Cell cycle and apoptosis Flashcards
Mitosis and cell cycle lead to
Cell growth and division (mitosis)
Production of two identical daughter cells, with DNA duplicated exactly and divided equally
Cell cycle
Ordered set of events
Interphase (longest phase) –> mitotic phase –> G0 (cells that cease division) –> G1 (cell grows) –> S phase (replication of DNA)
Mitosis and cell cycle are essential
Even in mature organisms
Mitosis
Interphase –> prophase (kineticores) –> metaphase –> anaphase –> telophase
Regulation of cell cycle
Extra- and intracellular signals
G1 checkpoint - growth and environment, DNA damage
G2 checkpoint - DNA daage
M checkpoint - chromosome alignment on spindle
Rao and Johnson Nuclear Fusion Expt
S + G1 –> 2S (S phase nucleus releases something that drives G1 nucleus into S)
S + G2 –> S + G2 (G2 nucleus is resistant to S phase promoting factor)
G1 + G2 –> G1 + G2 (G1 and G2 do not influence each other)
Interphase + M –> 2M (mitotic nuclei release mitosis-promoting factor that affects all interphase nuclei)
Cell cycle control
Cyclins:
- G1 cyclin (D)
- S-phase (E & A)
- M-phase (B & A)
- Levels rise and fall with stages of the cell cycle (D remains constantly high)
Cyclin dependent kinases (Cdks)
Trigger major cell cycle transitions
Phophorylate proteins that control cell cycle
Levels remain fairly constant
Must appropriate cyclin to be activated
Activity control by Cdk inhibitors
-certain cdks bind to certain kinases at diff stages of cell cycle
MPF
Mitosis promoting factor initiates mitosis
Mitotic cyclins destroyed
activates anaphase promoting factor and chromatids separate (M)
G1 cyclins
bind to cdks and prepare chromosomes for replication
SPF
S phase promoting factor enters nucleus and prepares DNA for replication
When is cyclin E destroyed
After S phase
When does mitotic cyclin conc. increase
G2 phase
G0
‘Quiescent’
Cells that have permanently or temporarily left cell cycle e.g. lymphcyte
Terminal differentiation e.g. neuron, epithelial cell
Active repression of genes needed for cell cycle
Cell cycle in disease
Dysregulated cell growth = cancer
Many cell cycle regulatory genes are tumour suppressor genes
p53
Blocks cell cycle if DNA damaged
Mutated in approx. 50% of cancers
p27
Cyclin dependent kinase inhibitor
< levels predict poor outcome in breast cancer
Cell cycle in oral pathology
Mtosis visible in H&E
Number indicated active growth e.g. ulcer healing
Location e.g. suprabasal may indicate pathology
Apoptosis
Programmed cell death
Essential for normal development
Destroys cells that may be threat (virus infected, immune, DNA damage)
Withdraw of positive signals (growth factors, hormones)
Receipt of negative signals (e.g. UV, death activators, hypoxia)
Apoptosis vs necrosis
controlled/ uncontrolled
energy dependent / no ATP required
cells shrink/ swell
membrane intact / no membrane integrity
non-inflammatory/ inflammatory
no scarring/ scarring
individual or small cell groups / large cell groups
nuclear fragmentation/ nuclear dissoloution
physiological (can be pathological)/ pathological
2 main pathways of inducers and pathways
Intrinsic: mitochondrion and cytochrome c
-if cyt c released, combines with apaf-1 –> cascade –> apoptosis
-bcl-2 protein binds to apaf-1 –> stops it initiating apoptosis
-tumour associated cells might block pathway
Extrinsic: ligand binds to death receptor
-conformational change initiates cascade –> apoptosis
-e.g. cytotocis T cells kills other cells this way
Caspases
Proteolytic enzymes (cysteine proteases)
Effectors of apoptosis
Present as inactive proenzymes (zymogen)
Activity controlled by number of mechanisms
Caspase activation cascade
Caspase 9 activates caspase 2, 3, 6, 7, 8, 10
Capsase substates
Cytoskeleton
Nuclear membrane
Activation of DNase
Bcl-2
Apoptosis in dental physiology
Craniofacial growth & development Homeostasis in mucosa, skin and pulp Tooth development Bone remodelling (osteoblasts die by apop.) Wound healing (inflammatory cells)
Apoptosis in disease
Avoidance in cancer = survival/ proliferation
HPV inactivates p53
Epstein Barr Virus protein similar to Bcl-2
Melanoma inhibits expression of Apaf-1)
Fas antagonists block T cell cytoxicity
Autoimmune e.g. SLE (lupus), rheumatoid arthritis
Apoptosis in disease: increase in apoptosis
Neurodegenerative, HIV
Apoptosis in oral cancer and salivary gland tumours
Bcl-2, fas. p53 differentially expressed
Apoptosis in lymphomas
Reduced apoptosis
Apoptosis in odontogenic tumours and cysts
Active expression of apoptotic proteins by lining
Apoptosis in Sjogren’s syndrome
Epithelium sensitive to apoptosis
Apoptosis in oral pathology
Apoptotic bodies/ cells visible under H&E (tend to pull away from other cells due to shrinkage)
-highly eosinophilic due to high conc. of enzymes
Common conditions such as Lichen Planus
