Tumour pathology 4 MW % + Flashcards
Normal cell cycle
Mitosis
- mechanism of cellular replication
- nuclear division plus cytokinesis
Mitotic division generates 2 genetically identical daughter cells
Cell Cycle = time interval between mitotic divisions
Cell cycle diagram
- G0: Exit from cell cycle. Stopped undergoing mitosis indefinitely
- G1 : Cell growth. Metabolically active; duplicates organelles and cytosolic components and centrosome replication begins
- S: DNA Replication
- G2: Preperation for mitosis. Cell growth continues; enzymes and other proteins are synthesized; centrosome replication completed.
Cell cycle phases pic 2
Cell cycle control
- A cell must progress through cycle phases in the correct sequence in order to produce viable progeny
- DNA synthesis and mitosis must occur sequentially
- Quality control ensures genetic fidelity (accuracy) in daughter cells
–each cell must receive a full chromosome complement
–mutations in DNA sequences must not pass on
Name the external and intrinsic factors in cell cycle control?
External factors
- Hormones,
- Growth factors
- Cytokines
- Stroma
Intrinsic factors
- Critical checkpoints ⇒ Restriction point (R)
- prior to restriction point progress through G1 depends on external stimuli
- after restriction point progression becomes autonomous (free)
Phases of cell cycle
Other cell cycle checkpoints
- If cell size inadequate - G1 or G2 arrest
- If nutrient supply inadequate - G1 arrest
- Essential external stimulus lacking - G1 arrest
- If the DNA is not replicated - S arrest
- If DNA damage is detected - G1 or G2 arrest
- Chromosome mis-alignment - M-phase arrest
What are the checkpoints?
- System of cyclically active and inactive enzymes
- Catalytic sub-unit activated by a regulatory sub-unit
-catalytic subunits are called cyclin-dependent kinases (CDKs) (Substrate)
- regulatory sub-units are called cyclins (enzyme)
- The active enzyme complex - CDK/cyclin complex
Cyclins and cyclin-dependent kinases
- Different CDKs and cyclins operate at sequential stages of the cycle
- Active CDK/cyclin complexes phosphorylate target proteins
- Phosphorylation results in activation/inactivation of that substrate
- Substrates regulate events in the next cycle phase
Regulation of CDK activity
- CDKs are constitutively expressed in an inactive form
- Cyclins accumulate and are destroyed as cycle progresses
Regulation by CDK inhibitors (CKIs)
- INK4A family bind to CDK4 and 6 and prevent association of these CDKs with their cyclin regulatory proteins
- 2nd family of CKIs - CIP/KIP family
- These inhibitor molecules bind to cyclin/CDK complexes
The Retinoblastoma gene
- Encodes a 110 kDa phosphoprotein (pRb) expressed in almost every cell of the human body
- pRb is hypophosphorylated (partial phosphorylation)
- phosphorylation increases as cells progress through the cell cycle
- active cyclin D/CDK complexes phosphorylate pRb
pRb functon
- The most important target is E2F transcription factor
- Hypophosphorylated/active Rb inactivates E2F
- Phosphorylated/inactive pRb loses affinity for E2F
- Free E2F transcription factor activates vital target genes
E2F is a potent stimulator of cell cycle entry
Note: Active pRb applies a brake to the cell cycle
Carcinogenesis
- Cancer is a genetic disease
- Carcinogenesis is caused by mutation of genetic material that upsets the normal balance between proliferation and apoptosis (cell death)
- uncontrolled proliferation of cells leads to tumours
- Only mutations in genes regulating cell division, apoptosis, and DNA repair cause a cell to lose control of proliferation
Carcinogenesis factors►
Non-lethal genetic damage
–Environmental agents
- Chemicals
- Radiation
- Oncogenic viruses
Inherited
DNA damage response
- Cells with mutated p53 do not G1 arrest or repair damaged DNA
- Genetically damaged cells proliferate and form malignant neoplasms
