Quantitative modeling and analysis of the transforming growth factor β signaling pathway
|
|
- Leonard Dean
- 6 years ago
- Views:
Transcription
1 Quantitatie modeling and analysis of the transforming growth factor β signaling pathway Seung-Wook hung, Fayth L. Miles, arlton R. ooper, Mary. Farach-arson, and Babatunde A. Ogunnaike Uniersity of Delaware, Newark, DE, USA Introduction Transforming growth factor-β (TGF-β) proteins are members of a superfamily of secreted okines that control a dierse array of cellular processes including cell proliferation, differentiation, motility, adhesion, angiogenesis, apoptosis, and immune sureillance. The TGF-β signaling cascade begins when extracellular TGF-β binds to and brings together Type I and Type II TGF-β receptor serine/threonine kinases on the cell surface, whereby the Type II receptor phosphorylates and actiates the Type I receptor. The actiated Type I receptor, in turn, propagates the signal through phosphorylation of receptor-bound (R-)Smad transcription factors (Smad2/3 and Smad/5/8). The actiated R-Smads form hetero-oligomers with Smad4 and rapidly translocate into the leus, undergoing continuous leooplasmic shuttling by interacting with the lear pore complex. Once in the leus, the actiated Smad complexes bind to specific promoters and ultimately regulate expression of target genes, generating approximately fie hundred gene responses in a cell- and context-specific manner, 2. The TGF-β signaling pathway has become an attractie but problematic target for oncology drug deelopment because of its apparently paradoxical roles in tumorigenesis and metastasis. In normal and early phase tumorigenic epithelial cells, TGF-β functions as a potent tumor suppressor primarily by inducing cell cycle arrest and apoptosis. Howeer, in the intermediate and late stages of carcinogenesis, tumor cells become resistant to the growth inhibitory effects of TGF-β and show eleated expression of TGF-β. The ligand is oerexpressed in clinical cancer samples, with increasing leels correlating with poor clinical outcomes. The role of TGF-β therefore appears to become one of tumor promotion, apparently supporting growth, suberting the immune system, and also facilitating, inasion, epithelial to mesenchymal transition (EMT), and angiogenesis. This finding has created the widely held perception that TGF-β acts as a tumor promoter in adanced tumorigenesis and metastasis 3. Although it is known that most cancer cell lines representing the entire spectrum of tumor progression hae actie TGF-β signaling pathways, detailed mechanisms of how a single stimulus, TGF-β, induces such a dierse array of responses during cancer progression are not known. This is primarily due to the complexity of the signaling cascade system in which a ariety of signaling components changing dynamically oer different time scales interact with one another. Since quantitatie understanding and analysis of such a complex regulatory circuit are not possible ia qualitatie human intuition alone, mathematical descriptions that lead to predictie models are necessary. To improe our understanding of complex TGF-β signaling quantitatiely, we hae deeloped a comprehensie, dynamic model of the canonical TGF-β pathway ia Smad transcription factors, based on the most up-to-date information aailable in the literature. Through simulation and model analysis, our model proides insight into the signal-response relationship between the binding of TGF-β to its receptor at the cell surface and the actiation of downstream effectors in the signaling cascade. In particular, we use the model to carry out
2 in-silico mutations from which we generate seeral hypotheses regarding potential mechanisms for how TGF-β s tumor-suppressie roles may appear to morph into tumorpromoting roles. Model Formulation Our model incorporates the following essential molecular processes: (i) sequential actiation of receptors induced by TGF-β; (ii) receptor internalization to endosomes and recycling; (iii) R-Smad phosphorylation by receptor complex; (i) R-Smad-Smad4 complex formation in the oplasm and leus; () leooplasmic shuttling of Smads; (i) dissociation and dephosphorylation of actiated Smads; (ii) constitutie and ligand-induced degradation of proteins; and (iii) protein synthesis. The components of the oerall TGF-β signaling pathway as featured in our model are depicted in Figure. The resulting model is a system of 7 non-linear ordinary differential equations (ODEs) with 37 kinetic parameters arising from chemical reactions represented by mass action kinetics (Table ). Figure. Schematic representation of the pathway components in the model.
3 Table. Model Equations = k a[ TGFβ [ RII k d [ TGFβ : RII = k 3 = k 3int [ R [ R : S2 5 5cat in = k2a[ TGFβ : RII[ RI k2d [ R = k R [ S2 k [ R : S a[ in 4d in = k [ ps2 [ S4 k6 [ ps2s4 6 6a d = k [ ps2s4 = k [ ps2s4 7 7imp = k [ S2S4 9 9d = k imp[ S4 kexp[ S4 3 = k3syn k3deg[ RI = k k S4 5 5syn 5deg[ = k [ ps2 7 7imp ' 9 9dp = k [ RII 2 2int k 2rec[ RII in 8 8dp 0 = k0imp[ S2 k0 exp[ S2 2 = k2syn k2 deg[ RII = k k S2 4 4syn 4deg[ = + 6 = k ( k6deg k6lid )[ R [ ps2 [ S4 k8 = k [ ps 2 = k [ ps 2 = k 23 [ R 23rec in [ ps2s4 8 8a d 20 20lid = k [ RI k [ RI 22 22int 22rec in RII R S2 TGFβ : RII = = R in = = = = ps2 RI = R in : S2 ps2s = = ps2s4 S4 S2S4 = = S4 S2 = = = 6 + = RIIin RIin = 2 = 22 ps2 + + The approach to obtain model parameter alues is summarized as follows:. Initial Rough Estimation: Seeral kinetic parameter alues were determined through an extensie literature search; some were computed using aailable in itro experimental data; we also used physical constraints to determine others. The remaining unknown parameters were proided with initial estimates and reasonable upper and lower bounds by comparison with similar circumstances in the literature (e.g. similar steps in preious models or other signaling pathway models) and from known physical limitations (e.g. the diffusion-limited rates, M - s - ).
4 2. Parametric Sensitiity Analysis: To identify which parameters are the most important and which must therefore be estimated most precisely, using the set of initial estimates determined in Step aboe, we performed local parameter sensitiity analysis to determine the effect of parametric changes on the set of fie system responses of interest for which experimental measurements are aailable (i.e. total Smad2 in the leus and the oplasm 4, total phosphorylated Smad2 in the leus and the oplasm 4, 5, and total Smad4 in the leus 4 ). The computations are based on the following expression for the normalized sensitiity coefficient (NS): p j yi ( t, p) NSij ( t) =, i =,2,..., 5; j =,..., 37 yi p j p where y and p respectiely denote the system response ariables and kinetic parameters. A total of 3 parameters were selected to be estimated more precisely because of their high sensitiity coefficients and/or because we had little or no confidence in their initial alues. 3. Least Squares Fitting to Data: We fit our model predictions simultaneously to corresponding in itro experimental data from the literature, ia local minimization of the sum of squared residual errors: * 2 min R( p) = ( yi ( t, p) yi ( t)) i 2 where y i (t,p) and y * i (t) denote, respectiely, model predictions for a gien trial of parameter alues, p, and the corresponding experimental measurements, for each measured ariable, i. The experimental data used for the cure-fitting are time courses of (i) total Smad2 in the leus 4, (ii) total Smad2 in the oplasm 4, (ii) total phosphorylated Smad2 in the leus 5, (i) total phosphorylated Smad2 in the oplasm 4, and () total Smad4 in the leus Identifiability: We performed a practical identifiability analysis to determine whether the unknown parameters of the postulated model can be uniquely estimated from the aailable data, following Birtwistle et al. 6. Briefly, approximate local confidence interals for the parameter set are gien by, N N S t p T I i = tα / 2 ( Z Z) ii N N t where N t and N p respectiely denote the number of experimental data time points and the N number of parameters to be estimated; t N t p α / 2 is the Student s t-distribution statistic ealuated with N t -N p degrees of freedom, at confidence leel 00(- α)%, (with α as the tail area probability typically set at 0.05 to yield a 95% confidence leel); S is the sum of squared errors, and Z is the model sensitiity matrix ealuated at the current parameter alues. The i th parameter is said to be practically locally identifiable only if the magnitude of its approximate confidence interal is less than a specified tolerance i.e. I < ε. 5. Identifiable Parameter Estimate Refinement: Estimated alues for identifiable parameters were further refined by repeating Step 4 (local identifiability test) followed by Step 3 (local least squares estimation). After obtaining the best estimates of this subset of parameters, we carried out a final least squares estimation of the entire parameter set. p i i
5 Results and Discussion To help understand quantitatiely which aspects of the pathway most affect the system behaior, we carried out parameter sensitiity analysis for lear psmad2-smad4 complex, which is necessary for TGF-β-induced transcriptional regulation. Figure 2 shows normalized sensitiity coefficients as a function of time for the 0 most important parameters. The most important features of this plot are summarized as follows: () Immediately after ligand stimulation, the output ariable is strongly affected by four of this set of most sensitie parameters: in order of importance, these are k 4a (binding of Smad2 to actie receptors), k 3int (internalization of receptor complexes), k 7imp (lear import of psmad2-smad4), and k 2a (complex formation of actiated TβRII and TβRI). (2) On the other hand, in the mid- to longer time interal after ligand stimulation, the following parameters become more important: in order of importance, these are k 8a (association of lear psmad2 and Smad4), and k 8d (dissociation of lear psmad2-smad4), k exp (lear export of Smad4), k 20lid (ligandinduced degradation of psmad2), k imp (lear import of Smad4), k 23rec (recycling of internalized receptor complexes), k 3int (internalization of receptor complexes), and k 4a (binding of Smad2 to actie receptors). 0.8 Normalized Sensitiity oefficient (NS) k 2a k 3int k 4a k 7imp k imp k exp k 8a k 8d k 20lid k 23rec Time (hr) Figure 2. Model parameter sensitiities for select parameters with the greatest influence on phosphorylated Smad2-Smad4 complex in the leus. These results hae biologically important consequences. In particular, the increasing nature of the sensitiity coefficients of k 8a and k 8d oer time shows that both the formation of psmad2-smad4 complex in the leus and its dissolution are crucial for lear retention of these complexes. To examine how ariations in Smad complex formation in the leus
6 affects lear accumulation of actiated Smad complexes, we aried the rate of association between lear psmad2 and Smad4 (k 8a ) 0-fold. Figure 3 shows that while rapid formation of the complex between lear psmad2 and Smad4 induces prolonged and enhanced lear accumulation of psmad2-smad4 complex, slow binding of psmad2 and Smad4 leads to shortened and attenuated retention of psmad2 complex in the leus. Thus, these results imply that the lear complex formation step plays an important role in regulating the intensity and duration of TGF-β-targeted transcriptional actiities through psmad2 complexes. More importantly, the results imply that psmad2 complex-mediated response to TGF-β stimulation may be significantly attenuated by competitie inhibition or by interference from other lear molecules that also hae high affinity for either psmad2 or Smad4. This inhibitory action ultimately gies rise to a significant reduction in the rate of association between these proteins. Taken together, these results reeal that the step of complex formation between psmad2 and Smad4 is closely associated with modulation of TGF-β-induced signal patterns..6 Relatie oncentration of ps2s ontrol Fast. association of psmad2 and Smad4 Slow. association of psmad2 and Smad Time (hr) Figure 3. The effect of ariations in the rate of lear psmad2-smad4 association To help understand how cancer cells can become resistant to the tumor-suppressor effects of TGF-β, but, at the same time, remain responsie to the tumor-promoter effects, we inestigated the effect on the TGF-β signaling system of abnormal alterations (e.g. mutations, deletions, downregulation, etc.) in receptors, using a 0-fold reduction in the initial leels and production rate of both Type I and Type II receptors to represent cancerous conditions. First, Figure 4 indicates that the amount of TGF-β needed to produce a saturated Smad-mediated response in cancer cells is far higher than that in healthy cells. Specifically, while the response for normal cells is essentially saturated with pm of TGF-β (with higher doses producing essentially the same response), at least 0 pm of TGF-β is required before the Smad-mediated response begins to approach saturation. This is, of course, a direct effect of the reduction in
7 the number of functional receptors in cancer cells which renders them less responsie to TGFβ stimulation. But this finding also indicates an important characteristic of cancerous cells: to elicit lear Smad-mediated actiity generally requires more TGF-β than normal. 0.9 Relatie oncentration of ps2s4 Nuc Normal ell ancerous ell TGF-β dose (pm) Figure 4. The effect of different concentrations of TGF-β on the maximum responses of actiated lear Smad2-Smad4 complex in normal cells (blue circles) and in cancerous cells (red triangles). Next, a head-to-head comparison of normal ersus cancerous cell responses reeals that the sharp drop in the leel of functional receptors in cancer cells leads to a marked decrease in the actiity of lear psmad complexes (Figure 5). ompared to the normal cell response, the peak actiity of lear psmad complexes in cancer cells was reduced by 65%, with the steady-state actiity also remaining comparatiely low. Interestingly, a reduction in the leel of receptors also slowed lear psmad responses. While lear psmads in the normal system reached maximum actiity in 55 min, their actiity under a cancerous condition peaked at 86 min. Taken together, these results indicate generally that a reduction in the leel of functional TGF-β receptors in cancer cells may lead to attenuated and slower TGF-βstimulated signaling responses ia Smad2. The specific implications of the model predictions in Figures 4 and 5 reeal some potentially important findings about TGF-β and cancer cells: (i) cancer cells require higher than normal leels of TGF-β in order to elicit significantly attenuated (and much slower) lear Smad-mediated actiity; (ii) but een the increased leels of TGF-β will neer be able to produce Smad-mediated responses that will be anywhere close to normal because of the saturation effect.
8 Relatie oncentration of ps2s Normal ancerous Time (hr) Figure 5. In silico mutation results: Responses of lear psmad-smad4 complex to 0-fold reduction in initial leels and protein synthesis rate constants of both Type I and Type II receptors. As shown aboe ia simulation, cancer cells may hae attenuated TGF-β-stimulated Smad pathway responses. ancer cells hae been confirmed experimentally to be resistant to the antiproliferatie effect of TGF-β, while showing typical pro-oncogenic responses. Such behaior may be explained in part by the following threshold hypothesis : in response to TGFβ, growth-inhibitory genes require higher threshold leels of lear Smad actiity for their expression than genes associated with pro-oncogenic and pro-metastatic effects. In other words, under normal conditions, or in the early stage of cancer progression, the antiproliferatie responses to TGF-β are predominant oer pro-oncogenic responses. This is because the transcriptional actiity of lear psmad is high enough to induce anti-growth gene expression. Howeer, as cancer progresses, this transcriptional actiity may decline significantly and thereby hardly exceed the threshold necessary for the expression of growthinhibition genes. Meanwhile, genes related to tumor-promoting effects may be relatiely insensitie to the attenuation of the transcriptional actiity by Smads, so that the expression of such genes remains approximately unchanged een under cancerous conditions. As a consequence, the dominance of tumor suppressor genes oer the tumor-promoter genes may be blunted in cancer cells. We beliee that further inestigation into differences in the temporal profiles of gene expression and thresholds of anti-growth and pro-oncogenic genes induced by TGF-β will proide some clues regarding the putatie dual effects of TGF-β.
9 onclusion In this work we hae presented a comprehensie computational model of the TGF-β signaling pathway that describes how an extracellular signal of TGF-β ligand is sensed by receptors and transmitted into the leus through intracellular Smad proteins. The model yields quantitatie insight into how TGF-β-induced responses can be modulated and regulated. The model also allows us to predict possible dynamic behaior of the Smad-mediated pathway in abnormal cells, and proides clues regarding possible mechanisms for explaining the seemingly contradictory roles of TGF-β during cancer progression. We beliee that incorporation of the effect of crosstalk among other important signaling cascades and detailed gene expression mechanisms into the current model will facilitate better understanding of the TGF-β paradox in cancer. References. Shi, Y., and J. Massague Mechanisms of TGF-β signaling from cell membrane to the leus. ell 3: Feng, X. H., and R. Derynck Specificity and ersatility in TGF-β signaling through Smads. Annu Re ell De Biol 2: Pardali, K., and A. Moustakas Actions of TGF-β as tumor suppressor and prometastatic factor in human cancer. Biochim Biophys Acta 775: Pierreux,. E., F. J. Nicolas, and. S. Hill Transforming growth factor β- independent shuttling of Smad4 between the oplasm and leus. Mol ell Biol 20: Inman, G. J., F. J. Nicolas, and. S. Hill Nucleooplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGFβ receptor actiity. Mol ell 0: Birtwistle, M. R., M. Hatakeyama, N. Yumoto, B. A. Ogunnaike, J. B. Hoek, and B. N. Kholodenko Ligand-dependent responses of the ErbB signaling network: experimental and modeling analyses. Mol Syst Biol 3:44.
Novel Quantitative Tools for Engineering Analysis of Hepatocyte Cultures used in Bioartificial Liver Systems
Noel Quantitatie Tools for Engineering Analysis of Hepatocyte Cultures used in Bioartificial Lier Systems M. Ierapetritou *, N. Sharma and M. L. Yarmush Department of Chemical & Biochemical Engineering
More informationMenachem Elimelech. Science and Technology for Sustainable Water Supply
Menachem Elimelech Science and Technology for Sustainable Water Supply Traditional methods for water purification are chemical and energy intensive. Highly effective, low-cost, robust technologies for
More informationSupplementary Materials for
www.sciencesignaling.org/cgi/content/full/6/305/ra106/dc1 Supplementary Materials for Controlling Long-Term Signaling: Receptor Dynamics Determine Attenuation and Refractory Behavior of the TGF-β Pathway
More informationControl of Cell Proliferation by Peptide Growth Factors. Autocrine Growth Factor Production Causes Malignant Transformation?
Control of Cell Proliferation by Peptide Growth Factors Autocrine Growth Factor Production Causes Malignant Transformation? Transforming Activities From Condition Media from a Tumor Cell Line Condition
More informationarxiv: v1 [q-bio.nc] 10 Jan 2014
Bidirectional Control of Absence Seizures by the Basal Ganglia: A Computational Eidence Mingming Chen 1,, Daqing Guo 1,,, Tiebin Wang 1, Wei Jing 1, Yang Xia 1, Peng Xu 1, Cheng Luo 1, Pedro A. Valdes-Sosa
More informationComputational Modeling of Mood and Feeling from Emotion
Computational Modeling of Mood and Feeling from Emotion Robert P. Marinier (rmarinie@umich.edu) Department of Electrical Engineering and Computer Science, 2260 Hayward Street Ann Arbor, MI 48109 USA John
More information1 INTRODUCTION. (1) regular physical activity to the prevention of obesity, type 2 diabetes, cardiovascular disease, some cancers and osteoporosis;
1 INTRODUCTION My main aim as far as my health is concerned at present is to increase my declining fitness leels and tone up my body. I am conscious of family tendency to heart disease, stroke and high
More informationThe Theoretical Basis of the Yellow and Red Clearance Intervals
52 The Theoretical Basis of the Yellow and Red Clearance Interals The purpose of this actiity is to show you some of the issues that must be considered when setting the yellow and red clearance interals.
More informationAvailable online at Procedia Engineering 7 (2010) Procedia Engineering 00 (2010)
Aailable online at www.sciencedirect.com Procedia Engineering 7 (2010) 371 376 Procedia Engineering 00 (2010) 000 000 Procedia Engineering www.elseier.com/locate/procedia www.elseier.com/locate/procedia
More informationThe Hallmarks of Cancer
The Hallmarks of Cancer Theresa L. Hodin, Ph.D. Clinical Research Services Theresa.Hodin@RoswellPark.org Hippocrates Cancer surgery, circa 1689 Cancer Surgery Today 1971: Nixon declares War on Cancer
More informationNoise characteristics and prior expectations in human visual speed perception
To appear: Nature Neuroscience, April 006 (estimated) Noise characteristics and prior expectations in human isual speed perception Alan A. Stocker and Eero P. Simoncelli Howard Hughes Medical Institute,
More informationNoise characteristics and prior expectations in human visual speed perception
6 Nature Publishing Group http://www.nature.com/natureneuroscience Noise characteristics and prior expectations in human isual speed perception Alan A Stocker & Eero P Simoncelli Human isual speed perception
More informationIdentification of influential proteins in the classical retinoic acid signaling pathway
Ghaffari and Petzold Theoretical Biology and Medical Modelling (2018) 15:16 https://doi.org/10.1186/s12976-018-0088-7 RESEARCH Open Access Identification of influential proteins in the classical retinoic
More informationPart I. Boolean modelling exercises
Part I. Boolean modelling exercises. Glucose repression of Icl in yeast In yeast Saccharomyces cerevisiae, expression of enzyme Icl (isocitrate lyase-, involved in the gluconeogenesis pathway) is important
More informationVII. Chronic Myelogenous Leukemia Research Program
CDMRP VII. Chronic Myelogenous Leukemia Research Program EXPLORING Vision To eradicate chronic myelogenous leukemia. Mission To identify and sponsor basic and clinical research in the field of chronic
More informationCONTINUING EDUCATION Coagulation and Platelet Function During Cardiopulmonary Bypass Surgery
CONINUING EDUCAION Coagulation and Platelet Function During Cardiopulmonary Bypass Surgery Christina Beurling-Harbury, M.D. Chief, Hematology Laboratory Associate Professor Stanford Uniersity Hospital,
More informationmirna Dr. S Hosseini-Asl
mirna Dr. S Hosseini-Asl 1 2 MicroRNAs (mirnas) are small noncoding RNAs which enhance the cleavage or translational repression of specific mrna with recognition site(s) in the 3 - untranslated region
More informationThe Role of Affect in Information Systems Research: A Critical Survey and A Research Model
Citation: Sun, Heshan and Ping Zhang (forthcoming), The Role of Affect in IS Research: A Critical Surey and a Research Model, in HCI in MIS (I): Foundations, Zhang, P. and Galletta, D. (eds), Series of
More informationEffects ofa contralateral interference tone on auditory recognition*
Perception & Psychophysics 1974, Vol. 15. No. 1. 16 20 Effects ofa contraleral interference tone on auditory recognition* EDWARD CUDAHYT and BARRY LESHOWTtt Arizona Ste L'niersity, Tempe. Arizona 85281
More informationPrinciples of Genetics and Molecular Biology
Cell signaling Dr. Diala Abu-Hassan, DDS, PhD School of Medicine Dr.abuhassand@gmail.com Principles of Genetics and Molecular Biology www.cs.montana.edu Modes of cell signaling Direct interaction of a
More informationCancer and Oncogenes Bioscience in the 21 st Century. Linda Lowe-Krentz
Cancer and Oncogenes Bioscience in the 21 st Century Linda Lowe-Krentz December 1, 2010 Just a Few Numbers Becoming Cancer Genetic Defects Drugs Our friends and family 25 More mutations as 20 you get older
More informationBiol403 MAP kinase signalling
Biol403 MAP kinase signalling The mitogen activated protein kinase (MAPK) pathway is a signalling cascade activated by a diverse range of effectors. The cascade regulates many cellular activities including
More informationEarly Embryonic Development
Early Embryonic Development Maternal effect gene products set the stage by controlling the expression of the first embryonic genes. 1. Transcription factors 2. Receptors 3. Regulatory proteins Maternal
More informationnumber Done by Corrected by Doctor Maha Shomaf
number 19 Done by Waseem Abo-Obeida Corrected by Abdullah Zreiqat Doctor Maha Shomaf Carcinogenesis: the molecular basis of cancer. Non-lethal genetic damage lies at the heart of carcinogenesis and leads
More informationCYTOKINE RECEPTORS AND SIGNAL TRANSDUCTION
CYTOKINE RECEPTORS AND SIGNAL TRANSDUCTION What is Cytokine? Secreted popypeptide (protein) involved in cell-to-cell signaling. Acts in paracrine or autocrine fashion through specific cellular receptors.
More informationCancer and Oncogenes Bioscience in the 21 st Century. Linda Lowe-Krentz October 11, 2013
Cancer and Oncogenes Bioscience in the 21 st Century Linda Lowe-Krentz October 11, 2013 Just a Few Numbers Becoming Cancer Genetic Defects Drugs Our friends and family 200 180 160 140 120 100 80 60 40
More informationVIII Curso Internacional del PIRRECV. Some molecular mechanisms of cancer
VIII Curso Internacional del PIRRECV Some molecular mechanisms of cancer Laboratorio de Comunicaciones Celulares, Centro FONDAP Estudios Moleculares de la Celula (CEMC), ICBM, Facultad de Medicina, Universidad
More informationLooking deeper into the science of Immuno-Oncology
Looking deeper into the science of Immuno-Oncology Using the body s natural immune response to fight cancer Bristol-Myers Squibb At the Forefront of Immuno-Oncology About These slides help explain key
More informationCHAPTER VII CONCLUDING REMARKS AND FUTURE DIRECTION. Androgen deprivation therapy is the most used treatment of de novo or recurrent
CHAPTER VII CONCLUDING REMARKS AND FUTURE DIRECTION Stathmin in Prostate Cancer Development and Progression Androgen deprivation therapy is the most used treatment of de novo or recurrent metastatic PCa.
More informationChapter 15: Signal transduction
Chapter 15: Signal transduction Know the terminology: Enzyme-linked receptor, G-protein linked receptor, nuclear hormone receptor, G-protein, adaptor protein, scaffolding protein, SH2 domain, MAPK, Ras,
More informationThe Adaptive Immune Responses
The Adaptive Immune Responses The two arms of the immune responses are; 1) the cell mediated, and 2) the humoral responses. In this chapter we will discuss the two responses in detail and we will start
More informationmicrorna as a Potential Vector for the Propagation of Robustness in Protein Expression and Oscillatory Dynamics within a cerna Network
microrna as a Potential Vector for the Propagation of Robustness in Protein Expression and Oscillatory Dynamics within a cerna Network Claude Gérard*,Béla Novák Oxford Centre for Integrative Systems Biology,
More informationLecture 15. Signal Transduction Pathways - Introduction
Lecture 15 Signal Transduction Pathways - Introduction So far.. Regulation of mrna synthesis Regulation of rrna synthesis Regulation of trna & 5S rrna synthesis Regulation of gene expression by signals
More informationLipids and Membranes
Lipids and Membranes Presented by Dr. Mohammad Saadeh The requirements for the Pharmaceutical Biochemistry I Philadelphia University Faculty of pharmacy Membrane transport D. Endocytosis and Exocytosis
More informationCell Signaling part 2
15 Cell Signaling part 2 Functions of Cell Surface Receptors Other cell surface receptors are directly linked to intracellular enzymes. The largest family of these is the receptor protein tyrosine kinases,
More informationRAS Genes. The ras superfamily of genes encodes small GTP binding proteins that are responsible for the regulation of many cellular processes.
۱ RAS Genes The ras superfamily of genes encodes small GTP binding proteins that are responsible for the regulation of many cellular processes. Oncogenic ras genes in human cells include H ras, N ras,
More informationPHSI3009 Frontiers in Cellular Physiology 2017
Overview of PHSI3009 L2 Cell membrane and Principles of cell communication L3 Signalling via G protein-coupled receptor L4 Calcium Signalling L5 Signalling via Growth Factors L6 Signalling via small G-protein
More informationP2-Microglobulin and Neopterin: Predictive Markers for Human
JOURNAL OF CLINICAL MICROBIOLOGY, Oct. 1990, p. 2215-2219 0095-1137/90/102215-05$02.00/0 Copyright 1990, American Society for Microbiology Vol. 28, No. 10 P2-Microglobulin and Neopterin: Predictie Markers
More informationMOLECULAR CELL BIOLOGY
1 Lodish Berk Kaiser Krieger scott Bretscher Ploegh Matsudaira MOLECULAR CELL BIOLOGY SEVENTH EDITION CHAPTER 13 Moving Proteins into Membranes and Organelles Copyright 2013 by W. H. Freeman and Company
More informationWhat do educators need to know about EBPs for children with autism? What specific strategies can improve outcomes for children with ASD?
Module Home Outline Module : This Module, second in a two-part series, highlights strategies that hae been shown to be effectie in teaching appropriate behaiors and skills and decreasing inappropriate
More informationBIO360 Fall 2013 Quiz 1
BIO360 Fall 2013 Quiz 1 1. Examine the diagram below. There are two homologous copies of chromosome one and the allele of YFG carried on the light gray chromosome has undergone a loss-of-function mutation.
More informationPotency Assays Throughout Product Development: Perspectives of an FDA Reviewer
Potency Assays Throughout Product Development: Perspectives of an FDA Reviewer Chana Fuchs, Ph.D. Division of Monoclonal Antibodies Office of Biotechnology Products Center for Drug Evaluation and Research
More informationCSF/serum matrix metallopeptidase-9 ratio discriminates neuro Behcßet from multiple sclerosis
BRIEF COMMUNICATION CSF/serum matrix metallopeptidase-9 ratio discriminates neuro Behcßet from multiple sclerosis Alessandra Aldinucci 1, Elena Bonechi 1, Tiziana Biagioli 2, Anna M. Repice 3, Mario M.
More informationChapter 11: Enzyme Catalysis
Chapter 11: Enzyme Catalysis Matching A) high B) deprotonated C) protonated D) least resistance E) motion F) rate-determining G) leaving group H) short peptides I) amino acid J) low K) coenzymes L) concerted
More informationBiological functions: role as tumor suppressor. Growth inhibitor. Inducer of apoptosis. Effects on cell differentiation.
TGF-beta and cancer Isabel Fabregat Departament de Ciències Fisiòlogiques II, Universitat de Barcelona Institut de Investigació Biomèdica de Bellvitge (IDIBELL) E-mail: ifabregat@ub.edu Máster en Oncología
More informationDiabetes Mellitus and Breast Cancer
Masur K, Thévenod F, Zänker KS (eds): Diabetes and Cancer. Epidemiological Evidence and Molecular Links. Front Diabetes. Basel, Karger, 2008, vol 19, pp 97 113 Diabetes Mellitus and Breast Cancer Ido Wolf
More informationSample Lab Report 1 from 1. Measuring and Manipulating Passive Membrane Properties
Sample Lab Report 1 from http://www.bio365l.net 1 Abstract Measuring and Manipulating Passive Membrane Properties Biological membranes exhibit the properties of capacitance and resistance, which allow
More informationReading Assignments: Chapter 16: Cell Communication Pgs ; 545 & Figure 16-15; ; work Q-1, 3, 4, 10, 12, 15, 16, 17, 20 & 23
Biol 205 Signal Transduction, the Social Contract and Rogue Cancer Cells Inside cancer web site http://www.insidecancer.org/ National Cancer Institute http://www.cancer.gov/cancerinfo/ Reading Assignments:
More informationG-Protein Signaling. Introduction to intracellular signaling. Dr. SARRAY Sameh, Ph.D
G-Protein Signaling Introduction to intracellular signaling Dr. SARRAY Sameh, Ph.D Cell signaling Cells communicate via extracellular signaling molecules (Hormones, growth factors and neurotransmitters
More informationMathematical and Computational Analysis of Adaptation via Feedback Inhibition in Signal Transduction Pathways
806 Biophysical Journal Volume 93 August 2007 806 821 Mathematical and Computational Analysis of Adaptation via Feedback Inhibition in Signal Transduction Pathways Marcelo Behar,* Nan Hao, y Henrik G.
More informationChemistry 106: Drugs in Society Lecture 19: How do Drugs Elicit an Effect? Interactions between Drugs and Macromolecular Targets 11/02/17
Chemistry 106: Drugs in Society Lecture 19: How do Drugs Elicit an Effect? Interactions between Drugs and Macromolecular Targets 11/02/17 Targets for Therapeutic Intervention: A Comparison of Enzymes to
More informationSOCCER INTRODUCING THE POWER PULL:
P ERFORMANCE SOCCER CONDITIONING A NEWSLETTER DEDICATED TO IMPROVING SOCCER PLAYERS WWW.PERFORMANCECONDITION.COM/SOCCER INTRODUCING THE POWER PULL: ENJOYING THE BENEFITS OF EXPLOSIVE LIFTING FOR SOCCER
More informationT cell maturation. T-cell Maturation. What allows T cell maturation?
T-cell Maturation What allows T cell maturation? Direct contact with thymic epithelial cells Influence of thymic hormones Growth factors (cytokines, CSF) T cell maturation T cell progenitor DN DP SP 2ry
More informationMultistep nature of cancer development. Cancer genes
Multistep nature of cancer development Phenotypic progression loss of control over cell growth/death (neoplasm) invasiveness (carcinoma) distal spread (metastatic tumor) Genetic progression multiple genetic
More informationModel Answer. M.Sc. Zoology (First Semester) Examination Paper LZT 103 (Endocrinology)
Model Answer M.Sc. Zoology (First Semester) Examination-2013 Paper LZT 103 (Endocrinology) Section A 1. (i) d (ii) b (iii) b (iv) c (v) c (vi) a (vii) c (viii) a (ix) d (x) b Section B Q.2 Answer Hormonal
More informationFIRST BIOCHEMISTRY EXAM Tuesday 25/10/ MCQs. Location : 102, 105, 106, 301, 302
FIRST BIOCHEMISTRY EXAM Tuesday 25/10/2016 10-11 40 MCQs. Location : 102, 105, 106, 301, 302 The Behavior of Proteins: Enzymes, Mechanisms, and Control General theory of enzyme action, by Leonor Michaelis
More informationTGF-β signaling dictates therapeutic targeting in prostate cancer
EDITORIAL TGF-β signaling dictates therapeutic targeting in prostate cancer Natasha Kyprianou University of Kentucky College of Medicine, Departments of Urology, Molecular Biochemistry, Pathology and Toxicology,
More informationAboriginal and Torres Strait Islander Male Health Module for Aboriginal Health Workers. Unit 10. Chronic disease and male-specific health issues
Aboriginal and Torres Strait Islander Male Health Module for Aboriginal Health Workers Unit 10. Chronic disease and male-specific health issues Content from: Unit 10. Chronic disease and male-specific
More informationBCHM3972 Human Molecular Cell Biology (Advanced) 2013 Course University of Sydney
BCHM3972 Human Molecular Cell Biology (Advanced) 2013 Course University of Sydney Page 2: Immune Mechanisms & Molecular Biology of Host Defence (Prof Campbell) Page 45: Infection and Implications for Cell
More informationBioNSi: A Discrete Biological Network Simulator Tool
BioNSi: A Discrete Biological Network Simulator Tool Amir Rubinstein 1, Noga Bracha 1, Liat Rudner 1, Noga Zucker 1, Hadas E. Sloin 2, and Benny Chor 1 1 Blavatnik School of Computer Science, Tel Aviv
More informationNANO 243/CENG 207 Course Use Only
L9. Drug Permeation Through Biological Barriers May 3, 2018 Lipids Lipid Self-Assemblies 1. Lipid and Lipid Membrane Phospholipid: an amphiphilic molecule with a hydrophilic head and 1~2 hydrophobic tails.
More informationT-cell activation T cells migrate to secondary lymphoid tissues where they interact with antigen, antigen-presenting cells, and other lymphocytes:
Interactions between innate immunity & adaptive immunity What happens to T cells after they leave the thymus? Naïve T cells exit the thymus and enter the bloodstream. If they remain in the bloodstream,
More informationT-cell activation T cells migrate to secondary lymphoid tissues where they interact with antigen, antigen-presenting cells, and other lymphocytes:
Interactions between innate immunity & adaptive immunity What happens to T cells after they leave the thymus? Naïve T cells exit the thymus and enter the bloodstream. If they remain in the bloodstream,
More informationTransformation of Normal HMECs (Human Mammary Epithelial Cells) into Metastatic Breast Cancer Cells: Introduction - The Broad Picture:
Transformation of Normal HMECs (Human Mammary Epithelial Cells) into Metastatic Breast Cancer Cells: Introduction - The Broad Picture: Spandana Baruah December, 2016 Cancer is defined as: «A disease caused
More informationIntroduction. Cancer Biology. Tumor-suppressor genes. Proto-oncogenes. DNA stability genes. Mechanisms of carcinogenesis.
Cancer Biology Chapter 18 Eric J. Hall., Amato Giaccia, Radiobiology for the Radiologist Introduction Tissue homeostasis depends on the regulated cell division and self-elimination (programmed cell death)
More informationCell Cell Communication
IBS 8102 Cell, Molecular, and Developmental Biology Cell Cell Communication January 29, 2008 Communicate What? Why do cells communicate? To govern or modify each other for the benefit of the organism differentiate
More informationBalancing speed and accuracy of polyclonal T cell activation: A role for extracellular feedback
Balancing speed and accuracy of polyclonal T cell activation: A role for extracellular feedback The Harvard community has made this article openly available. Please share how this access benefits you.
More informationEffects of the diuretics, triamterene and mersalyl on active sodium transport mechanisms in isolated frog skin
Br. J. Pharmac. (1971), 41, 552-557. Effects of the diuretics, triamterene and mersalyl on actie sodium transport mechanisms in isolated frog skin L. A. SALAKO* AND A. J. SMITH Department of Pharmacology
More informationCell Cell Communication
IBS 8102 Cell, Molecular, and Developmental Biology Cell Cell Communication January 29, 2008 Communicate What? Why do cells communicate? To govern or modify each other for the benefit of the organism differentiate
More informationA Theoretical Model of the Wnt Signaling Pathway in the Epithelial Mesenchymal Transition
Gasior et al. Theoretical Biology and Medical Modelling (2017) 14:19 DOI 10.1186/s12976-017-0064-7 RESEARCH Open Access A Theoretical Model of the Wnt Signaling Pathway in the Epithelial Mesenchymal Transition
More informationComputational Classification Approach to Profile Neuron Subtypes. from Brain Activity Mapping Data
Computational Classification Approach to Profile Neuron Subtypes from Brain Actiity Mapping Data Meng Li, 1,+ Fang Zhao, 1,+ Jason Lee, 1 Dong Wang, 1 Hui Kuang, 1,2 and Joe Z. Tsien 1,2,* 1 Brain and
More informationEnzyme-coupled Receptors. Cell-surface receptors 1. Ion-channel-coupled receptors 2. G-protein-coupled receptors 3. Enzyme-coupled receptors
Enzyme-coupled Receptors Cell-surface receptors 1. Ion-channel-coupled receptors 2. G-protein-coupled receptors 3. Enzyme-coupled receptors Cell-surface receptors allow a flow of ions across the plasma
More informationIn vitro scratch assay: method for analysis of cell migration in vitro labeled fluorodeoxyglucose (FDG)
In vitro scratch assay: method for analysis of cell migration in vitro labeled fluorodeoxyglucose (FDG) 1 Dr Saeb Aliwaini 13/11/2015 Migration in vivo Primary tumors are responsible for only about 10%
More informationACTIVE TRANSPORT OF SALICYLATE BY RAT JEJUNUM
Quarterly Journal of Experimental Physiology (1981) 66, 91-98 91 Printed in Great Britain ACTIVE TRANSPORT OF SALICYLATE BY RAT JEJUNUM R. B. FISHER University Laboratory of Physiology, Oxford (RECEIVED
More informationSrc-INACTIVE / Src-INACTIVE
Biology 169 -- Exam 1 February 2003 Answer each question, noting carefully the instructions for each. Repeat- Read the instructions for each question before answering!!! Be as specific as possible in each
More informationMiconazole Therapy for Treatment of Fungal Infections in Cancer Patients
NTIMICROBIL GENTS ND CHEMOTHERPY, Dec. 1979, p. 792-797 ol. 16, No. 6 66-484/79/12-792/6$2./ Miconazole Therapy for Treatment of Fungal Infections in Cancer Patients WILLIM M. JORDN, GERLD P. BODEY,t*
More informationSignaling Vascular Morphogenesis and Maintenance
Signaling Vascular Morphogenesis and Maintenance Douglas Hanahan Science 277: 48-50, in Perspectives (1997) Blood vessels are constructed by two processes: vasculogenesis, whereby a primitive vascular
More informationMCB*4010 Midterm Exam / Winter 2008
MCB*4010 Midterm Exam / Winter 2008 Name: ID: Instructions: Answer all 4 questions. The number of marks for each question indicates how many points you need to provide. Write your answers in point form,
More informationHypothesis. Brain Chip. Tsutomu Nakada 1. Center for Integrated Human Brain Science Brain Research Institute, University of Niigata
Hypothesis Brain Chip Tsutomu Nakada 1 Center for Integrated Human Brain Science Brain Research Institute, Uniersity of Niigata This article is the English ersion of the Brain Chip hypothesis preiously
More informationCells communicate with each other via signaling ligands which interact with receptors located on the surface or inside the target cell.
BENG 100 Frontiers of Biomedical Engineering Professor Mark Saltzman Chapter 6 SUMMARY In this chapter, cell signaling was presented within the context of three physiological systems that utilize communication
More informationDeregulation of signal transduction and cell cycle in Cancer
Deregulation of signal transduction and cell cycle in Cancer Tuangporn Suthiphongchai, Ph.D. Department of Biochemistry Faculty of Science, Mahidol University Email: tuangporn.sut@mahidol.ac.th Room Pr324
More informationOncoPPi Portal A Cancer Protein Interaction Network to Inform Therapeutic Strategies
OncoPPi Portal A Cancer Protein Interaction Network to Inform Therapeutic Strategies 2017 Contents Datasets... 2 Protein-protein interaction dataset... 2 Set of known PPIs... 3 Domain-domain interactions...
More informationLecture: CHAPTER 13 Signal Transduction Pathways
Lecture: 10 17 2016 CHAPTER 13 Signal Transduction Pathways Chapter 13 Outline Signal transduction cascades have many components in common: 1. Release of a primary message as a response to a physiological
More informationProtocol for A-549 VIM RFP (ATCC CCL-185EMT) TGFβ1 EMT Induction and Drug Screening
Protocol for A-549 VIM RFP (ATCC CCL-185EMT) TGFβ1 EMT Induction and Drug Screening Introduction: Vimentin (VIM) intermediate filament (IF) proteins are associated with EMT in lung cancer and its metastatic
More informationSolution key Problem Set
Solution key- 7.013 Problem Set 6-2013 Question 1 a) Our immune system is comprised of different cell types. Complete the table below by selecting all correct cell types from the choices provided. Cells
More informationChapter 20. Cell - Cell Signaling: Hormones and Receptors. Three general types of extracellular signaling. endocrine signaling. paracrine signaling
Chapter 20 Cell - Cell Signaling: Hormones and Receptors Three general types of extracellular signaling endocrine signaling paracrine signaling autocrine signaling Endocrine Signaling - signaling molecules
More informationCRITERIA FOR USE. A GRAPHICAL EXPLANATION OF BI-VARIATE (2 VARIABLE) REGRESSION ANALYSISSys
Multiple Regression Analysis 1 CRITERIA FOR USE Multiple regression analysis is used to test the effects of n independent (predictor) variables on a single dependent (criterion) variable. Regression tests
More informationIt is all in the enzymes
Enzyme regulation 1 It is all in the enzymes Enzymes can enhance the rates of metabolic (or other) reactions by many orders of magnitude. A rate enhancement of 10 17 means that what would occur in 1 second
More informationDrug Receptor Interactions and Pharmacodynamics
Drug Receptor Interactions and Pharmacodynamics Dr. Raz Mohammed MSc Pharmacology School of Pharmacy 22.10.2017 Lec 6 Pharmacodynamics definition Pharmacodynamics describes the actions of a drug on the
More informationINTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY Vol. 23, no. 4, 0-0 (2010)
INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY Vol. 23, no. 4, 0-0 (2010) NOVEL PERSPECTIVES IN THE DETECTION OF ORAL AND NASAL OXIDATIVE STRESS AND INFLAMMATION IN PEDIATRIC UNITED AIRWAY DISEASES
More informationPart-4. Cell cycle regulatory protein 5 (Cdk5) A novel target of ERK in Carb induced cell death
Part-4 Cell cycle regulatory protein 5 (Cdk5) A novel target of ERK in Carb induced cell death 95 1. Introduction The process of replicating DNA and dividing cells can be described as a series of coordinated
More informationSignaling. Dr. Sujata Persad Katz Group Centre for Pharmacy & Health research
Signaling Dr. Sujata Persad 3-020 Katz Group Centre for Pharmacy & Health research E-mail:sujata.persad@ualberta.ca 1 Growth Factor Receptors and Other Signaling Pathways What we will cover today: How
More informationNeoplasia 18 lecture 6. Dr Heyam Awad MD, FRCPath
Neoplasia 18 lecture 6 Dr Heyam Awad MD, FRCPath ILOS 1. understand the role of TGF beta, contact inhibition and APC in tumorigenesis. 2. implement the above knowledge in understanding histopathology reports.
More informationLQB383 Testbank. Week 8 Cell Communication and Signaling Mechanisms
LQB383 Testbank Week 8 Cell Communication and Signaling Mechanisms Terms to learn match the terms to the definitions --------------------------------------------------------------------------------------------------------------------------
More informationSection D: The Molecular Biology of Cancer
CHAPTER 19 THE ORGANIZATION AND CONTROL OF EUKARYOTIC GENOMES Section D: The Molecular Biology of Cancer 1. Cancer results from genetic changes that affect the cell cycle 2. Oncogene proteins and faulty
More informationReview Article MicroRNA as a Novel Modulator in Head and Neck Squamous Carcinoma
Journal of Oncology Volume 2010, Article ID 135632, 15 pages doi:10.1155/2010/135632 Reiew Article MicroRNA as a Noel Modulator in Head and Neck Squamous Carcinoma Li-Hsin Chen, 1, 2 Kun-Ling Tsai, 2,
More informationModeling Imatinib-Treated Chronic Myeloid Leukemia
Modeling Imatinib-Treated Chronic Myeloid Leukemia Cara Peters cpeters3@math.umd.edu Advisor: Dr. Doron Levy dlevy@math.umd.edu Department of Mathematics Center for Scientific Computing and Mathematical
More informationStructure and Function of Antigen Recognition Molecules
MICR2209 Structure and Function of Antigen Recognition Molecules Dr Allison Imrie allison.imrie@uwa.edu.au 1 Synopsis: In this lecture we will examine the major receptors used by cells of the innate and
More informationPupillary autonomic denervation with increasing duration of diabetes mellitus
Br J Ophthalmol 21;85:1225 123 1225 The Institute of Ophthalmology, Uniersity College Dublin, Mater Misericordiae Hospital, 6 Eccles Street, Dublin 7, Ireland M Cahill P Eustace V de Jesus Correspondence
More information