F: CELL Flashcards
Cellular Growth Regulation by F Miralles
What controls Cell Proliferation?
*LOB: Demonstrate an understanding of the mechanisms that control cell proliferation and cell death.
Cell proliferation is controlled by growth factors, cytokines, and interleukins that stimulate cell division.
These factors include EGF, FGF, Interleukins (IL2 & IL4), NGF, PDGF, and IGF1.
Additionally, cyclin-dependent kinases (CDKs) and cyclins play a crucial role in regulating the cell cycle.
Cellular Growth Regulation by F Miralles
What are CDKs?
*LOB: Demonstrate an understanding of the mechanisms that control cell proliferation and cell death.
are protein kinases characterized by needing a separate subunit - a cyclin - that provides domains essential for enzymatic activity.
Cellular Growth Regulation by F Miralles
What controls Cell Death?
*LOB: Demonstrate an understanding of the mechanisms that control cell proliferation and cell death.
Cell death, specifically apoptosis, is controlled by a coordinated program of cell dismantling, including DNA fragmentation and cell shrinkage. Key regulators of apoptosis include proteins like TNFα and members of the TNF family, as well as the TP53 gene, which can initiate apoptosis in response to DNA damage.
Cellular Growth Regulation by F Miralles
The loss of growth regulation in neoplasia.
*LOB: Relate these mechanisms to the loss of growth regulation in neoplasia.
- Neoplasia is characterized by the loss of growth regulation, often due to mutations or dysregulation of key control mechanisms.
- This can involve overactivation of growth factors, mutations in tumor suppressor genes like TP53, and alterations in cell cycle checkpoint control.
- As a result, cells in neoplastic growth lose their ability to control proliferation and evade apoptosis, leading to tumor formation.
Cellular Growth Regulation by F Miralles
How is cell cycle progression controlled at checkpoints?
*LOB: Relate these mechanisms to the loss of growth regulation in neoplasia.
Cyclin-CDK activity, post-translational modifications, and cyclin-dependent kinase inhibitors (CKIs) are involved in checkpoint regulation.
CDKs control cell cycle progression through phosphorylation of target proteins.
Cell Damage and Cell Death by Dr F Miralles
Causes and mechanisms of cell damage / death
*LOB: Describe the biochemical and morphological differences between cells undergoing necrosis and apoptosis.
Genetic
Abnormal number chromosomes (aneuploidy)
Abnormal chromosomes (deletions/translocations)
Increased fragility (Fanconi’s anaemia)
Failure of repair (Xeroderma pigmentosa)
Inborn errors (Storage disorders ie. Tay Sachs disease)
Traumatic Damage
Interruption of blood supply
Direct rupture of cells
Entry of foreign agents
Infection
Toxic agents
Competition for nutrients
Intracellular replication
- viruses/mycobacteria provoking
an immune response
Inflammation
Trauma
Thrombo-embolism
Atherosclerosis
Vasculitis
Physical
Irradiation
Heat
Cold
Barotrauma
Chemical
Acids/corrosives
Specific actions e.g. enzymes
Interference with metabolism e.g. alcohol
Cellular Growth Regulation by F Miralles
How does the retinoblastoma protein (RB) regulate the cell cycle?
*LOB: Relate these mechanisms to the loss of growth regulation in neoplasia.
RB controls the G1/S transition by binding to E2F transcription factors.
E2F Transcription Factors: E2F transcription factors are essential for the expression of genes required for DNA replication and entry into the S phase of the cell cycle. These genes include those encoding DNA polymerases, thymidine kinase, and other proteins necessary for DNA synthesis.
Inhibition of E2F: When RB is in its hypophosphorylated state, it acts as a “brake” on the cell cycle. It binds to E2F transcription factors and prevents them from activating the genes responsible for DNA replication. This inhibition ensures that DNA replication only occurs when conditions are appropriate, such as when the cell has received proper growth signals and its DNA is intact.
Hyperphosphorylation of RB: As the cell receives the necessary signals and progresses through the G1 phase, RB undergoes hyperphosphorylation. This process is driven by cyclin-dependent kinases (CDKs) and cyclin-CDK complexes. As RB becomes increasingly phosphorylated, it loosens its grip on E2F.
Release of E2F: When RB is sufficiently phosphorylated, it releases its inhibition on E2F transcription factors. This release allows E2F to activate the genes required for DNA replication, thus facilitating the transition from G1 to S phase.
Cellular Growth Regulation by F Miralles
Name some drugs that act on the M-phase of the cell cycle.
*LOB: Relate these mechanisms to the loss of growth regulation in neoplasia.
Colchicine ( prevents microtubule polymerization, leading to the arrest of cells in mitosis.)
Vinca alkaloids (inhibit microtubule polymerization by binding to tubulin subunits, leading to the formation of abnormal microtubules.)
Paclitaxel (microtubule polymerization and prevents depolymerization.)
Cell Damage and Cell Death by Dr F Miralles
Necrosis
*LOB: Describe the biochemical and morphological differences between cells undergoing necrosis and apoptosis.
most common cause of cell death. Occurs after stresses such as ischemia, trauma, chemical injury
Energy deprivation causes changes. (e.g. cells unable to produce ATP because of oxygen deprivation)
- Cells swell due to influx of water (ATP is required for ion pumps to work).
- Haphazard destruction of organelles and nuclear material by enzymes from ruptured lysosomes.
- Cellular debris stimulates an inflammatory cell response
Cell Damage and Cell Death by Dr F Miralles
Microscopic Appearance of Necrosis
*LOB: Describe the biochemical and morphological differences between cells undergoing necrosis and apoptosis.
- Chromatin condensation/shrinkage.
- Fragmentation of nucleus.
- Dissolution of the chromatin by DNase causing a fading in
the basophillia of the chromatin.
Opacification: denaturation of proteins with aggregation.
Complete digestion of cells by enzymes causing cell to liquify (liquefactive necrosis).
Release of enzymes such as creatine kinase or lactate dehydrogenase
Release of proteins such as myoglobin
Cell Damage and Cell Death by Dr F Miralles
Types of Necrosis
*LOB: Describe the biochemical and morphological differences between cells undergoing necrosis and apoptosis.
Coagulative necrosis - typically seen in hypoxic environments.
Cell outlines remain after cell death and can be observed by light microscopy (e.g. myocardial infarction, infarct of the spleen).
Liquefactive necrosis - is associated with cellular destruction and pus formation (e.g. pneumonia).
Caseous necrosis - is a mix of coagulative necrosis and liquefactive necrosis (e.g. tuberculosis).
Fatty necrosis - results from the action of lipases on fatty tissues (e.g. acute pancreatitis).
Fibrinoid necrosis - caused by immune-mediated vascular damage. It is marked by deposition of fibrin-like proteinaceous material in arterial walls, which appears smudgy and acidophilic on light microscopy.
Cell Damage and Cell Death by Dr F Miralles
Clinical Investigations Associated
With Cell Death
*LOB: Detail the different mechanisms of apoptotic cell death.
- Muscular dystrophy. Damaged muscles release creatine kinase and lactate dehydrogenase (M3 and M3H isoforms).
- Heart attack. Damaged muscle cells release lactate dehydrogenase (H3 and H3M isoforms).
- Bone and liver disease. Damaged tissues release alkaline phosphatase and lactate dehydrogenase isoforms (different isoforms specific to various tissues).
- Haemolytic anaemias. Damaged red cells release LDH1/2.
Cell Damage and Cell Death by Dr F Miralles
Apoptosis
*LOB: Describe the biochemical and morphological differences between cells undergoing necrosis and apoptosis.
programmed cell death. Designed to eliminate unwanted host cells through activation of a co-ordinated, internally programmed series of events effected by a dedicated set of gene products
Selective process for the deletion of superfluous, infected or transformed cells.
Involved in:-
Embryogenesis
Metamorphosis
Normal tissue turnover
Endocrine-dependent tissue atrophy
A variety of pathological conditions
Cells shrink as the cytoskeleton is disassembled.
Orderly packaging of organelles and nuclear fragments in membrane bound vesicles.
New molecules expressed on vesicle membranes stimulate phagocytosis, no inflammatory response.
Cell Damage and Cell Death by Dr F Miralles
Microscopic Appearance of Apoptosis
*LOB: Describe the biochemical and morphological differences between cells undergoing necrosis and apoptosis.
- Nuclear chromatin condenses on nuclear membrane.
- DNA cleavage.
- Shrinkage of cell. Organelles packaged into membrane vesicles.
- Cell fragmentation. Membrane bound vesicles bud off.
- Phagocytosis of cell fragments by macrophage and adjacent cell.
- No leakage of cytosolic components.
- Expression of charged sugar molecules on outer and inner sucface of
membranes (recognised by macrophage and enhances phagocytosis - Protein cleavage by proteases, caspases
Cell Damage and Cell Death by Dr F Miralles
Autophagy
*LOB: Describe the biochemical and morphological differences between cells undergoing necrosis and apoptosis.
: Autophagy is responsible for the degradation of normal proteins involved in cellular remodeling found during metamorphosis, aging and differentiation as well as for the digestion and removal of abnormal proteins that would otherwise accumulate following toxin exposure, cancer, or disease. An example is the death of breast cancer cells induced by Tamoxifen.
Cell Damage and Cell Death by Dr F Miralles
Apoptosis is mediated by an intracellular proteolytic cascade
*LOB: Detail the different mechanisms of apoptotic cell death.
Cell Damage and Cell Death by Dr F Miralles
What cellular events are triggered by TNF to induce apoptotic cell death?
*LOB: Detail the different mechanisms of apoptotic cell death.
TNF induces the formation of a death-inducing signaling complex (DISC), which activates various cellular mechanisms involved in apoptotic cell death.
These mechanisms include:
- Disruption of Lamin A and B in the nuclear envelope
- Activation of PARP for DNA repair
- Involvement of DNA-PK in DNA repair processes
- Interaction with Topoisomerase II during DNA replication
- Activation of Raf-1 signaling pathway
- Inhibition of Akt/PKB pathway involved in cell survival
- Activation of STAT1 signaling for cellular responses
- Regulation of eIF4 to impact translation processes.
Cell Damage and Cell Death by Dr F Miralles
What is the apoptosome?
*LOB: Detail the different mechanisms of apoptotic cell death.
Cytochrome C forms a complex which induces caspases
Cell Damage and Cell Death by Dr F Miralles
How is cytochrome c regulated?
*LOB: Detail the different mechanisms of apoptotic cell death.
Bcl-2 is an anti-apoptotic protein on the outer mitochondrial membrane
Maintains mitochondrial membrane integrity and blocking the activation of downstream apoptotic pathways.
Cell Damage and Cell Death by Dr F Miralles
How does Bcl-2 contribute to apoptosis?
*LOB: Detail the different mechanisms of apoptotic cell death.
Bcl-2, an anti-apoptotic protein, prevents apoptosis by inhibiting the release of cytochrome c (Cyt C) from the mitochondria.
Transcriptionally upregulated molecules molecules bind to Bcl-2, causing its dissociation from the mitochondrial membrane. As a result, cytochrome c is released into the cytoplasm, where it participates in the formation of apoptosomes, initiating the apoptotic cascade.
Cell Damage and Cell Death by Dr F Miralles
What cancerous gene prevents apoptosis?
*LOB: Detail the different mechanisms of apoptotic cell death.
Mutations in the p53 gene are the most common mutations
in cancer. Some mutations destroy the ability of p53 to induce
Apoptosis.
