marie Carlisle Aug 2018

Deciphering The Role Of Human Arylamine N-Acetyltransferase 1 (Nat1) In Breast Cancer Cell Metabolism Using A Systems Biology Approach., Samantha Marie Carlisle

Electronic Theses and Dissertations

Background: Human arylamine N-acetyltransferase 1 (NAT1) is a phase II xenobiotic metabolizing enzyme found in almost all tissues. NAT1 can additionally hydrolyze acetyl-coenzyme A (acetyl-CoA) in the absence of an arylamine substrate. NAT1 expression varies inter-individually and is elevated in several cancers including estrogen receptor positive (ER+) breast cancers. Additionally, multiple studies have shown the knockdown of NAT1, by both small molecule inhibition and siRNA methods, in breast cancer cells leads to decreased invasive ability and proliferation and decreased anchorage-independent colony formation. However, the exact mechanism by which NAT1 expression affects cancer risk and progression remains unclear. Additionally, consequences ...


Egfr Signaling From The Early Endosome., Julie A. Gosney Aug 2018

Egfr Signaling From The Early Endosome., Julie A. Gosney

Electronic Theses and Dissertations

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is an integral component of proliferative signaling. When activated by a ligand at the plasma membrane, EGFR dimerizes with another ErbB family receptor, leading to kinase domain activation and transphosphorylation of C-terminus tyrosine residues. These phosphotyrosines act as crucial regulators of EGFR signaling as effector proteins dock to the receptor at these sites. The receptor undergoes clathrin-mediated endocytosis into early endosomes, where it can then be trafficked to a lysosome for degradation. However, the kinase domain of EGFR retains its activity during trafficking, suggesting that EGFR can continue ...


The Rational Design, Synthesis, Characterization, And Biological Evaluation Of Cancer-Targeting Immunostimulatory Peptide-Protein Conjugates And Tripeptides, Keith Smith Aug 2018

The Rational Design, Synthesis, Characterization, And Biological Evaluation Of Cancer-Targeting Immunostimulatory Peptide-Protein Conjugates And Tripeptides, Keith Smith

Seton Hall University Dissertations and Theses (ETDs)

With the advent of cancer immunotherapy and the rise in applications of synthetic biologics, there has been a steady decline in the incidence of cancer. Despite this trend, there is an anticipated 1.7 million new cancer cases with an estimated 610,000 deaths expected by the end of 2018.2 Therefore, the call for continued efforts in creating more effective treatment options are still in high demand. In this thesis, the rational design of a semi-synthetic cancer-targeting immunostimulatory peptide-protein bioconjugate—using N-succinimidyl carbamate chemistry is described. This bio-orthogonal chemistry approach was used to conjugate the synthetic Pep42, cancer-targeting peptide ...


Computational Analysis Of Genomic Variants Affecting Predicted Microrna:Target Interactions In Prostate Cancer., Angélica Paola Hernández Pérez Jul 2018

Computational Analysis Of Genomic Variants Affecting Predicted Microrna:Target Interactions In Prostate Cancer., Angélica Paola Hernández Pérez

KGI Theses and Dissertations

Prostate cancer (PCa) is the most common cancer of men in the United States and is third only to lung and colon as a cause of cancer death. Clinical behavior of the disease is variable and the combination of prostate-specific antigen (PSA) screening and Gleason score staging are currently the best available molecular and pathology tools to predict outcomes. Cancer biology research establishes microRNAs (miRNAs) as key molecular components in both normal and pathological states. Thus, elucidating miRNAs perturbed by genomic alterations will expand our understanding of the molecular taxonomy of PCa with the aim to complement current practices in ...


Llc Tumor Cells-Derivated Factors Reduces Adipogenesis In Co-Culture System, Magno Alves Lopes, Felipe Oliveira Franco, Felipe Henriques, Sidney Barnabe Peres, Miguel Luiz Batista Jr. Jul 2018

Llc Tumor Cells-Derivated Factors Reduces Adipogenesis In Co-Culture System, Magno Alves Lopes, Felipe Oliveira Franco, Felipe Henriques, Sidney Barnabe Peres, Miguel Luiz Batista Jr.

Open Access Articles

Cancer cachexia (CC) is a multifactorial syndrome with an unknown etiology. The primary symptom is the progressive reduction of the body weight. Recently, down-regulation of adipogenic and lipogenic genes were demonstrated to be early affected during cachexia progression in adipose tissue (AT), resulting in AT remodeling. Thus, this study aimed to evaluate in a co-culture system the influence of the Lewis Lung Carcinoma (LLC) tumor cells (c/c-LLC) in an established pre-adipocyte cell line 3T3-L1 adipogenic capacity. c/c-LLC in the presence of 3T3-L1 caused a reduction in lipids accumulation, suggesting that secretory tumor cells products may affect adipogenesis. Interestingly ...


Etv4 Transcription Factor And Mmp13 Metalloprotease Are Interplaying Actors Of Breast Tumorigenesis, Mandy Dumortier, Franck Ladam, Isabelle Damour, Sophie Vacher, Ivan Bieche, Nathalie Marchand, Yvan De Launoit, David Tulasne, Anne Chotteau-Lelievre Jul 2018

Etv4 Transcription Factor And Mmp13 Metalloprotease Are Interplaying Actors Of Breast Tumorigenesis, Mandy Dumortier, Franck Ladam, Isabelle Damour, Sophie Vacher, Ivan Bieche, Nathalie Marchand, Yvan De Launoit, David Tulasne, Anne Chotteau-Lelievre

Open Access Articles

BACKGROUND: The ETS transcription factor ETV4 is involved in the main steps of organogenesis and is also a significant mediator of tumorigenesis and metastasis, such as in breast cancer. Indeed, ETV4 is overexpressed in breast tumors and is associated with distant metastasis and poor prognosis. However, the cellular and molecular events regulated by this factor are still misunderstood. In mammary epithelial cells, ETV4 controls the expression of many genes, MMP13 among them. The aim of this study was to understand the function of MMP13 during ETV4-driven tumorigenesis.

METHODS: Different constructs of the MMP13 gene promoter were used to study the ...


Developing Droplet Based 3d Cell Culture Methods To Enable Investigations Of The Chemical Tumor Microenvironment, Jacqueline A. De Lora Jul 2018

Developing Droplet Based 3d Cell Culture Methods To Enable Investigations Of The Chemical Tumor Microenvironment, Jacqueline A. De Lora

Biomedical Sciences ETDs

Adaptation of cancer cells to changes in the biochemical microenvironment in an expanding tumor mass is a crucial aspect of malignant progression, tumor metabolism, and drug efficacy. In vitro, it is challenging to mimic the evolution of biochemical gradients and the cellular heterogeneity that characterizes cancer tissues found in vivo. It is well accepted that more realistic and controllable in vitro 3D model systems are required to improve the overall cancer research paradigm and thus improve on the translation of results, but multidisciplinary approaches are needed for these advances. This work develops such approaches and demonstrates that new droplet-based cell-encapsulation ...


Identification Of A Novel Invasion-Promoting Region In Insulin Receptor Substrate 2, Jose Mercado-Matos, Jenny Janusis, Sha Zhu, Samuel S. Chen, Leslie M. Shaw Jun 2018

Identification Of A Novel Invasion-Promoting Region In Insulin Receptor Substrate 2, Jose Mercado-Matos, Jenny Janusis, Sha Zhu, Samuel S. Chen, Leslie M. Shaw

University of Massachusetts Medical School Faculty Publications

Although the insulin receptor substrate (IRS) proteins IRS1 and IRS2 share considerable homology and activate common signaling pathways, their contributions to breast cancer are distinct. IRS1 has been implicated in the proliferation and survival of breast tumor cells. In contrast, IRS2 facilitates glycolysis, invasion, and metastasis. To determine the mechanistic basis for IRS2-dependent functions, we investigated unique structural features of IRS2 that are required for invasion. Our studies revealed that the ability of IRS2 to promote invasion is dependent upon upstream insulin-like growth factor 1 receptor (IGF-1R)/insulin receptor (IR) activation and the recruitment and activation of phosphatidylinositol 3-kinase (PI3K ...


Cell Clustering Mediated By The Adhesion Protein Pvrl4 Is Necessary For Alpha6beta4 Integrin-Promoted Ferroptosis Resistance In Matrix-Detached Cells, Caitlin W. Brown, John J. Amante, Arthur M. Mercurio Jun 2018

Cell Clustering Mediated By The Adhesion Protein Pvrl4 Is Necessary For Alpha6beta4 Integrin-Promoted Ferroptosis Resistance In Matrix-Detached Cells, Caitlin W. Brown, John J. Amante, Arthur M. Mercurio

University of Massachusetts Medical School Faculty Publications

Ferroptosis is an iron-dependent form of programmed cell death characterized by the accumulation of lipid-targeting reactive oxygen species that kill cells by damaging their plasma membrane. The lipid-repair enzyme glutathione peroxidase 4 (GPX4) protects against this oxidative damage and enables cells to resist ferroptosis. Recent work has revealed that matrix-detached carcinoma cells can be susceptible to ferroptosis and that they can evade this fate through the signaling properties of the alpha6beta4 integrin, which sustains GPX4 expression. Although these findings on ferroptosis are provocative, they differ from those in previous studies indicating that matrix-detached cells are prone to apoptosis, via a ...


Dynamics Of Human Protein Kinase Aurora A Linked To Drug Selectivity, Warintra Pitsawong, Vanessa Buosi, Renee Otten, Roman V. Agafonov, Adelajda Zorba, Nadja Kern, Steffen Kutter, Gunther Kern, Ricardo Ap Padua, Xavier Meniche, Dorothee Kern Jun 2018

Dynamics Of Human Protein Kinase Aurora A Linked To Drug Selectivity, Warintra Pitsawong, Vanessa Buosi, Renee Otten, Roman V. Agafonov, Adelajda Zorba, Nadja Kern, Steffen Kutter, Gunther Kern, Ricardo Ap Padua, Xavier Meniche, Dorothee Kern

Open Access Articles

Protein kinases are major drug targets, but the development of highly-selective inhibitors has been challenging due to the similarity of their active sites. The observation of distinct structural states of the fully-conserved Asp-Phe-Gly (DFG) loop has put the concept of conformational selection for the DFG-state at the center of kinase drug discovery. Recently, it was shown that Gleevec selectivity for the Tyr-kinase Abl was instead rooted in conformational changes after drug binding. Here, we investigate whether protein dynamics after binding is a more general paradigm for drug selectivity by characterizing the binding of several approved drugs to the Ser/Thr-kinase ...


Cip2a Facilitates The G1/S Cell Cycle Transition Via B-Myb In Human Papillomavirus 16 Oncoprotein E6-Expressing Cells, Yonghao Tian, Hanxiang Chen, Lijun Qiao, Wenhao Zhang, Jingyi Zheng, Weiming Zhao, Jason J. Chen, Weifang Zhang Jun 2018

Cip2a Facilitates The G1/S Cell Cycle Transition Via B-Myb In Human Papillomavirus 16 Oncoprotein E6-Expressing Cells, Yonghao Tian, Hanxiang Chen, Lijun Qiao, Wenhao Zhang, Jingyi Zheng, Weiming Zhao, Jason J. Chen, Weifang Zhang

Open Access Articles

Infection with high-risk human papillomaviruses (HR-HPVs, including HPV-16, HPV-18, HPV-31) plays a central aetiologic role in the development of cervical carcinoma. The transforming properties of HR-HPVs mainly reside in viral oncoproteins E6 and E7. E6 protein degrades the tumour suppressor p53 and abrogates cell cycle checkpoints. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that is involved in the carcinogenesis of many human malignancies. Our previous data showed that CIP2A was overexpressed in cervical cancer. However, the regulation of CIP2A by HPV-16E6 remains to be elucidated. In this study, we demonstrated that HPV-16E6 significantly up-regulated CIP2A mRNA and ...


Imp3 Stabilization Of Wnt5b Mrna Facilitates Taz Activation In Breast Cancer, Sanjoy Samanta, Santosh Guru, Ameer L. Elaimy, John J. Amante, Jianhong Ou, Jun Yu, Lihua Julie Zhu, Arthur M. Mercurio May 2018

Imp3 Stabilization Of Wnt5b Mrna Facilitates Taz Activation In Breast Cancer, Sanjoy Samanta, Santosh Guru, Ameer L. Elaimy, John J. Amante, Jianhong Ou, Jun Yu, Lihua Julie Zhu, Arthur M. Mercurio

Open Access Articles

Insulin-like growth factor-2 mRNA-binding protein 3 (IMP3) is an oncofetal protein associated with many aggressive cancers and implicated in the function of breast cancer stem cells (CSCs). The mechanisms involved, however, are poorly understood. We observed that IMP3 facilitates the activation of TAZ, a transcriptional co-activator of Hippo signaling that is necessary for the function of breast CSCs. The mechanism by which IMP3 activates TAZ involves both mRNA stability and transcriptional regulation. IMP3 stabilizes the mRNA of an alternative WNT ligand (WNT5B) indirectly by repressing miR145-5p, which targets WNT5B, resulting in TAZ activation by alternative WNT signaling. IMP3 also facilitates ...