Medicine and Health Sciences Commons^™

C-Terminal Binding Protein 2 Is A Novel Tumor Suppressor Targeting The Myc-Irf4 Axis In Multiple Myeloma, Coty Hing Yau Cheung, Chi Keung Cheng, Kam Tong Leung, Chi Zhang, Chi Yan Ho, Xi Luo, Angel Yuet Fong Kam, Tian Xia, Thomas Shek Kong Wan, Herbert Augustus Pitts, Natalie Pui Ha Chan, Joyce Sin Cheung, Raymond Siu Ming Wong, Xiao-Bing Zhang, Margaret Heung Ling Ng

Journal Articles

Multiple myeloma (MM) cells are addicted to MYC and its direct transactivation targets IRF4 for proliferation and survival. MYC and IRF4 are still considered "undruggable," as most small-molecule inhibitors suffer from low potency, suboptimal pharmacokinetic properties, and undesirable off-target effects. Indirect inhibition of MYC/IRF4 emerges as a therapeutic vulnerability in MM. Here, we uncovered an unappreciated tumor-suppressive role of C-terminal binding protein 2 (CTBP2) in MM via strong inhibition of the MYC-IRF4 axis. In contrast to epithelial cancers, CTBP2 is frequently downregulated in MM, in association with shortened survival, hyperproliferative features, and adverse clinical outcomes. Restoration of CTBP2 exhibited potent …

Stabilization Of Interdomain Interactions In G Protein Α Subunits As A Determinant Of Gαi Subtype Signaling Specificity, Tyler J Lefevre, Wenyuan Wei, Elizaveta Mukhaleva, Sai Pranathi Meda Venkata, Naincy R Chandan, Saji Abraham, Yong Li, Carmen W Dessauer, Nagarajan Vaidehi, Alan V Smrcka

Journal Articles

Highly homologous members of the Gαi family, Gαi1-3, have distinct tissue distributions and physiological functions, yet their biochemical and functional properties are very similar. We recently identified PDZ-RhoGEF (PRG) as a novel Gαi1 effector that is poorly activated by Gαi2. In a proteomic proximity labeling screen we observed a strong preference for Gαi1 relative to Gαi2 with respect to engagement of a broad range of potential targets. We investigated the mechanistic basis for this selectivity using PRG as a representative target. Substitution of either the helical domain (HD) from Gαi1 into Gαi2 or substitution of a single amino acid, A230 …

Loss Of Tumor Suppressor Tmem127 Drives Ret-Mediated Transformation Through Disrupted Membrane Dynamics, Timothy J Walker, Eduardo Reyes-Alvarez, Brandy D Hyndman, Michael G Sugiyama, Larissa C B Oliveira, Aisha N Rekab, Mathieu J F Crupi, Rebecca Cabral-Dias, Qianjin Guo, Patricia L M Dahia, Douglas S Richardson, Costin N Antonescu, Lois M Mulligan

Journal Articles

Internalization from the cell membrane and endosomal trafficking of receptor tyrosine kinases (RTKs) are important regulators of signaling in normal cells that can frequently be disrupted in cancer. The adrenal tumor pheochromocytoma (PCC) can be caused by activating mutations of the rearranged during transfection (RET) receptor tyrosine kinase, or inactivation of TMEM127, a transmembrane tumor suppressor implicated in trafficking of endosomal cargos. However, the role of aberrant receptor trafficking in PCC is not well understood. Here, we show that loss of TMEM127 causes wildtype RET protein accumulation on the cell surface, where increased receptor density facilitates constitutive ligand-independent activity and …

Rcc2 Promotes Prostate Cancer Cell Proliferation And Migration Through Hh/Gli1 Signaling Pathway And Cancer Stem-Like Cells, Shenghan Wang, Zhentao Lei, Wei Liu, Jie Xiong, Yuqiang Shi, Lin Yang, Qiang Gao, Kai Le, Bao Zhang

Journal Articles

BACKGROUND: Regulator of chromosome condensation 2 (RCC2) was a telophase disk-binding protein on mitosis, and functions as an oncogene in many human cancers. However, its role on prostate cancer (PCa) was unknown. The goal of this study is to explore the function of RCC 2 on PCa development.

METHODS: The expression of RCC2 and its methylation level, its correlation with lymph node metastasis or disease-free survival (DFS) was analyzed using TCGA database. The effect of RCC2 on PCa cell proliferation, migration and invasion were detected using CCK-8, cell colony formation, Transwell and wood healing assays. RNA-seq and GSEA analysis were …

Increased Igfbp2 Levels By Placenta-Derived Mesenchymal Stem Cells Enhance Glucose Metabolism In A Taa-Injured Rat Model Via Ampk Signaling Pathway, Dae-Hyun Lee, Hyeri Park, Jun-Hyeong You, Jin Seok, Dong-Wook Kwon, Young-Ran Kim, Gi-Jin Kim

Journal Articles

The insulin resistance caused by impaired glucose metabolism induces ovarian dysfunction due to the central importance of glucose as a source of energy. However, the research on glucose metabolism in the ovaries is still lacking. The objectives of this study were to analyze the effect of PD-MSCs on glucose metabolism through IGFBP2-AMPK signaling and to investigate the correlation between glucose metabolism and ovarian function. Thioacetamide (TAA) was used to construct a rat injury model. PD-MSCs were transplanted into the tail vein (2 × 10

Direct Modulators Of K-Ras-Membrane Interactions, Johannes Morstein, Rebika Shrestha, Que N Van, César A López, Neha Arora, Marco Tonelli, Hong Liang, De Chen, Yong Zhou, John F Hancock, Andrew G Stephen, Thomas J Turbyville, Kevan M Shokat

Journal Articles

Protein-membrane interactions (PMIs) are ubiquitous in cellular signaling. Initial steps of signal transduction cascades often rely on transient and dynamic interactions with the inner plasma membrane leaflet to populate and regulate signaling hotspots. Methods to target and modulate these interactions could yield attractive tool compounds and drug candidates. Here, we demonstrate that the conjugation of a medium-chain lipid tail to the covalent K-Ras(G12C) binder MRTX849 at a solvent-exposed site enables such direct modulation of PMIs. The conjugated lipid tail interacts with the tethered membrane and changes the relative membrane orientation and conformation of K-Ras(G12C), as shown by molecular dynamics (MD) …

The Gpcr-Gαs-Pka Signaling Axis Promotes T Cell Dysfunction And Cancer Immunotherapy Failure, Victoria H Wu, Bryan S Yung, Farhoud Faraji, Robert Saddawi-Konefka, Zhiyong Wang, Alexander T Wenzel, Miranda J Song, Meghana S Pagadala, Lauren M Clubb, Joshua Chiou, Sanju Sinha, Marin Matic, Francesco Raimondi, Thomas S Hoang, Rebecca Berdeaux, Dario A A Vignali, Ramiro Iglesias-Bartolome, Hannah Carter, Eytan Ruppin, Jill P Mesirov, J Silvio Gutkind

Journal Articles

Immune checkpoint blockade (ICB) targeting PD-1 and CTLA-4 has revolutionized cancer treatment. However, many cancers do not respond to ICB, prompting the search for additional strategies to achieve durable responses. G-protein-coupled receptors (GPCRs) are the most intensively studied drug targets but are underexplored in immuno-oncology. Here, we cross-integrated large singe-cell RNA-sequencing datasets from CD8+ T cells covering 19 distinct cancer types and identified an enrichment of Gαs-coupled GPCRs on exhausted CD8+ T cells. These include EP2, EP4, A2AR, β1AR and β2AR, all of which promote T cell dysfunction. We also developed transgenic mice expressing a chemogenetic CD8-restricted Gαs–DREADD to activate …

Adenosine Metabolized From Extracellular Atp Ameliorates Organ Injury By Triggering A2br Signaling, Taha Kelestemur, Zoltán H Németh, Pal Pacher, Jennet Beesley, Simon C Robson, Holger K Eltzschig, György Haskó

Journal Articles

BACKGROUND: Trauma and a subsequent hemorrhagic shock (T/HS) result in insufficient oxygen delivery to tissues and multiple organ failure. Extracellular adenosine, which is a product of the extracellular degradation of adenosine 5' triphosphate (ATP) by the membrane-embedded enzymes CD39 and CD73, is organ protective, as it participates in signaling pathways, which promote cell survival and suppress inflammation through adenosine receptors including the A

METHODS: T/HS shock was induced by blood withdrawal from the femoral artery in wild-type, global knockout (CD39, CD73, A

RESULTS: T/HS upregulated the expression of CD39, CD73, and the A

CONCLUSION: In conclusion, the CD39-CD73-A

Lipid Nanoparticle-Mediated Mrna Delivery In Lung Fibrosis, Matteo Massaro, Suhong Wu, Gherardo Baudo, Haoran Liu, Scott Collum, Hyunho Lee, Cinzia Stigliano, Victor Segura-Ibarra, Harry Karmouty-Quintana, Elvin Blanco

Journal Articles

mRNA delivery enables the specific synthesis of proteins with therapeutic potential, representing a powerful strategy in diseases lacking efficacious pharmacotherapies. Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by excessive extracellular matrix (ECM) deposition and subsequent alveolar remodeling. Alveolar epithelial type 2 cells (AEC2) and fibroblasts represent important targets in IPF given their role in initiating and driving aberrant wound healing responses that lead to excessive ECM deposition. Our objective was to examine a lipid nanoparticle (LNP)-based mRNA construct as a viable strategy to target alveolar epithelial cells and fibroblasts in IPF. mRNA-containing LNPs measuring ∼34 nm had …

Ras Nanoclusters Are Cell Surface Transducs That Convert Extracellular Stimuli To Intracellular Signalling, Yong Zhou, John F Hancock

Journal Articles

Mutations of rat sarcoma virus (RAS) oncogenes (HRAS, KRAS and NRAS) can contribute to the development of cancers and genetic disorders (RASopathies). The spatiotemporal organization of RAS is an important property that warrants further investigation. In order to function, wild-type or oncogenic mutants of RAS must be localized to the inner leaflet of the plasma membrane (PM), which is driven by interactions between their C-terminal membrane-anchoring domains and PM lipids. The isoform-specific RAS-lipid interactions promote the formation of nanoclusters on the PM. As main sites for effector recruitment, these nanoclusters are biologically important. Since the spatial distribution of lipids is …

Glycolysis Regulates Kras Plasma Membrane Localization And Function Through Defined Glycosphingolipids, Junchen Liu, Ransome Van Der Hoeven, Walaa E Kattan, Jeffrey T Chang, Dina Montufar-Solis, Wei Chen, Maurice Wong, Yong Zhou, Carlito B Lebrilla, John F Hancock

Journal Articles

Oncogenic KRAS expression generates a metabolic dependency on aerobic glycolysis, known as the Warburg effect. We report an effect of increased glycolytic flux that feeds into glycosphingolipid biosynthesis and is directly linked to KRAS oncogenic function. High resolution imaging and genetic approaches show that a defined subset of outer leaflet glycosphingolipids, including GM3 and SM4, is required to maintain KRAS plasma membrane localization, with GM3 engaging in cross-bilayer coupling to maintain inner leaflet phosphatidylserine content. Thus, glycolysis is critical for KRAS plasma membrane localization and nanoscale spatial organization. Reciprocally oncogenic KRAS selectively upregulates cellular content of these same glycosphingolipids, whose …

Anti-Diabetic Effects Of Glp1 Analogs Are Mediated By Thermogenic Interleukin-6 Signaling In Adipocytes, Absalon D Gutierrez, Zhanguo Gao, Vala Hamidi, Liang Zhu, Karla Bermudez Saint Andre, Kayla Riggs, Monika Ruscheinsky, Hongyu Wang, Yongmei Yu, Charles Miller, Hernan Vasquez, Heinrich Taegtmeyer, Mikhail G Kolonin

Journal Articles

Mechanisms underlying anti-diabetic effects of GLP1 analogs remain incompletely understood. We observed that in prediabetic humans exenatide treatment acutely induces interleukin-6 (IL-6) secretion by monocytes and IL-6 in systemic circulation. We hypothesized that GLP1 analogs signal through IL-6 in adipose tissue (AT) and used the mouse model to test if IL-6 receptor (IL-6R) signaling underlies the effects of the GLP1-IL-6 axis. We show that liraglutide transiently increases IL-6 in mouse circulation and IL-6R signaling in AT. Metronomic liraglutide treatment resulted in AT browning and thermogenesis linked with STAT3 activation. IL-6-blocking antibody treatment inhibited STAT3 activation in AT and suppressed liraglutide-induced …

Anti-Diabetic Effects Of Glp1 Analogs Are Mediated By Thermogenic Interleukin-6 Signaling In Adipocytes, Absalon D Gutierrez, Zhanguo Gao, Vala Hamidi, Liang Zhu, Karla Bermudez Saint Andre, Kayla Riggs, Monika Ruscheinsky, Hongyu Wang, Yongmei Yu, Charles Miller, Hernan Vasquez, Heinrich Taegtmeyer, Mikhail G Kolonin

Journal Articles

Mechanisms underlying anti-diabetic effects of GLP1 analogs remain incompletely understood. We observed that in prediabetic humans exenatide treatment acutely induces interleukin-6 (IL-6) secretion by monocytes and IL-6 in systemic circulation. We hypothesized that GLP1 analogs signal through IL-6 in adipose tissue (AT) and used the mouse model to test if IL-6 receptor (IL-6R) signaling underlies the effects of the GLP1-IL-6 axis. We show that liraglutide transiently increases IL-6 in mouse circulation and IL-6R signaling in AT. Metronomic liraglutide treatment resulted in AT browning and thermogenesis linked with STAT3 activation. IL-6-blocking antibody treatment inhibited STAT3 activation in AT and suppressed liraglutide-induced …

The Emerging Role Of Notch3 Receptor Signalling In Human Lung Diseases, Manish Bodas, Bharathiraja Subramaniyan, Harry Karmouty-Quintana, Peter F Vitiello, Matthew S Walters

Journal Articles

The mammalian respiratory system or lung is a tree-like branching structure, and the main site of gas exchange with the external environment. Structurally, the lung is broadly classified into the proximal (or conducting) airways and the distal alveolar region, where the gas exchange occurs. In parallel with the respiratory tree, the pulmonary vasculature starts with large pulmonary arteries that subdivide rapidly ending in capillaries adjacent to alveolar structures to enable gas exchange. The NOTCH signalling pathway plays an important role in lung development, differentiation and regeneration post-injury. Signalling via the NOTCH pathway is mediated through activation of four NOTCH receptors …

Targeted Therapeutics And Novel Signaling Pathways In Non-Alcohol-Associated Fatty Liver/Steatohepatitis (Nafl/Nash), Xiaohan Xu, Kyle L Poulsen, Lijuan Wu, Shan Liu, Tatsunori Miyata, Qiaoling Song, Qingda Wei, Chenyang Zhao, Chunhua Lin, Jinbo Yang

Journal Articles

Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form of NAFL, can be progressive and more susceptible to developing cirrhosis and hepatocellular carcinoma. Currently, lifestyle interventions are the most essential and effective strategies for preventing and controlling NAFL without the development of fibrosis. While there are still limited appropriate drugs specifically to treat NAFL/NASH, growing progress is being seen in elucidating the pathogenesis and identifying therapeutic targets. In this review, we discussed recent developments in etiology and prospective therapeutic targets, as well as pharmacological candidates in pre/clinical trials and patents, with a …

Whole-Genome Association Analyses Of Sleep-Disordered Breathing Phenotypes In The Nhlbi Topmed Program, Brian E Cade, Jiwon Lee, Tamar Sofer, Heming Wang, Man Zhang, Han Chen, Sina A Gharib, Daniel J Gottlieb, Xiuqing Guo, Jacqueline M Lane, Jingjing Liang, Xihong Lin, Hao Mei, Sanjay R Patel, Shaun M Purcell, Richa Saxena, Neomi A Shah, Daniel S Evans, Craig L Hanis, David R Hillman, Sutapa Mukherjee, Lyle J Palmer, Katie L Stone, Gregory J Tranah, Gonçalo R Abecasis, Eric A Boerwinkle, Adolfo Correa, L Adrienne Cupples, Robert C Kaplan, Deborah A Nickerson, Kari E North, Bruce M Psaty, Jerome I Rotter, Stephen S Rich, Russell P Tracy, Ramachandran S Vasan, James G Wilson, Xiaofeng Zhu, Susan Redline

Journal Articles

BACKGROUND: Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing.

METHODS: The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation < 90%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap.

RESULTS: We identified a …

Crosstalk Between Beta-Adrenergic And Insulin Signaling Mediates Mechanistic Target Of Rapamycin Hyperactivation In Liver Of High-Fat Diet-Fed Male Mice, Sadia Ashraf, Nadia Ashraf, Gizem Yilmaz, Romain Harmancey

Journal Articles

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. While increased nutrient intake and sympathetic activity have been associated with the disease, the pathogenesis of NAFLD remains incompletely understood. We investigated the impact of the interaction of high dietary fat and sugar intake with increased beta-adrenergic receptor (β-AR) signaling on the activity of nutrient-sensing pathways and fuel storage in the liver. C57BL/6J mice were fed a standard rodent diet (STD), a high-fat diet (HFD), a high-fat/high-sugar Western diet (WD), a high-sugar diet with mixed carbohydrates (HCD), or a high-sucrose diet (HSD). After 6 week on …

Crosstalk Between Beta-Adrenergic And Insulin Signaling Mediates Mechanistic Target Of Rapamycin Hyperactivation In Liver Of High-Fat Diet-Fed Male Mice, Sadia Ashraf, Nadia Ashraf, Gizem Yilmaz, Romain Harmancey

Journal Articles

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. While increased nutrient intake and sympathetic activity have been associated with the disease, the pathogenesis of NAFLD remains incompletely understood. We investigated the impact of the interaction of high dietary fat and sugar intake with increased beta-adrenergic receptor (β-AR) signaling on the activity of nutrient-sensing pathways and fuel storage in the liver. C57BL/6J mice were fed a standard rodent diet (STD), a high-fat diet (HFD), a high-fat/high-sugar Western diet (WD), a high-sugar diet with mixed carbohydrates (HCD), or a high-sucrose diet (HSD). After 6 week on …

Oral Versus Gastrointestinal Mucosal Immune Niches In Homeostasis And Allostasis, Lina J Suárez, Silie Arboleda, Nikola Angelov, Roger M Arce

Journal Articles

Different body systems (epidermis, respiratory tract, cornea, oral cavity, and gastrointestinal tract) are in continuous direct contact with innocuous and/or potentially harmful external agents, exhibiting dynamic and highly selective interaction throughout the epithelia, which function as both a physical and chemical protective barrier. Resident immune cells in the epithelia are constantly challenged and must distinguish among antigens that must be either tolerated or those to which a response must be mounted for. When such a decision begins to take place in lymphoid foci and/or mucosa-associated lymphoid tissues, the epithelia network of immune surveillance actively dominates both oral and gastrointestinal compartments, …

Hypoxia-Inducible Factor-2Α Reprograms Liver Macrophages To Protect Against Acute Liver Injury Through The Production Of Interleukin-6, Rachel Y Gao, Meng Wang, Qihui Liu, Dechun Feng, Yankai Wen, Yang Xia, Sean P Colgan, Holger K Eltzschig, Cynthia Ju

Journal Articles

BACKGROUND AND AIMS: Acetaminophen (APAP) overdose represents the most frequent cause of acute liver failure, resulting in death or liver transplantation in more than one third of patients in the United States. The effectiveness of the only antidote, N-acetylcysteine, declines rapidly after APAP ingestion, long before patients are admitted to the clinic with symptoms of severe liver injury. The direct hepatotoxicity of APAP triggers a cascade of innate immune responses that may exacerbate or limit the progression of tissue damage. A better understanding of this complex mechanism will help uncover targets for therapeutic interventions.

APPROACH AND RESULTS: We observed that …

Transcriptional Insights Into Pathogenesis Of Cutaneous Systemic Sclerosis Using Pathway Driven Meta-Analysis Assisted By Machine Learning Methods, Xiao Xu, Meera Ramanujam, Sudha Visvanathan, Shervin Assassi, Zheng Liu, Li Li

Journal Articles

Pathophysiology of systemic sclerosis (SSc, Scleroderma), an autoimmune rheumatic disease, comprises of mechanisms that drive vasculopathy, inflammation and fibrosis. Understanding of the disease and associated clinical heterogeneity has advanced considerably in the past decade, highlighting the necessity of more specific targeted therapy. While many of the recent trials in SSc failed to meet the primary end points that predominantly relied on changes in modified Rodnan skin scores (MRSS), sub-group analysis, especially those focused on the basal skin transcriptomic data have provided insights into patient subsets that respond to therapies. These findings suggest that deeper understanding of the molecular changes in …

Adenosine At The Interphase Of Hypoxia And Inflammation In Lung Injury, Xiangyun Li, Nathanial K Berg, Tingting Mills, Kaiying Zhang, Holger K Eltzschig, Xiaoyi Yuan

Journal Articles

Hypoxia and inflammation often coincide in pathogenic conditions such as acute respiratory distress syndrome (ARDS) and chronic lung diseases, which are significant contributors to morbidity and mortality for the general population. For example, the recent global outbreak of Coronavirus disease 2019 (COVID-19) has placed viral infection-induced ARDS under the spotlight. Moreover, chronic lung disease ranks the third leading cause of death in the United States. Hypoxia signaling plays a diverse role in both acute and chronic lung inflammation, which could partially be explained by the divergent function of downstream target pathways such as adenosine signaling. Particularly, hypoxia signaling activates adenosine …

Cellular Dynamic Simulator: An Event Driven Molecular Simulation Environment For Cellular Physiology, Michael J Byrne, M Neal Waxham, Yoshihisa Kubota

Journal Articles

In this paper, we present the Cellular Dynamic Simulator (CDS) for simulating diffusion and chemical reactions within crowded molecular environments. CDS is based on a novel event driven algorithm specifically designed for precise calculation of the timing of collisions, reactions and other events for each individual molecule in the environment. Generic mesh based compartments allow the creation / importation of very simple or detailed cellular structures that exist in a 3D environment. Multiple levels of compartments and static obstacles can be used to create a dense environment to mimic cellular boundaries and the intracellular space. The CDS algorithm takes into …

Thoracic Aortic Disease In Tuberous Sclerosis Complex: Molecular Pathogenesis And Potential Therapies In Tsc2+/- Mice, Jiumei Cao, Limin Gong, Dong-Chuan Guo, Ulrike Mietzsch, Shao-Qing Kuang, Callie S Kwartler, Hazim Safi, Anthony Estrera, Michael J Gambello, Dianna M Milewicz

Journal Articles

Tuberous sclerosis complex (TSC) is a genetic disorder with pleiotropic manifestations caused by heterozygous mutations in either TSC1 or TSC2. One of the less investigated complications of TSC is the formation of aneurysms of the descending aorta, which are characterized on pathologic examination by smooth muscle cell (SMC) proliferation in the aortic media. SMCs were explanted from Tsc2(+/-) mice to investigate the pathogenesis of aortic aneurysms caused by TSC2 mutations. Tsc2(+/-) SMCs demonstrated increased phosphorylation of mammalian target of rapamycin (mTOR), S6 and p70S6K and increased proliferation rates compared with wild-type (WT) SMCs. Tsc2(+/-) SMCs also had reduced expression of …

Cardiomyocyte Pdgfr-Beta Signaling Is An Essential Component Of The Mouse Cardiac Response To Load-Induced Stress, Vishnu Chintalgattu, Di Ai, Robert R Langley, Jianhu Zhang, James A Bankson, Tiffany L Shih, Anilkumar K Reddy, Kevin R Coombes, Iyad N Daher, Shibani Pati, Shalin S Patel, Jennifer S Pocius, George E Taffet, L Maximillian Buja, Mark L Entman, Aarif Y Khakoo

Journal Articles

PDGFR is an important target for novel anticancer therapeutics because it is overexpressed in a wide variety of malignancies. Recently, however, several anticancer drugs that inhibit PDGFR signaling have been associated with clinical heart failure. Understanding this effect of PDGFR inhibitors has been difficult because the role of PDGFR signaling in the heart remains largely unexplored. As described herein, we have found that PDGFR-beta expression and activation increase dramatically in the hearts of mice exposed to load-induced cardiac stress. In mice in which Pdgfrb was knocked out in the heart in development or in adulthood, exposure to load-induced stress resulted …

Keap1 E3 Ligase-Mediated Downregulation Of Nf-Kappab Signaling By Targeting Ikkbeta., Dung-Fang Lee, Hsu-Ping Kuo, Mo Liu, Chao-Kai Chou, Weiya Xia, Yi Du, Jia Shen, Chun-Te Chen, Longfei Huo, Ming-Chuan Hsu, Chia-Wei Li, Qingqing Ding, Tsai-Lien Liao, Chien-Chen Lai, Ann-Chi Lin, Ya-Hui Chang, Shih-Feng Tsai, Long-Yuan Li, Mien-Chie Hung

Journal Articles

IkappaB kinase beta (IKKbeta) is involved in tumor development and progression through activation of the nuclear factor (NF)-kappaB pathway. However, the molecular mechanism that regulates IKKbeta degradation remains largely unknown. Here, we show that a Cullin 3 (CUL3)-based ubiquitin ligase, Kelch-like ECH-associated protein 1 (KEAP1), is responsible for IKKbeta ubiquitination. Depletion of KEAP1 led to the accumulation and stabilization of IKKbeta and to upregulation of NF-kappaB-derived tumor angiogenic factors. A systematic analysis of the CUL3, KEAP1, and RBX1 genomic loci revealed a high percentage of genome loss and missense mutations in human cancers that failed to facilitate IKKbeta degradation. Our …

Creb Mediates Prostaglandin F2alpha-Induced Muc5ac Overexpression., Wen-Cheng Chung, Seung-Hee Ryu, Hongxia Sun, Darryl C Zeldin, Ja Seok Koo

Journal Articles

Mucus secretion is an important protective mechanism for the luminal lining of open tubular organs, but mucin overproduction in the respiratory tract can exacerbate the inflammatory process and cause airway obstruction. Production of MUC5AC, a predominant gel-forming mucin secreted by airway epithelia, can be induced by various inflammatory mediators such as prostaglandins. The two major prostaglandins involved in inflammation are PGE(2) and PGF(2alpha). PGE(2)-induced mucin production has been well studied, but the effect of PGF(2alpha) on mucin production remains poorly understood. To elucidate the effect and underlying mechanism of PGF(2alpha) on MUC5AC production, we investigated the signal transduction of PGF(2alpha) …

Extended Kalman Filter For Estimation Of Parameters In Nonlinear State-Space Models Of Biochemical Networks, Xiaodian Sun, Li Jin, Momiao Xiong

Journal Articles

It is system dynamics that determines the function of cells, tissues and organisms. to develop mathematical models and estimate their parameters are an essential issue for studying dynamic behaviors of biological systems which include metabolic networks, genetic regulatory networks and signal transduction pathways, under perturbation of external stimuli. In general, biological dynamic systems are partially observed. Therefore, a natural way to model dynamic biological systems is to employ nonlinear state-space equations. Although statistical methods for parameter estimation of linear models in biological dynamic systems have been developed intensively in the recent years, the estimation of both states and parameters of …

A Schiff Base Connectivity Switch In Sensory Rhodopsin Signaling, Oleg A Sineshchekov, Jun Sasaki, Brian J Phillips, John L Spudich

Journal Articles

Sensory rhodopsin I (SRI) in Halobacterium salinarum acts as a receptor for single-quantum attractant and two-quantum repellent phototaxis, transmitting light stimuli via its bound transducer HtrI. Signal-inverting mutations in the SRI-HtrI complex reverse the single-quantum response from attractant to repellent. Fast intramolecular charge movements reported here reveal that the unphotolyzed SRI-HtrI complex exists in two conformational states, which differ by their connection of the retinylidene Schiff base in the SRI photoactive site to inner or outer half-channels. In single-quantum photochemical reactions, the conformer with the Schiff base connected to the cytoplasmic (CP) half-channel generates an attractant signal, whereas the conformer …

Killing Of Human Melanoma Cells Induced By Activation Of Class I Interferon-Regulated Signaling Pathways Via Mda-7/Il-24., Suhendan Ekmekcioglu, John B Mumm, Malini Udtha, Sunil Chada, Elizabeth A Grimm

Journal Articles

Restoration of the tumor-suppression function by gene transfer of the melanoma differentiation-associated gene 7 (MDA7)/interleukin 24 (IL-24) successfully induces apoptosis in melanoma tumors in vivo. To address the molecular mechanisms involved, we previously revealed that MDA7/IL-24 treatment of melanoma cells down-regulates interferon regulatory factor (IRF)-1 expression and concomitantly up-regulates IRF-2 expression, which competes with the activity of IRF-1 and reverses the induction of IRF-1-regulated inducible nitric oxide synthase (iNOS). Interferons (IFNs) influence melanoma cell survival by modulating apoptosis. A class I IFN (IFN-alpha) has been approved for the treatment of advanced melanoma with some limited success. A class II IFN …