cell proliferation Flashcards
what is cell proliferation
the increase in cell number (needed for homeostasis)
control of normal cell proliferation
- signal is sent from a mitogen (growth factor) to induce homeostasis
why is the mitogenic signal needed?
- cells can’t divide unless they have passed the restriction point at the end of the G1 phase
- they can only divide if the signal has been sent, the cell is undamaged, and the environment is right for it to divide
- the mitogen signal allows to overcome the R point
Mitogen Activated Protein Kinase (MAPK) signalling cascade
- intrasignalling cascade that works downstream from signalling receptor
- it’s needed to sustain phosphorylation
types of MAPK
- ERK pathway - growth factor
- p38 pathway and JNK pathway - DNA damage, cytokines, osmotic stress activating inflammation or apoptosis
- they all have 3 proteins in a cascade
stages of cell proliferation
- mitogen binds to complementary receptor
- receptor becomes phosphorylated
- receptor activation leads to the activation of g proteins
- activated g protein attracts the first protein of the signalling cascade to become activated
- signal is relayed from one signal to another (via phosphorylation)
- signal finally relayed to transcription factors to induce cellular response
turning off mitogenic signal at start
- release of mitogen is mediated by proteinases e.g. metalloproteinases
- blocking the action of metalloproteinases, you can block the release of the mitogen
- done through downregulation of receptor
turning off mitogenic signal - receptor
- after receptor is phosphorylated, they are targeted for degradation
- they are tagged with ubiquitin which means they are delivered to the endosome where they fuse to the lysosome
- degraded so that no signal can be sent
how does p53 act as a tumour suppressor
- when cells sense DNA damage, kinases acting as sensors cause the phosphorylation of p53
- phosphorylation of p53 prevents Mdm2 binding to p53 and hence blocks its degradation
- p53 levels accumulate and co-ordinates the required response
turn over of p53
- p53 is continuously synthesised and destroyed
- Mdm2 binds to p53 tagging it for degradation by the proteasome
what are cdks
cyclin dependent kinases
- regulators at control points in cell progression of cell cycle
how cdks work
- bound to respective cyclins they act on proteins
- they are kept at a constant level and are inactive
- need to be bound to cyclin to be activated
- when active they phosphorylate its substrate
what is the function of the R point?
- first r point at the G1 phase halts the cell cycle
- means the cell can’t progress until appropriate level of mitogenic signal and optimum conditions are met
mitogenic signals stimulating hyperphosphorylation of Rb
- mitogen signalling activate transcription factors
- transcription factors bind to DNA and codes for cyclin D mRNA
- cyclin D mRNA is translated to produce cyclin D
- cyclin D-binds and activates Cdk4/6
- Cdk4/6 phosphorylates Rb which inactivates Rb and causes it to release its inhibition on E2f
- E2f is now active and induces gene expression of cyclin E and other cyclins
how can a cell pass the R point
cells need inactive Rb (retinoblastoma protein) and free E2f
what do Cdk inhibitors do?
- bind to cyclin Cdk complexes to block action, so block cell cycle progression
- prevent passage of R point
s phase
- DNA replicated
- synthesize chromatin proteins for packaging copied DNA into chromosmes
g2 phase
delay the commitment of entering mitosis
- grows in size and checks DNA is faultless
prophase and prometaphase
- cyclin B-Cdk1 phosphorylates proteins
- condensing of DNA
- formation of mitotic spindles
- breakdown of nuclear envelope
- preparation for chromosome segregation
metaphase
- chromosomes move to the poles
- spindle assembly checkpoints (SAC)
- unattached kinetochores to the spindle is detected by SAC (can’t entre anaphase)
anaphase and telophase
- chromatids are connected by cohesion proteins
- cyclin B-Cdk1 tiggers the breakdown of cohesions
- separation of chromatids need activation of anaphase promoting complex to destroy the connection
- deactivation of cyclin B-Cdk1 results in spindle disassembly and reformation of nuclear envelope
what is necrosis
cell death due to injury or exposure to toxic chemicals
what is apoptosis
programmed cell death
what is caspases
proteases which cleave other proteins
stages of caspases
- caspases cleaves proteins of the cytoskeleton - bulging out of the membrane
- caspases cleave proteins of the nuclear envelope causing the nucleases to breakdown
- caspases activate nuclease which cut DNA into fragments
- cell breaks into several apoptotic bodies
- apoptotic bodies are cleared by macrophages through phagocytosis
intrinsic pathway of cell death
- DNA damage - P53 activated
- expression of pyroptotic protein
- protein leads to the release of cytochrome C from the mitochondria
- signal of DNA damage comes from within the cell
extrinsic pathway of cell death
- death receptor and death ligand