The cell in health and disease II Flashcards
what are the signals which cells respond to?
pathogens
damage to neighbouring cells
contact with neighbouring cells which is mediated by adhesion molecules or gap junction signalling.
contact with the surrounding extracellular matrix- mediated by integrins.
Cells can also respond to secreted molecules such as growth factors, cytokines and hormones.
give an overview on receptor-mediated signalling
Receptor mediated signalling is a very important communication mechanism for cells. Receptors can be present within the cell or on the cell surface. Intracellular receptors are transcription factors in that they cause DNA to be transcribed. These receptors are activated by lipid-soluble ligands that can easily cross cell membranes. Examples of lipid soluble ligands include vitamin D and steroid hormones such as oestrogen and testosterone.
Cell surface receptors are usually transmembrane proteins with extracellular domains which bond soluble secreted ligands.
what can happen after a ligand binds to a cell surface receptor?
one of four things can happen;
- An ion channel can open. This happens typically at a synapse between electrically excitable cells at a neuromuscular junction.
- A G-protein is activated and this is how eg. hormones mediate their effects.
- A tyrosine kinase is activated. Tyrosine kinase activation is how growth signals operate, driving cell division.
- A latent transcription factor is activated. This activation is a common feature of multiple pathways which regulate normal cell development.
A kinase is an enzyme that modifies other proteins, by chemically adding phosphate groups, that is phosphorylation. Tyrosine kinase phosphorylates particular tyrosine residues. Phosphatases can remove this phosphate inhibiting signalling.
(PICTURE)
Name and describe the different types of receptors
Receptor Tyrosine Kinases (RTKs) include the receptors for insulin, epidermal growth factor and platelet derived growth factor. EGF binds to to this receptor.
Immune receptors, integrins and some cytokine receptors are examples of receptors which have no intrinsic kinase activity. These use a cytoplasmic tyrosine kinase to phosphorylate the receptor or other proteins.
GPCRs cross the membrane 7 times. After ligand binding, the receptor associates with a GTP-binding protein (G protein) that contains GDP. Ligand binding exchanges GDP for GTP, activating signalling. Adrenaline binds to a G-protein coupled receptor.
Nuclear hormones such as oestrogen bind to a hormone receptor which then activates transcription of target genes.
nuclear hormones such as oestrogen bind to a hormone receptor which then activates transcription of target genes.
Transcription refers to the creation of a complimentary strand of RNA copied from a DNA sequence. This results in the formation of messenger RNA (mRNA), which is used to synthesize a protein via another process called translation.
- Most pathways which transduce the signal from the membrane do so by activating a transcription factor which then migrates to the nucleus to bind to the DNA.
- MYC and JUN are examples of transcription factors which we will meet again when we talk about cancer. These factors activate genes which cause growth.
- P53 is known as the guardian of the genome and is an example of a transcription factor which stops growth and this factor is also important in control of cancer.
how do growth factors work?
- they stimulate the activity of proteins which are needed for cell survival, growth and division.
- promote the entry of cells into the cell cycle.
- relieve blocks on cell cycle progression.
- prevent apoptosis
- enhance synthesis of cell components
give an example of a growth factor
EPIDERMAL GROWTH FACTOR (EGF)
source: macrophages, keratinocytes and other epithelial cells
function: proliferation of keratinocytes + fibroblasts. Migration of keratinocytes. Formation of granulation tissue.
what is the extracellular matrix (ECM)?
The ECM is secreted by cells and surrounds them in tissues. It has long been understood to be the structural support for cells since its characteristics set the characteristics of the tissue (i.e. bone compared to cartilage compared to brain). However, instead of simply being a passive, mechanical support for cells, it is in fact an extraordinarily complex scaffold composed of a variety of biologically active molecules that are highly regulated and critical for determining the action and fate of the cells that it surrounds.
what are the functions of the ECM?
Support cell anchorage, polarity and migration.
Control cell proliferation via growth factors and integrin signalling.
Provides a scaffold for tissue renewal.
Creates tissue microenvironments.
what are the components of the ECM?
The extracellular matrix is made up of structural proteins such as collagen fibres which gives tissue tensile strength and elastin which gives tissue the ability to recoil
after stretching.
The second component of extracellular matrix is water hydrated gels. These gels include proteoglycans and hyaluronan which gives the extracellular matrix the ability
to resist compression and which also provide lubrication. These gels are important for example in joint cartilage.
Other extracellular matrix components include fibronectin and laminin which are examples of adhesive glycoproteins. Adhesion receptors are also important.
give an overview on collagen
- the major structural protein in the human body.
- 2 types of collagen: fibrillar and non-fibrillar collagen
- has a triple helical structure which gives it significant strength. This tensile strength is further enhanced by the presence of lateral cross links of the triple helices by covalent bonds which require vitamins C to form.
- Genetic defects in collagens cause e.g. osteogenesis imperfecta and Ehlers-Danlos syndrome.
Give an overview on elastin
Elastin is important in the structure of heart valves, blood vessels, the uterus, skin and ligaments.
- It confers the ability on tissue to recoil after deformation.
- Elastin is associated with a mesh-like network composed of fibrillin.
- Marfan’s syndrome is caused by a mutation in the fibrillin-1 gene. Typical
characteristics of Marfan’s syndrome include being tall, having abnormally long and slender limbs, fingers and toes (arachnodactyly), heart defects and
lens dislocation where the lens of the eye falls into an abnormal position.
give an overview on integrins
- A large family of transmembrane glycoproteins which allow cells to attach to the ECM.
- They link the intracellular skeleton to the outside world, and they mediate cell to cell interaction for example between endothelium which lines blood vessels and white blood cells in the setting of inflammation.
- They play a central role in platelet aggregation and can trigger signaling which influences locomotion, proliferation, cell shape and cell differentiation.
Cell proliferation is necessary for development, maintenance of homeostasis and replacement of dead or damaged cells. DNA must be accurately replicated, and all other cell constituents must be synthesised. The sequence of events that results in cell division is called the cell cycle.
give an overview of the cell cycle
In the G1 phase, the cell is active. It duplicates organelles and components of the cytosol and starts to replicate centrosomes. In the S phase, DNA is replicated and then it passes into the G2 phase where growth continues, protein is synthesised, and replication of the centrosomes is completed. The cell then moves through the mitotic phases of prophase, metaphase, anaphase and telophase, producing two daughter cells. The cell may
then exit from the cycle.
Cell cycle progression is driven by proteins called cyclins and cyclin-associated enzymes called cyclin-dependent kinases (CDKs). There are three checkpoints in the cycle. describe them
G1/S checkpoint: check if cell nutrition, size and environment are favourable and that all DNA is intact.
G2/M checkpoint checks to see that all DNA is completely replicated
metaphase/anaphase checkpoint will check if all the DNA is intact and if all chromosomes are attached to the mitotic spindle.
These quality control checkpoints ensure that cells with genetic imperfections do not complete replication. DNA repair mechanisms are triggered if DNA abnormalities are detected and if the abnormality is too severe, the cells either undergo apoptosis or enter into a state of senescence, primarily through p53-dependent mechanisms. Cyclin-dependent kinase inhibitors (CDKIs) enforce these cell-cycle checkpoints.
