Tumour pathology 4 Flashcards
What is cell cycle
Time interval between mitotic division
What is the timing for the cell cycle
G1- 8 hours
S- 10hr
G2-5hrs
M-hr
What is external factors in the cell cycle
Hormones, growth factors, cytokines, stroma
What is intrinsic factors in cell cycle
critical checkpoints - Restriction point (R)
prior to restriction point progress what does G1 depends
external stimuli
After restriction point what does the progression of the cell cycle become
autonomous - indépendant
What are the reasons G1 or G2 arrest the cell cycle
If cell size inadequate - G1 or G2 arrest
If nutrient supply inadequate - G1 arrest
Essential external stimulus lacking - G1 arrest
If DNA damage is detected - G1 or G2 arrest
when Mphase arrest the cell cycle
Chromosome mis-alignment - M-phase arrest
Where are the checkpoints in the cell cycle
G1 G2 M
What are checkpoints?
catalytic subunits are called cyclin-dependent kinases (CDKs) activated by regulatory sub-units called cyclins
What is the checkpoint active enzyme complex called
CDK/cyclin complex
How do CDK/cyclin complex work as check point mediators
phosphorylation of target proteins resulting in activation/inactivation of that substrate
What does the substrate do in the next phase of the cell cycle
Regulates events
What happens to cyclins in the cell cycle
accumulate and are destroyed by cell progress
How are CDKS expressed
inactive form
What two families of CDK inhibitors (CDKis) are important to checkpoints?
INK4A family and CIP/KIP family
How do CDK inhibitors work
Bind to CDK complex
What do active cyclin D/CDK complexes phosphorylate
pRb
What is hypophosphorylated pRbs function
bind to E2F
What happens when pRb is phosphorylated?
Becomes inactivated and looses its affinity for E2F, therefore free E2F can activate vital target genes stimulating cell cycle entry
What does active pRb act as
a brake in the cell cycle
What normal balance does carcinogeneis upset
Proliferation and apoptosis
Where can mutations occur to cause a cell to loose control of its proliferation
genes regulating cell division,
apoptosis,
DNA repair
What is the environmental agents causing cacinognesuis
Chemicals
Radiation
Oncogenic viruses
What is damaged in DNA by various oxidizing and alkylating agents
purine and pyrimidine bases
What is DNA adducts
Chemical carcinogens or their active metabolites react with DNA forming covalently bound products
What does adduct formation at particular chromosome site cause
cancer
High-energy radiation is carcinogenic if received in sufficient doses of what types of radiation
ultraviolet radiation (UV-B present in sunlight)
X-rays
Gamma radiation
What is the primary defect in cancer
Uncontrolled cell proliferation via
cell cycle dysregulation
What are the two regulatory pathways frequently disrupted in the cell cycle
The cyclin D-pRb-E2F pathway - G2 check point
p53 pathway - G1 checkpoint
What happens if the The cyclin D-pRb-E2F pathway
Absent or inactive pRb releases the cell cycle brake
Where are all cancers disregulated due to mutations
G1-S
Disregulation at the G1 - S is because of the Mutation in what four potential genes
Rb, CDK4, cyclin D and p16 (multiple tumor suppressor)
What is the function of P53
Maintain the integrity of cells by facilitating DNA repair and arresting at G1
Where are p53 levels increased
in damaged cells
What happens to cells with mutated p53 gene
do not G1 arrest or repair damaged DNA
therefore damaged cells proliferate and form malignant neoplasms
What mutations in other genes mimic the effect of pRb loss and drive proliferation
Mutational activation of cyclin D or CDK4
Mutational inactivation of CDKIs
What cancer is cause by the amplification of cyclin dependant kinase
Melanoma, sacroma
What is the malignant mutation is caused by the p16(INK4a) that inhibits CDk’s
melanoma
What malignant cancer arrises from rB mutation
retinoblastoma
How do retrovirus cause cancer
insert onocongene into host causing rapid cell division
