Chapter 1: The Cell as a Unit of Health and Disease Flashcards
What proportion of the human genome is protein-coding?
The human genome contains about 3.2 billion DNA base pairs, of which 20 000 (about 1.5%) are protein-encoding genes.
What proportion of the human genome is involved in gene regulation?
The human genome contains about 3.2 billion DNA base pairs, of which about 80% binds proteins and is thought to regulate gene expression.
List the major classes of functional non-protein-coding sequences in the human genome.
- Promoter and enhancer regions that provide binding sites for transcription factors.
- Binding sites for factors that organise and maintain higher order chromatin structures.
- Noncoding regulatory RNAs (eg. micro-RNAs, long noncoding RNAs). More than 60% of the human genome is transcribed into RNAs that are never translated into protein, but which nevertheless regulate gene expression.
- Mobile genetic elements (eg. transposons). These represent up to one third of the human genome.
- Special structural regions of DNA (eg. telomeres, centromeres).
What are the two most common forms of DNA variation in the human genome?
- Single-nucleotide polymorphisms (SNPs).
- Copy number variations (CNVs).
Define epigenetics.
Epigenetics is the regulation of gene expression that is not caused by alterations in the DNA sequence. Epigenetics helps to explain why different cells can express different parts of the host genome.
Discuss DNA packaging in cell nuclei with reference to nucleosomes, histones and chromatin.
Segments of DNA bind to low molecular weight proteins known as histones.
Each segment of DNA bound to a histone is known as a nucleosome.
The nucleosomes then stack together and the DNA-histone complexes are collectively referred to as chromatin.
What is the difference between heterochromatin and euchromatin?
Heterochromatin describes densely packed and therefore inactive segments of nuclear chromatin.
Euchromatin describes cytochemically dispersed (or unwound) transcriptionally active chromatin. Histones can be remodelled to allow different segments of the genome to be accessible to RNA polymerases. This is thought to account for differing gene expression and different phenotypes in the setting of an identical genotype.
Describe noncoding RNAs (eg. micro-RNA and long noncoding RNA).
- Micro-RNAs (miRNA) are involved in posttranscriptional gene regulation. miRNA are able to modulate gene expression by binding to messenger RNA (mRNA) and ‘silencing’ it.
- Long noncoding RNAs (lncRNA) modulate gene expression in many ways to inhibit or promote gene expression. For example, lncRNA can bind to chromatin and thereby inhibit RNA polymerase from transcribing genes in the region.
What is the role of the rough endoplasmic reticulum?
Protein synthesis. Proteins are then moved to the Golgi apparatus for packaging and organising.
What is the difference between lysosomes, proteasomes and peroxisomes?
- Lysosomes contain degradative enzymes that break down macromolecules such as proteins, lipids and nucleic acids.
- Proteasomes chew up denatured proteins to produce peptides. They can be involved in antigen-presentation and often help to consume negative regulatory proteins.
- Peroxisomes break down fatty acids and produce hydrogen peroxide.
What is the role of the mitochondria?
Oxidative phosphorylation to produce ATP for cellular energy needs.
To a lesser degree it also produces intermediaries needed for anaerobic metabolism. Furthermore, mitochondrial damage often triggers programmed cell death.
Describe the structure and function of the cell membrane.
The plasma cell membrane is a bilayer composed of phospholipids, cholesterol and proteins.
Each phospholipid has both a hydrophobic tail and a hydrophilic head. They are arranged such that the hydrophobic tails interact with each other within the cell membrane while the hydrophilic heads are exposed to the aqueous cytoplasmic or extracellular environments.
The cell membrane is liberally studded with proteins and glycoproteins that are involved in:
- ion and metabolite transport;
- fluid-phase and receptor mediated uptake of macromolecules; and
- cell-ligand, cell-matrix and cell-cell interactions.
What are the two major mechanisms of endocytosis?
- Caveolae-mediated endocytosis describes non-coated invaginations of the plasma membrane and is sometimes referred to as ‘cellular sipping’ or potocytosis.
- Pinocytosis and receptor-mediated endocytosis allow consumption of larger molecules by pinching off a specialised area of plasma membrane coated by clathrins. These clathrin-coated vesicles are then combined with endosomes and lysosomes to digest their contents. In this way receptor-bound proteins are ingested.
What are the three major cytoskeletal proteins?
- Actin microfilaments, which polymerise to control cell shape and movement. - Intermediate filaments, which impart tensile strength and allow a cell to withstand mechanical stress. - Microtubules, which essentially act as cables along which motor proteins transport molecules, organelles and vesicles.
What are the three major types of cell junctions?
- Tight junctions, which create an occlusive barrier between cells to prevent molecules and ions slipping in between cells. - Desmosomes, which mechanically attach cells to their neighbours or to the extracellular matrix. Often formed by association between cadherins in the cell wall. - Gap junctions, which allow intercellular chemical and electrical communication as well as the exchange of ions and small molecules. Gap junctions are formed by multiple tiny pores made up of transmembrane proteins known as connexins. Permeability is reduced by low intracellular pH and elevated intracellular calcium concentration.
What is the morphologic difference between the rough and smooth endoplasmic reticulum?
The presence of membrane-bound ribosomes.
What is the function of ribosomes?
Ribosomes translate mRNA into proteins.
Which cells are known to have a prominent smooth endoplasmic reticulum?
Steroid-secreting cells (eg. gonads, adrenals) or cells that catabolise lipid-soluble molecules (eg. the liver). Also, muscle cells have a modified smooth endoplasmic reticulum known as the sarcoplasmic reticulum, which acts as a calcium reservoir.
What are lysosomes and proteasomes?
Lysosomes are membrane-bound organelles that contain acid hydrolases which are used to breakdown molecules. These hydrolases include proteases, nucleases, lipases and glycosidases among others. Proteasomes degrade cytosolic proteins that are tagged for destruction by ubiquitin. These are generally senescent or misfolded proteins.
What are mitochondria?
Mitochondria are organelles which provide the enzymatic machinery for oxidative phosphorylation. They are also implicated in anabolic metabolism and are key regulators of programmed cell death.
Discuss the role of mitochondria in cell death.
There are two pathways of cell death: necrosis and apoptosis. Mitochondrial damage due to external cellular injury results in mitochondrial permeability transition pores that dissipate the proton potential and inhibit ATP generation. This leads to cellular death. Programmed cell death can be brought about by mitrochondria which leak cytochrome C, which activates caspases in the cytosol and leads to apoptosis.
Discuss the role of mitochondria in energy generation.
Each mitochondrion has two membranes, an inner membrane folded into cristae, and an outer membrane.
Within the inner membrane is the core matrix. This is the site of the citric acid cycle (Kreb’s cycle) as the enzymes of the citric acid cycle are found in the core matrix. As hydrogen ions are produced they move into the intermembrane space, where they then reenter the core matrix to follow the electrochemical gradient. The reentry into the core matrix generates ATP in the intermembrane space.
What are the three steps involved in cellular respiration?
- Glycolysis
- Citric acid cycle
- Electron transport chain
List the different types of cell signalling.
- Paracrine signalling. A signal that affect nearby cells only before being rapidly degraded or trapped by the extracellular matrix.
- Autocrine signalling. A signal that acts on the same cell that has secreted it, often as a way to amplify a process.
- Synaptic signalling. The transfer of neurotransmitters between neurons.
- Endocrine signalling. A signal is released into the bloodstream and acts on a distant cell.
What is the term for a signalling molecule?
A ligand.
What is the end result of cell signalling?
Virtually all cell signals result in changes to the intracellular environment through modulation of gene expression. This is achieved through signal transduction from an activated receptor-ligand complex to various transcription factors which then bind and localise nuclear DNA, ultimately changing gene expression.
What is a growth factor?
A growth factor is a protein that typically has a major role in cell proliferation. Growth factors often have secondary non-growth functions such as migration, differentiation and synthetic capacity.
How do growth factors promote growth?
By binding to receptors that ultimately modulate expression of genes that can:
- promote entry of cells into the cell cycle;
- relieve a block on cell cycle progression;
- prevent apoptosis; and
- enhance biosynthesis of cellular components needed for cell division (eg. nucleic acids, lipids, proteins).
List some common growth factors and their roles.
What is the relationship between growth factors and cancers?
Growth factors are often over expressed in cancerous cells. Therapeutics can target these growth factors and their receptors to improve treatment of such cancers. The HER2 receptor in breast cancer, for example, is a member of the epidermal growth factor (EGF) family.
What is signal transduction?
Signal transduction is the process of conveying an extracellular signal to the intracellular target, usually nuclear DNA.
Discuss vascular endothelial growth factors (VEGFs).
VEGFs are the major angiogenic factors. They stimulate the formation of blood vessels in injury and tumours. They are also produced at sites of inflammation and result in vascular dilatation and increased vascular permeability. Hypoxia is the major inducer of VEGF secretion.
What are the stages of the cell cycle?
- G1 (presynthetic growth)
- S (DNA synthesis)
- G2 (premitotic growth)
- M (mitotic)
Figure 1-17 Robbins & Cotran
How is the cell cycle regulated?
The cell cycle is regulated by activators and inhibitors. Cell cycle progress is driven by cyclins and cyclin-dependent kinases (CDKs). There are checkpoints in the cell cycle that ensure DNA has been replicated without errors. These occur at G1-S and G2-M. The checkpoints are policed by CDK inhibitors (CDKIs) which can slow or stop the cell cycle.
Figure 1-18 Robbins & Cotran
What are stem cells?
Stem cells are undifferentiated cells which can produce the different differentiated cell types of the body. Stem cells are defined by two properties: (1) self-renewal, thus allowing stem cells to maintain their numbers (2) asymmetric replication, in which one daughter cell differentiates and the other remains undifferentiated to maintain the stem cell population
Discuss transforming growth factor beta (TGF-Beta).
TGF-Beta is a pleiotropic growth factor with a wide range of effects. Primarily it drives scar formation and has anti-inflammatory effects. Scar formation is driven by stimulating the production of collagen, fibronectin and proteoglycans and inhibits matrix metalloproteinase activity. TGF-Beta also drives fibrosis in the lung, liver and kidneys in the setting of chronic inflammation. Anti-inflammatory effects are achieved by inhibiting lymphocyte proliferation and activity of other leukocytes.
What are collagens?
Collagens are structural proteins composed of three separate polypeptide chains braided into a ropelike triple helix. There are fibrillar collagens (eg. types I, II, III, V) which are found in the connective tissue such as bone, tendon and cartilage. These fibrillar collagens are very strong due to cross-linking between the triple helices. This cross-linking is vitamin C dependent. There are also non-fibrillar collagens (eg. type IV) which contribute to basement membranes.
What is elastin?
Elastin fibres are fibrous proteins of the extracellular matrix which consist of a central core of elastin with an associated meshlike network composed of fibrillin. Elastin allows tissues to recoil and recover their shape after physical deformation (eg. vessels, uterus, skin, ligaments).
What are proteoglycans?
Proteoglycans are proteins of the extracellular matrix which form highly hydrated compressible gels that confer resistance to compressive forces. Prominent in joint cartilage.
What is fibronectin?
Fibronectin is an adhesive glycoprotein that forms a major part of the extracellular matrix. It is synthesised by a variety of cells including fibroblasts, monocytes and endothelium. It has a central role in wound healing, where it provides a scaffold for extracellular matrix deposition.
What is laminin?
Laminin is the most abundant glycoprotein in the basement membrane. It attaches cells to the basement membrane and has a small role in cell signalling.
What are integrins?
Integrins are transmembrane glycoproteins that connect cells to the structural components of the extracellular matrix (eg. fibronectin and laminin). Integrins also have a role in leukocyte adhesion and vascular migration. Integrin receptors can also trigger signalling cascades influence cell locomotion, proliferation and differentiation.
