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Characterization Of Cdk(5) Inhibitor, 20-223 (Aka Cp668863) For Colorectal Cancer Therapy, Caroline M. Robb, Smit Kour, Jacob I. Contreras, Ekta Agarwal, Carter J. Barger, Sandeep Rana, Yogesh Sonawane, Beth K. Neilsen, Margaret Taylor, Smitha Kizhake, Rhishikesh N. Thakare, Sanjib Chowdhury, Jing Wang, Jennifer D. Black, Michael A. Hollingsworth, Michael G. Brattain, Amarnath Natarajan 2018 University of Nebraska Medical Center

Characterization Of Cdk(5) Inhibitor, 20-223 (Aka Cp668863) For Colorectal Cancer Therapy, Caroline M. Robb, Smit Kour, Jacob I. Contreras, Ekta Agarwal, Carter J. Barger, Sandeep Rana, Yogesh Sonawane, Beth K. Neilsen, Margaret Taylor, Smitha Kizhake, Rhishikesh N. Thakare, Sanjib Chowdhury, Jing Wang, Jennifer D. Black, Michael A. Hollingsworth, Michael G. Brattain, Amarnath Natarajan

Journal Articles: Biochemistry & Molecular Biology

Colorectal cancer (CRC) remains one of the leading causes of cancer related deaths in the United States. Currently, there are limited therapeutic options for patients suffering from CRC, none of which focus on the cell signaling mechanisms controlled by the popular kinase family, cyclin dependent kinases (CDKs). Here we evaluate a Pfizer developed compound, CP668863, that inhibits cyclin-dependent kinase 5 (CDK5) in neurodegenerative disorders. CDK5 has been implicated in a number of cancers, most recently as an oncogene in colorectal cancers. Our lab synthesized and characterized CP668863 – now called 20-223. In our established colorectal cancer xenograft model, 20-223 reduced tumor ...


Wnt Secretion Proteins Modulate Rankl-Induced Expression Of Aire In Thymic Epithelial Cells, Daniel Pollack 2018 CUNY City College

Wnt Secretion Proteins Modulate Rankl-Induced Expression Of Aire In Thymic Epithelial Cells, Daniel Pollack

Master's Theses

Thymic epithelial cells (TEC) are essential for a proper adaptive immune response by regulating thymocyte development and establishing central tolerance. In the thymus, TECs differentially express Wnt proteins, which activate canonical and non-canonical Wnt signaling pathways. Wnt signaling is thought to regulate cell survival, proliferation, and development although the direct molecular mechanisms in TECs have yet to be elucidated. The inducible inhibition of canonical Wnt signaling with Dkk1 leads to a rapid loss of TEC progenitors as well as a decline in mature Aire-expressing mTECs. Therefore, we explore the role of Wnt ligands potentially responsible for stimulating and/or regulating ...


The Function Of Erbin, A Scaffold Protein, As A Tumor Suppressor In Colon Cancer, Payton D. Stevens 2018 University of Kentucky

The Function Of Erbin, A Scaffold Protein, As A Tumor Suppressor In Colon Cancer, Payton D. Stevens

Theses and Dissertations--Molecular and Cellular Biochemistry

Erbin belongs to the LAP (leucine-rich repeat and PDZ domain) family of scaffolding proteins that play important roles in orchestrating cell signaling. Here, we show that Erbin functions as a tumor suppressor in colon cancer. Analysis of Erbin expression in patient specimens reveals that Erbin is downregulated at both mRNA and protein levels in tumor tissues. Functionally, knockdown of Erbin disrupts epithelial cell polarity and increases cell proliferation in 3D culture. In addition, silencing Erbin results in an increase in the amplitude and duration of signaling through Akt and RAS/RAF pathways. Moreover, Erbin-loss induces epithelial-mesenchymal transition (EMT), which coincides ...


Coevolving Residues And The Expansion Of Substrate Permissibility In Laglidadg Homing Endonucleases, Thomas A. McMurrough 2017 The University of Western Ontario

Coevolving Residues And The Expansion Of Substrate Permissibility In Laglidadg Homing Endonucleases, Thomas A. Mcmurrough

Electronic Thesis and Dissertation Repository

Genome-editing (GE) is a form of genetic engineering that permits the deliberate manipulation of genetic material for the study of biological processes, agricultural and industrial biotechnologies, and developing targeted therapies to cure human disease. While the potential application of GE is wide-ranging, the efficacy of most strategies is dependent upon the ability to accurately introduce a double-stranded break at the genomic location where alterations are desired. LAGLIDADG homing endonucleases (LHEs) are a class of mobile genetic element that recognize and cleave 22-bp sequences of DNA. Given this high degree of specificity, LHEs are powerful GE reagents, but re-engineering their recognition ...


Three-Dimensional Context Rather Than Nls Amino Acid Sequence Determines Importin Α Subtype Specificity For Rcc1., Rajeshwer S. Sankhala, Ravi K. Lokareddy, Salma Begum, Ruth A. Pumroy, Richard E. Gillilan, Gino Cingolani 2017 Thomas Jefferson University

Three-Dimensional Context Rather Than Nls Amino Acid Sequence Determines Importin Α Subtype Specificity For Rcc1., Rajeshwer S. Sankhala, Ravi K. Lokareddy, Salma Begum, Ruth A. Pumroy, Richard E. Gillilan, Gino Cingolani

Department of Biochemistry and Molecular Biology Faculty Papers

Active nuclear import of Ran exchange factor RCC1 is mediated by importin α3. This pathway is essential to generate a gradient of RanGTP on chromatin that directs nucleocytoplasmic transport, mitotic spindle assembly and nuclear envelope formation. Here we identify the mechanisms of importin α3 selectivity for RCC1. We find this isoform binds RCC1 with one order of magnitude higher affinity than the generic importin α1, although the two isoforms share an identical NLS-binding groove. Importin α3 uses its greater conformational flexibility to wedge the RCC1 β-propeller flanking the NLS against its lateral surface, preventing steric clashes with its Armadillo-core. Removing ...


Niche Cadherins Control The Quiescence-To-Activation Transition In Muscle Stem Cells., Aviva J. Goel, Marysia-Kolbe Rieder, Hans-Henning Arnold, Glenn L. Radice, Robert S. Krauss 2017 Icahn School of Medicine at Mount Sinai

Niche Cadherins Control The Quiescence-To-Activation Transition In Muscle Stem Cells., Aviva J. Goel, Marysia-Kolbe Rieder, Hans-Henning Arnold, Glenn L. Radice, Robert S. Krauss

Department of Medicine Faculty Papers

Many adult stem cells display prolonged quiescence, promoted by cues from their niche. Upon tissue damage, a coordinated transition to the activated state is required because non-physiological breaks in quiescence often lead to stem cell depletion and impaired regeneration. Here, we identify cadherin-mediated adhesion and signaling between muscle stem cells (satellite cells [SCs]) and their myofiber niche as a mechanism that orchestrates the quiescence-to-activation transition. Conditional removal of N-cadherin and M-cadherin in mice leads to a break in SC quiescence, with long-term expansion of a regeneration-proficient SC pool. These SCs have an incomplete disruption of the myofiber-SC adhesive junction and ...


Xenobiotic-Induced Activation Of Human Aryl Hydrocarbon Receptor Target Genes In Drosophila Is Mediated By The Epigenetic Chromatin Modifiers, Angelina A. Akishina, J. E. Vorontsova, Roman O. Cherezov, Ilja B. Mertsalov, Olga G. Zatsepina, Mikhail S. Slezinger, Vladislav M. Panin, Svetlana Petruk, Grigori N. Enikolopov, Alexander M. Mazo, Olga B. Simonova, Boris A. Kuzin 2017 Russian Academy of Sciences

Xenobiotic-Induced Activation Of Human Aryl Hydrocarbon Receptor Target Genes In Drosophila Is Mediated By The Epigenetic Chromatin Modifiers, Angelina A. Akishina, J. E. Vorontsova, Roman O. Cherezov, Ilja B. Mertsalov, Olga G. Zatsepina, Mikhail S. Slezinger, Vladislav M. Panin, Svetlana Petruk, Grigori N. Enikolopov, Alexander M. Mazo, Olga B. Simonova, Boris A. Kuzin

Department of Biochemistry and Molecular Biology Faculty Papers

Aryl hydrocarbon receptor (AHR) is the key transcription factor that controls animal development and various adaptive processes. The AHR's target genes are involved in biodegradation of endogenous and exogenous toxins, regulation of immune response, organogenesis, and neurogenesis. Ligand binding is important for the activation of the AHR signaling pathway. Invertebrate AHR homologs are activated by endogenous ligands whereas vertebrate AHR can be activated by both endogenous and exogenous ligands (xenobiotics). Several studies using mammalian cultured cells have demonstrated that transcription of the AHR target genes can be activated by exogenous AHR ligands, but little is known about the effects ...


Additional Sex Combs Interacts With Enhancer Of Zeste And Trithorax And Modulates Levels Of Trimethylation On Histone H3k4 And H3k27 During Transcription Of Hsp70., Taosui Li, Jacob W Hodgson, Svetlana Petruk, Alexander Mazo, Hugh W Brock 2017 University of British Columbia

Additional Sex Combs Interacts With Enhancer Of Zeste And Trithorax And Modulates Levels Of Trimethylation On Histone H3k4 And H3k27 During Transcription Of Hsp70., Taosui Li, Jacob W Hodgson, Svetlana Petruk, Alexander Mazo, Hugh W Brock

Department of Biochemistry and Molecular Biology Faculty Papers

BACKGROUND: Maintenance of cell fate determination requires the Polycomb group for repression; the trithorax group for gene activation; and the enhancer of trithorax and Polycomb (ETP) group for both repression and activation. Additional sex combs (Asx) is a genetically identified ETP for the Hox loci, but the molecular basis of its dual function is unclear.

RESULTS: We show that in vitro, Asx binds directly to the SET domains of the histone methyltransferases (HMT) enhancer of zeste [E(z)] (H3K27me3) and Trx (H3K4me3) through a bipartite interaction site separated by 846 amino acid residues. In Drosophila S2 cell nuclei, Asx interacts ...


Redox Control And Mechanism Of Spx-Activated Transcription In Bacillus Subtilis, Cierra Birch 2017 Oregon Health & Science University

Redox Control And Mechanism Of Spx-Activated Transcription In Bacillus Subtilis, Cierra Birch

Scholar Archive

No abstract provided.


Finding Human Proteins That Bind To A Lassa Virus Protein, Maria Alejandra Pardo Ruge, Veronica J. Heintz, Douglas J. LaCount 2017 University of Los Andes, Colombia

Finding Human Proteins That Bind To A Lassa Virus Protein, Maria Alejandra Pardo Ruge, Veronica J. Heintz, Douglas J. Lacount

The Summer Undergraduate Research Fellowship (SURF) Symposium

Viral hemorrhagic fevers are severe illnesses caused by many different viruses. Lassa Virus is one of these important pathogens in Western Africa, causing hemorrhagic fever and eventually death without early medical treatment. There is no vaccine and there is little information on host-pathogen interactions. Therefore, the interaction between viral proteins and host targets is useful to understand Lassa virus’s lifecycle and pathology, and to develop ways to prevent infection. In this project, we study the nucleoprotein of Lassa virus (NP), which has been reported to have anti-interferon (IFN) activity through elimination of double stranded RNA (dsRNA). These features could ...


Ubqln1 : A Multi-Domain Protein With Multiple Functions., Zimple Kurlawala 2017 University of Louisville

Ubqln1 : A Multi-Domain Protein With Multiple Functions., Zimple Kurlawala

Electronic Theses and Dissertations

There are 5 Ubiquilin proteins (UBQLN1-4, UBQLN-L), which are evolutionarily conserved and structurally similar. UBQLN proteins have 3 functional domains: N-terminal ubiquitin-like domain (UBL), C-terminal ubiquitin-associated domain (UBA) and STI chaperone-like regions in the middle. Alterations in UBQLN1 gene have been detected in a variety of disorders including Alzheimer’s disease, Amyotropic Lateral Sclerosis and lung cancer. UBQLN1 has been largely studied in neurodegenerative disorders in the context of protein quality control. Several studies have hypothesized that the UBA domain of UBQLN1 binds to poly-ubiquitin chains of substrate and shuttles it to the proteasome via its UBL domain for degradation ...


Impact Of Somatic Pi3k Pathway And Erbb Family Mutations On Pathological Complete Response (Pcr) In Her2-Positive Breast Cancer Patients Who Received Neoadjuvant Her2-Targeted Therapies., Sinead Toomey, Alex J. Eustace, Joanna Fay, Katherine M. Sheehan, Aoife Carr, Malgorzata Milewska, Stephen F. Madden, Ausra Teiserskiene, Elaine W. Kay, Norma O'Donovan, William Gallagher, Liam Grogan, Oscar Breathnach, Janice Walshe, Catherine Kelly, Brian Moulton, M John Kennedy, Guiseppe Gullo, Arnold DK Hill, Colm Power, Deirdre Duke, Niamh Hambly, John Crown, Bryan T. Hennessy 2017 Royal College of Surgeons in Ireland

Impact Of Somatic Pi3k Pathway And Erbb Family Mutations On Pathological Complete Response (Pcr) In Her2-Positive Breast Cancer Patients Who Received Neoadjuvant Her2-Targeted Therapies., Sinead Toomey, Alex J. Eustace, Joanna Fay, Katherine M. Sheehan, Aoife Carr, Malgorzata Milewska, Stephen F. Madden, Ausra Teiserskiene, Elaine W. Kay, Norma O'Donovan, William Gallagher, Liam Grogan, Oscar Breathnach, Janice Walshe, Catherine Kelly, Brian Moulton, M John Kennedy, Guiseppe Gullo, Arnold Dk Hill, Colm Power, Deirdre Duke, Niamh Hambly, John Crown, Bryan T. Hennessy

Molecular Medicine Articles

BACKGROUND: The Cancer Genome Atlas analysis revealed that somatic EGFR, receptor tyrosine-protein kinase erbB-2 (ERBB2), Erb-B2 receptor tyrosine kinase 3 (ERBB3) and Erb-B2 receptor tyrosine kinase 4 (ERBB4) gene mutations (ERBB family mutations) occur alone or co-occur with somatic mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) in 19% of human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Because ERBB family mutations can activate the PI3K/AKT pathway and likely have similar canonical signalling effects to PI3K pathway mutations, we investigated their combined impact on response to neoadjuvant HER2-targeted therapies.

METHODS: Baseline tumour biopsies ...


The 11s Proteasomal Activator Regγ Impacts Polyglutamine-Expanded Androgen Receptor Aggregation And Motor Neuron Viability Through Distinct Mechanisms., Jill M. Yersak, Heather L. Montie, Erica S. Chevalier-Larsen, Yuhong Liu, Lan Huang, Martin Rechsteiner, Diane E. Merry 2017 Thomas Jefferson University

The 11s Proteasomal Activator Regγ Impacts Polyglutamine-Expanded Androgen Receptor Aggregation And Motor Neuron Viability Through Distinct Mechanisms., Jill M. Yersak, Heather L. Montie, Erica S. Chevalier-Larsen, Yuhong Liu, Lan Huang, Martin Rechsteiner, Diane E. Merry

Department of Biochemistry and Molecular Biology Faculty Papers

Spinal and bulbar muscular atrophy (SBMA) is caused by expression of a polyglutamine (polyQ)-expanded androgen receptor (AR). The inefficient nuclear proteasomal degradation of the mutant AR results in the formation of nuclear inclusions containing amino-terminal fragments of the mutant AR. PA28γ (also referred to as REGγ) is a nuclear 11S-proteasomal activator with limited proteasome activation capabilities compared to its cytoplasmic 11S (PA28α, PA28β) counterparts. To clarify the role of REGγ in polyQ-expanded AR metabolism, we carried out genetic and biochemical studies in cell models of SBMA. Overexpression of REGγ in a PC12 cell model of SBMA increased polyQ-expanded AR ...


Structure Activity Relationship Studies Of Novel Diarylpentanoid Analogs Targeting The Androgen Receptor In Prostate Cancer Cells, Haili Coffin, Marco Bisoffi 2017 Chapman University

Structure Activity Relationship Studies Of Novel Diarylpentanoid Analogs Targeting The Androgen Receptor In Prostate Cancer Cells, Haili Coffin, Marco Bisoffi

Student Research Day Abstracts and Posters

The development of prostate cancer (PCa) relies strongly on the activation of the androgen receptor (AR) signaling pathway by its natural ligand dihydrotestosterone. Furthermore, PCa progression to metastatic disease represents oncogene addiction to AR activity. Androgen ablation therapy is thus a mainstay therapy against this disease, but the development of ligand-independent AR activation and persisting AR expression eventually leads to castration resistant PCa (CRPC). Therefore, down-regulation of AR expression in PCa cells may be an effective therapeutic modality. The diarylpentanoid ca27 has previously been shown to down-regulate AR expression by an unknown mechanism of action. The present work represents a ...


Pediatric Leukemia: Diagnosis To Treatment–A Review, Samantha C. Bernard, Ehab H. Abdelsamad, Paisley A. Johnson, Daniel L. Chapman, Madhukiran Parvathaneni 2017 Harrisburg University of Science and Technology

Pediatric Leukemia: Diagnosis To Treatment–A Review, Samantha C. Bernard, Ehab H. Abdelsamad, Paisley A. Johnson, Daniel L. Chapman, Madhukiran Parvathaneni

Faculty Works

Leukemia is cancer of the blood and bone marrow, it is the most common cancer found in children and is found to be more than one fourth of pediatric cancers. It causes white blood cells to become abnormal and the body to become weak. This deficiency in the immune system reduces the body's ability to fight infection or simple airborne illnesses, causing extensive treatment of common pathogens and cancer treatment. The present review covers all topics, from diagnosis to treatment of pediatric leukemia, as well as the stages of growth and physiological changes throughout the process. As leukemia has ...


Effect Of Obesity And Exercise On The Expression Of The Novel Myokines, Myonectin And Fibronectin Type Iii Domain Containing 5, Jonathan M. Peterson, Ryan Mart, Cherie E. Bond 2017 East Tennessee State University

Effect Of Obesity And Exercise On The Expression Of The Novel Myokines, Myonectin And Fibronectin Type Iii Domain Containing 5, Jonathan M. Peterson, Ryan Mart, Cherie E. Bond

Jonathan Peterson

Metabolic dysfunction in skeletal muscle is a major contributor to the development of type 2 diabetes. Endurance exercise training has long been established as an effective means to directly restore skeletal muscle glucose and lipid uptake and metabolism. However, in addition to the direct effects of skeletal muscle on glucose and lipids, there is renewed interest in the ability of skeletal muscle to coordinate metabolic activity of other tissues, such as adipose tissue and liver. The purpose of this study was to examine the effects of endurance exercise on the expression level of two novel muscle-derived secreted factors, or myokines ...


Role Of Dendritic Cells In Pathology Of Respiratory Syncytial Virus Infection In Neonates, Bishwas Shrestha 2017 University of Tennessee Health Science Center

Role Of Dendritic Cells In Pathology Of Respiratory Syncytial Virus Infection In Neonates, Bishwas Shrestha

Theses and Dissertations (ETD)

Respiratory syncytial virus (RSV) is one of the leading causes of bronchiolitis in children. We have shown that neonatal mice respond to primary RSV infection with T helper type 2 (Th2) biased immune responses, which are enhanced following reinfection. Dendritic cells (DCs) including myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) play important roles in driving host responses to RSV infection. mDCs present antigens to help Th cells differentiate, and pDCs protect against viral infection through type I interferons (IFNs). Despite data demonstrating importance of mDCs and pDCs in protection against RSV, it has not been studied in an age appropriate ...


Foxo3 Increases Mir-34a To Cause Palmitate-Induced Cholangiocyte Lipoapoptosis., Sathish Kumar Natarajan, Bailey A. Stringham, Ashley M. Mohr, Cody J. Wehrkamp, Sizhao Lu, Mary A. Smith, Dee Harrison-Findik, Justin L. Mott 2017 University of Nebraska Medical Center

Foxo3 Increases Mir-34a To Cause Palmitate-Induced Cholangiocyte Lipoapoptosis., Sathish Kumar Natarajan, Bailey A. Stringham, Ashley M. Mohr, Cody J. Wehrkamp, Sizhao Lu, Mary A. Smith, Dee Harrison-Findik, Justin L. Mott

Journal Articles: Biochemistry & Molecular Biology

Nonalcoholic steatohepatitis (NASH) patients have elevated plasma saturated free fatty acid levels. These toxic fatty acids can induce liver cell death and our recent results demonstrated that the biliary epithelium may be susceptible to lipotoxicity. Here, we explored the molecular mechanisms of cholangiocyte lipoapoptosis in cell culture and in an animal model of NASH. Treatment of cholangiocytes with palmitate (PA) showed increased caspase 3/7 activity and increased levels of cleaved poly (ADP-ribose) polymerase and cleaved caspase 3, demonstrating cholangiocyte lipoapoptosis. Interestingly, treatment with PA significantly increased the levels of microRNA miR-34a, a pro-apoptotic microRNA known to be elevated in ...


Kinetic Studies Of Dna Repair Enzyme Alkbh2, Michael R. Vittori 2017 University of Rhode Island

Kinetic Studies Of Dna Repair Enzyme Alkbh2, Michael R. Vittori

Senior Honors Projects

The genomes of living organisms are under constant bombardment from various sources, including chemical modification stemming from processes within the organisms themselves or from exogenous agents, and from radiation. These sources of genomic damage may induce structural changes in the genome’s most basic functional units, the nucleotides that comprise DNA. Damage to an organism’s DNA may result in the production of dysfunctional or nonfunctional proteins. Failure to repair such damage may result in the compounding of successive mutations within the organism’s genome, the pathogenesis of cancer and various genetic disorders in humans. To ensure their viability, organisms ...


Chemical And Structural Characterization Of A Model Post-Termination Complex (Potc) For The Ribosome Recycling Reaction: Evidence For The Release Of The Mrna By Rrf And Ef-G., Nobuhiro Iwakura, Takeshi Yokoyama, Fabio Quaglia, Kaoru Mitsuoka, Kazuhiro Mio, Hideki Shigematsu, Mikako Shirouzu, Akira Kaji, Hideko Kaji 2017 Thomas Jefferson University

Chemical And Structural Characterization Of A Model Post-Termination Complex (Potc) For The Ribosome Recycling Reaction: Evidence For The Release Of The Mrna By Rrf And Ef-G., Nobuhiro Iwakura, Takeshi Yokoyama, Fabio Quaglia, Kaoru Mitsuoka, Kazuhiro Mio, Hideki Shigematsu, Mikako Shirouzu, Akira Kaji, Hideko Kaji

Department of Biochemistry and Molecular Biology Faculty Papers

A model Post-Termination Complex (PoTC) used for the discovery of Ribosome Recycling Factor (RRF) was purified and characterized by cryo-electron microscopic analysis and biochemical methods. We established that the model PoTC has mostly one tRNA, at the P/E or P/P position, together with one mRNA. The structural studies were supported by the biochemical measurement of bound tRNA and mRNA. Using this substrate, we establish that the release of tRNA, release of mRNA and splitting of ribosomal subunits occur during the recycling reaction. Order of these events is tRNA release first followed by mRNA release and splitting almost simultaneously ...


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