Copy of Chapter 1’s The Cell as a Unit of Health and Disease PDF

MTY1227: HISTOPATHOLOGIC AND CYTOLOGIC TECHNIQUES (LEC) Week No. 2: Chapter 1’s The Cell as a Unit of Health and Disease Professor: Dr. Jayson Wee Source: Robbin’s Pathology, 10th Edition by Kumar, Abbas, et al....

MTY1227: HISTOPATHOLOGIC AND CYTOLOGIC TECHNIQUES (LEC) Week No. 2: Chapter 1’s The Cell as a Unit of Health and Disease Professor: Dr. Jayson Wee Source: Robbin’s Pathology, 10th Edition by Kumar, Abbas, et al. Telomeres (chromosome TOPIC OUTLINE Special Structural ends) and centromeres Introduction DNA Regions The Genome (chromosome "tethers"). Cellular Housekeeping Cellular Metabolism and Mitochondrial Function Cellular Activation IMPORTANCE OF NONCODING DNA Growth Factors and Receptors Polymorphisms: genetic variations. Extracellular Matrix Maintaining Cell Populations o Many disease-associated genetic variations are in noncoding regions. Gene regulation may have a larger role in disease INTRODUCTION causation than protein structural changes. PATHOLOGY Human Genetic Similarity: Derived from Greek: pathos = suffering, logos = o Humans are >99.5% DNA-identical; 99% study. identical to chimpanzees. Modern medicine: Study of disease. o Individual variation lies in 200 nucleotides DNA METHYLATION in length. High levels: ○ Chromatin condensation Micro-RNAs (miRNAs) ○ Transcriptional silencing 22 nucleotides on Tightly regulated by: average. ○ Methyltransferases Modulate the ○ Demethylating enzymes translation of target ○ Methylated-DNA-binding proteins mRNAs into their corresponding HISTONE MODIFYING FACTORS proteins. Chromatin Remodeling Complexes Posttranscriptional Chromatin Writer Complexes silencing of gene Chromatin Erases and Readers expression: conserved Chromatin Remodeling Complexes mechanism of gene Reposition nucleosomes on DNA. regulation present in Exposing or obscuring gene regulatory elements all eukaryotes. like promoters. 6000 miRNA genes contain a human genome. Chromatin Writer Complexes miRNA regulates Marks: denote histone modifications. multiple protein- Incudes: methylation, acetylation, and coding genes. phosphorylation of specific histone amino acid Pri-miRNA: residues. transcription of miRNA that produces a primary transcript. Lysines and arginines. ○ Processed Can lead to into smaller transcriptional segments. Histone activation or repression Methylation ○ Trimming by depending on which the enzyme histone residue is Dicer. marked. ○ Generates 21-30 nucleotides mature single- stranded miRNAs that associate with Lysine residues. RNA-induced silencing complex Occurs through histone (multiprotein aggregate). acetyl transferases. Base pairing between miRNA strand and its target Open up chromatin and mRNA: Histone ○ RISC induces mRNA cleavage or repress Acetylation increase transcription. Histone deacetylases translation. (HDAC): reverses the ○ Target mRNA is post-transcriptionally process; leads to silenced. chromatin condensation. Small Interfering RNAs (siRNAs) Short RNA sequences introduced into cells. 2 Notes by Maximo, D.J. & Meroy, C. J.  Week 2: Chapter 1’s The Cell as a Unit of Health and Disease Substrates for Dicer. Interact with the RISC complex analogous to miRNAs. Target specific mRNA species. Synthetic Knockdown technology: study gene function. siRNAs Promising as therapeutic agents to silence pathogenic genes. At least 30,000 in the human genome. Module gene expression through: Long ○ Bind to regions of chromatin Noncoding restricting RNA polymerase RNA access to coding genes. (lncRNA) ○ XIST: forms cloak on X chromosome for inactivation. GENE EDITING Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRs) and Cas (CRISPR-associated genes) ○ Linked genetic elements that endow CATABOLIZATION OF CELLS prokaryotes with a form of acquired Cells catabolize molecules/ proteins/ organelles immunity to phages and plasmids. that they endocytose. CRISPRs Takes place at three (3) different sites: ○ Transcribed and processed into an RNA ○ Proteasomes sequence. ○ Lysosomes ○ Binds and directs the nuclease Cas9 to a ○ Peroxisomes sequence. can trigger or shut down ○ Cleavage and destruction of the phage. cellular signaling pathways. ○ Gene editing repurposes the process by artificial guide RNAs (gRNAs). “Disposal” complexes that gRNAs degrade denatured or Proteasomes ○ Bind Cas9. “tagged” cytosolic proteins ○ Complementary to a DNA sequence of and release short peptides. interest. ○ Cas9 induces double-strand DNA breaks. High specific cleavage sites repair lead to: ○ Random disruptive mutations in the Intracellular organelles that targeted sequences through contain enzymes like nonhomologous end joining (NHEJ). proteins, polysaccharides, ○ Precise introduction of new sequences of lipids, and nucleic acids. interest by homologous recombination. Lysosomes Phagocytosed microbes and damaged or unwanted CELLULAR HOUSEKEEPING cellular organelles are Compartmentalized within membrane-bound degraded and eliminated. intracellular organelles. Where final catabolism ○ Allows for the creation of unique occurs. intracellular environments optimal for certain enzymes or metabolic pathways. Rough Endoplasmic Reticulum (RER) ○ Where new proteins destined for the Organelles that contain plasma membrane or secretions are catalase, peroxidase, and synthesized and physically assembled in other oxidative enzymes. Peroxisomes Breakdown of very long chain the Golgi apparatus. Free Ribosomes fatty acids; generating ○ Where proteins intended for the cytosol hydrogen peroxide. are synthesized. Smooth Endoplasmic Reticulum (SER) ○ Serves as a site of steroid hormone and lipoprotein synthesis for gonads and Endosomal Vesicles: shuttle internalized liver. material to the appropriate intracellular sites or ○ Modification of hydrophobic compounds. direct newly synthesized materials to the cell surface or targeted organelle. Cytoskeleton 3 Notes by Maximo, D.J. & Meroy, C. J.  Week 2: Chapter 1’s The Cell as a Unit of Health and Disease ○ Orchestrates the movement of both organelles and proteins within the cell Inner face and of the cell in its environment. Confers a negative ○ Regulate cellular shape and charge and is intracellular organization. involved in ○ Requisites for maintaining cell polarity. electrostatic Adenosine Triphosphate interactions with ○ Power cells. Phosphatidylserine proteins. ○ Made through oxidative phosphorylation It becomes an “eat in the mitochondria. me” signal for Mitochondria phagocytes in cells ○ Source of metabolic intermediates undergoing needed for anabolic metabolism. apoptosis. ○ Sites of synthesis of certain macromolecules. ○ Contain important sensors of cell damage that can initiate and regulate the Extracellular face process of apoptotic cell death. Gangliosides: with ○ Last only about 10 days. complex sugar linkages and CELL GROWTH AND MAINTENANCE terminal sialic acids Require a constant supply of both energy and that confer negative Glycolipids and charges. the building blocks that are needed for synthesis sphingomyelin of macromolecules. Cell-cell and cell- Organellar biogenesis: all organelles have to be matrix interactions replicated. Inflammatory cell recruitment Sperm-egg PLASMA MEMBRANE: PROTECTION AND NUTRIENT interactions ACQUISITION Fluid bilayers of amphipathic phospholipids with: ○ Hydrophilic head groups: face the Lipid rafts: membrane components associate aqueous environment. laterally with each other in the bilayer. ○ Hydrophobic lipid tails: interact with Plasma membrane is liberally studded with a each other to form a barrier to passive variety of proteins and glycoproteins involved in: diffusion of large or charged molecules. ○ Ion and metabolite transport Bilayer is composed of a heterogeneous ○ Fluid-phase and receptor-mediated collection of different phospholipids. uptake of macromolecules Asymmetric partitioning of phospholipids is ○ Cell-ligand, cell-matrix, and cell-cell important in several cellular processes: interactions Proteins interact with the lipid bilayer by one of four general arrangements: Inner membrane Electrostatic scaffold for intracellular proteins. GENERAL ARRANGEMENTS OF PROTEIN INTERACTION Polyphosphoinositid WITH LIPID BILAYER Phosphatidylinositol es: hydrolyzed by phospholipase C to Transmembrane (integral) proteins: one or more generate intracellular relatively hydrophobic a-helical segments that second signals like traverse the lipid bilayer. diacylglycerol and Proteins synthesized in cytosol and post- inositol translationally attached to prenyl groups/ fatty trisphosphate. acids insert into the cytosolic side of the plasma membrane. Glycosylphosphatidylinositol (GPI) anchors on the extracellular face of the membrane. Extracellular proteins can be noncovalently associated with transmembrane proteins, which serve to anchor them to the cell. LARGER COMPLEXES OF PLASMA MEMBRANE PROTEINS May assemble under the control of: ○ Chaperone molecules in the RER or; ○ Lateral diffusion in the plasma membrane. 4 Notes by Maximo, D.J. & Meroy, C. J.  Week 2: Chapter 1’s The Cell as a Unit of Health and Disease Lateral Diffusion: dimerize or trimerize in the Larger molecules: presence of ligand to form signaling units. ○ Uptake occurs after binding to specific Glycocalyx: functions as a chemical and cell-surface receptors. mechanical barrier; involved in cell-cell and cell- ○ Internalization occurs through a matrix interactions. membrane invagination process by intracellular matrix of clathrin proteins. PASSIVE MEMBRANE DIFFUSION Clathrin: a hexamer of proteins that Small, nonpolar molecules spontaneously assembles into a basketlike ○ O2 and CO2: dissolve in lipid bilayers and lattice to drive the invagination process. rapidly diffuse across them. ○ Hydrophobic molecules: estradiol or CAVEOLAE-MEDIATED ENDOCYTOSIS vitamin D. Caveolae (”little caves”): non coated plasma Small polar molecules membrane invaginations associated with GPI- ○