Tumour Pathology 4 Flashcards
What is mitosis?
Mechanism of cellular replication
What does mitotic division generate?
Two genetically identical daughter cells
What is a cell cycle?
Time interval between miotic division
What is the cell cycle made up of?
G0
G1
S
G2
M
What happens during G0?
Left cell cycle and stopped dividing
What happens during G1?
Synthesis of components needed for DNA synthesis
What happens during S?
DNA synthesis
What happens during G2?
Preparation for mitosis
What happens during M?
Mitosis and cell division
How much cell divisions occur per second in humans?
25 x 106
How many cells are in the body?
1013
What does quality control insure?
Genetic fidelity:
Each cell must recieve a full chromosome compliment
Mutations in DNA sequences must not pass on
What factors is the cell cycle control by?
External factors
Intrinsic factors
What external factors control the cell cycle?
Hormones
Growth factors
Cytokines
Stroma
What intrinsic factor controls the cell cycle?
Critical checkpoints (restriction point R)
What does progress before and after restriction point R depend on?
Prior depends on external factors
After becomes autonomous
Where is R?
At the end of G1
What does G1 control mechanism ensure?
Everything is ready for DNA synthesis
What does G2 control mechanism ensure?
Everything is ready for cell division
What do checkpoints in G1 check?
Cell size is inadequete
Nutrition supply inadequete
Essential external stimulus lacking
DNA damage detected
What do checkpoints in S check?
DNA is not replicated
Chromosome mis-alignment
What do checkpoints in G2 do?
Cell size is inadequete
DNA damage is detected
What are checkpoints?
Systems of cyclically active and inactive enzymes
What is a catalytic subunit activated by?
Regulatory subunit
What are cyclin dependant kinases (CDK)?
Catalytic subunits
What are the catalytic subunits?
Cyclin-dependent kinases (CDK)
What are cyclines?
Regulatory subunits
What are the active enzyme component of checkpoints called?
CDK/cyclin complex
What is the process of cyclines and cyclin dependant kinases?
1) Different CDKs and cyclines operate at sequential stages of the cycle
2) Active CDK/cyclin complex phosphorylates target proteins
3) Phosphorylation results in activation/inactivation
4) Substrates regulate events in the next cycle phase
How are CDKs regulated?
CDKs are constitutively expressed in an inactive form, whereas cyclines accumulate and are destroyed as cycle progresses
CDKs inhibitors (CKIs)
What are the 2 families of CKIs?
INK4A family
CIP/KIP family
What do molecules of the INK4A family do?
Bind to CDK4 and 6 and prevent association of these with their cyclin regulatory proteins
What are the members of the INK4A family?
P16INK4A
P15INK4B
P18INK4C
P19INK4D
What is a member of the CIP/KIP family?
P21CIP1
What do CDK inhibitors do?
Bind to the cyclin/CDK complexes
What does the Retinoblastoma gene do?
Encodes a 110kDa phophoprotein (pRb) which is hypophosphorylated
What does hypophosphorylated mean?
Phosphorylated to a less than normal extent
What does phosphorylation do?
Increases a cells progress through the cycle
What is pRb phosphorylated by?
Active cyclin D/CDK complex
What does pRb target?
E2F transcription factor
What does a hypphosphorylated/active Rb do?
Inactivates E2F
What does a phosphorylated/inactive Rb do?
Loses affinity for E2F
When is Rb active?
When it is hypophosphorylated
When is Rb inactive?
When it is phosphorylated
What does E2F do?
It is a potent stimulator of cell cycle entry. free E2F transcription factor activates vital target genes
What does pRb binding to E2F do to the cell cycle?
Stops it
What is carcinogenesis?
The initiation of cancer formation
What is carcinogenesis caused by?
Mutation of genetic material that upsets the normal balance between proliferation and apoptosis
What does uncontrolled proliferation lead to?
Tumours
Loss of the ability to control proliferation is due to mutations in genes regulating?
Cell division
Apoptosis
DNA
What is carcinogenesis caused by specifically?
Envrionmental agents
Inherited
What environmental agents can cause carcinogenesis?
Chemicals
Radiation
Oncogene viruses
What is the process of chemical carcinogenesis?
1) Purine and pyrimidine bases in DNA are critically damaged by oxidising and alkylating agents
2) Chemical carcinogens or their active metabolites react with DNA forming covalent bound productes (DNA adducts)
3) Adduct formation at particular chromosome sites cause cancer
What are critical targets for radiation damage?
Purines and pyrimidine bases in DNA
What is the primary defect in cancer?
Uncontrolled proliferation due to cell cycle dysregulation
What are 2 regulatory pathways that frequently cause cancer?
Cyclin D-pRb-E2F pathway
P53 pathway
What genes are the cause of dysregulation at G1 to S causing most cancers?
Rb
CDK4
Cyclin D
P16
What is the function of P53?
Maintain genetic integrity
How do P53 levels change in damaged cells?
They increase
What does the increase of P53 in damaged cells do?
Induces a cycle arrest at G1
Facilitates DNA repair
Severe damage of P53 leads to P53-induced apoptosis
What happens if there is no P53 present?
No cell arrest
Genetically damaged cells proliferate and form malignant tumours
