Life and Death of the cell Flashcards
What is endocrine signaling?
hormone secretion into blood by endocrine gland to influence distant target cells
What is autocrine signaling?
targets a site on the same cell
what is paracrine signaling?
secretory cell releases signals that impact an adjacent target cell
what is the difference between external and internal signals for cell proliferation?
external signals - bind to receptors on the cell surface
intracellular signalling triggere activation of proliferative pathways inside of the cell
what are the three types of extracellular signlas regulating cell prolifeartion/ cell death?
- mitogens- stimulate cell division by relieving intracellular negative controls that block cell cycle progress
- growth factors- stimulate cell growth (increased cell mass) by promoting synthesis of proteins and by inhibiting their degradation
- survival factors- promote cell survival by suppressing apoptosis (programmed cell death)
what type of molecules are growth factors usually?
usually a protein or steroid hormone that binds to specific receptors on the cell surface and transduce signal into cell
what are cyclin-cyclin depdendent kinase complexes?
CDK complexes regulate transition through the cell cycle
- G1 cyclins help promote passage through the restriction point in late G1
- G1/S-cyclins bind Cdks at the end of G1 and commit the cell to DNA replicaiton
- S-cyclins bind Cdks during S phase and are required for the initiation of DNA replicaiton
- M-cyclins promote the events of mitosis
what is the cyclin dependent kinase complex composed of?
cyclins + cyclin dependent kinases = cyclin dependent kinase complex
What are cyclins?
they are regulatory subunits- increase and decrease during cell cycle - act as substrate for CDK enzyme switching on kinase activity degraded at certain points in cell cycle
do CDKs or cyclins fluctuate during the cell cycle?
levels of CDK are steady
but levels of cyclin proteins fluctuate during the cell cycle
what activates Cyclin dependent kinases?
Cyclin binding - causes partial activation of CDK, then phosphorylation by ‘CDKactivating kinase’ activates the enzyme fully
describe the loss of cell cycle regulation in mantle cell lymphoma
expression of cyclin D1 is placed under control of the IgH promoter
as a result of chromosomal translocation, the upregulation of cyclin D 1 is induced
Cyclin D1 is bound to CDK4 - activates the transcription factor E2F -releasing it from negative regulation by the tumor suppressor Rb -
E2F drives the cell cycle through the G1-S phase of the cell cycle
what does the addition of growth factor to G0 arrested cells do?
it induces transcription of many genes - some early response genes are transcription factors that activate transcription of late response genes
late response genes include mid and late G1 cyclins and Cdks- activate genes invovled with DNA synthesis
What is p53?
the ‘guardian of the genome ‘
- transcription factor
- activated by DNA damage
- stops cell replicating
- p53 mutations are prevalent in many cancers
describe how p53 works?
it is a tumor supressor
- induces p21, which inhibits kinase activity of cyclin -cdk complex, Rb is not phosphorylated and remains boudn to E2F - S phase genes NOT turned on
- if DNA damage is repaired, p53 levels drop, p21 decreases so the cyclincdk can phosphorylate Rb to release E2F- S phase genes turned on and cell proliferation proceeds
- If DNA damage not repaired - p53 remains high and cel undergoes apoptosis
what’s the difference between apoptosis and necrosis?
apoptosis = cell death which is a programmed sequence of events that leads to elimination of cells without releasing harmful substances into the surrounding area
necrosis = occurs when a cell is damaged by an external force such as poison, injury, lack of blood supply etc
What role do extrinsic signals have in the regulation of apoptosis?
Extrinsic signals - initiated from neighboring cells - most cells require signals to stay alive “trophic factors” the absence of trophic factors causes cells to activate apoptosis
in other instances, cells recieve signals to commit suicide from other cells, particularly important in developmental process
what role to intrinsic signals play in apoptosis?
intrinsic signals - cell senses damage and initiates its own death - if DNA damage exceeds the repair capabilities of the cell integrity of DNA is impaired
what is the difference between the extrinsic and intrinsic pathway of cell death?
Extrinsic
- initiated by formation of a death -inducing cell surface receptor signalling complex
- leads to activation of initator caspase 8
Intrinsic
- mediated by changes in mitochondrial function
- regulated by anti-apoptotic Bcl2 family members
- associated with activation of initator caspase 9
what activates the “death receptor” of the extrensic apoptotic pathway?
- ligand binds
- trimerisation of receptor
- activation of initiator pro-caspase 8
- activates other caspases ultimately leading to apoptosis
what role does p53 play in the intrinsic apoptotic pathway?
- cytoplasmic P53 antagonises anti-apoptotic effect of Bcl2- which results in the mitochondrial outer-membrane permeabilization and release of cytochrome C into cytosol
- Cytochrome C binds to Apaf1 - apoptotic protease activating factor
- cytochrome C-Apaf1 complex binds to initiator caspase 9
- the pro-apoptotic proteins activate caspase 9
- caspases induce DNA fragmentation
actions of caspases results in???
- DNA fragmentation by endonuclease
- loss of cell shape and organelle breakdown
- cell fragmentation into apoptotic bodies
- apoptotic bodies phagocytosed by macrophages
What role does overexpression of BCL2 have in cancer?
it is an anti-apoptotic protein - so overexpression of BCL2 is found in a number of forms of leukemia
What role do ‘decoy receptors’ play in cancer?
Decoy receptors - bind death signal ligands but do not transduce signal -
these are overexpressed in many cancers
