4) Cell Cycle Flashcards
What are the stages of the cell cycle?
Mitosis
Interphase: G1, S, G2
Describe the changes to DNA content in the cell during the stages of the cell cycle:
G1 - 2N diploid
S - 2N-4N
G2 - 4N tetraploid
M - 4N-2N
Describe the function of CDKs:
Serine/threonine kinases which promote cell cycle progression when bound to cyclins
How do CDK and cyclin levels change during the cell cycle?
CDK protein levels mainly stable, cyclin levels rise and fall so activation of CDK oscillates
What CDK/cyclin complexes are needed in G1?
CyclinD/CDK4-6
What CDK/cyclin complex are needed in G1 to S progression
CyclinE/CDK2
What CDK/cyclin complex are needed in S and G2 phases and why?
CyclinA/CDK2
Triggers polymerase activity
What CDK/cyclin complex promotes entry into mitosis?
CyclinB/CDK1
How do CDK/cyclin complexes interact with pRB and E2F in G1?
CDK complex phosphorylates RB to allow E2F to carry out transcription of S phase genes
What factors positively regulate the cyclinD/CDK4-6 complex?
Growth factor, MAPK, myc oncogene, PI3K
What factors negatively regulate the cyclinD/CDK4-6 complex and how?
Inhibitor of kinase 4 (INK4)
p16, p15, p18, p19
Bind CDK4 to prevent complex forming
What factors negatively regulate the cyclinE/CDK2 complex and how?
CDK-interacting protein/kinase inhibitor protein
p21-CIP1, p27-KIP1
Bind to complex and inhibit the kinase activity
How does p16 (INK4A) protect from cancer?
Protects against lots of oncogenic activity due to mutations e.g. in moles
Give examples of cancers in which p16 is lost:
Pancreatic cancer, T cell ALL, glioblastoma
Give examples of cancer in which cyclin D1/CDK4 is overexpressed:
Mantle cell lymphoma, breast cancer
How does CDK1 promote progression through mitosis?
CDK1 phosphorylates substrates involved in nuclear envelop breakdown, chromosome condensation and mitotic spindle assembly
How is the cyclinB/CDK1 activated?
Activated by CDC25 phosphatase removing the phosphates that inactive the complex
How is the cyclinB/CDK1 inactivated in the case of DNA damage?
If there is damage kinase check 1 is activated and causes wee1 to phosphorylate the complex
Explain the spindle assembly checkpoint:
Allows mitosis to continue if the chromosomes are properly attached to the spindle apparatus. If there is go signal, SAC promotes degradation of cyclin B for mitosis progression
What is the result of a defective spindle assembly checkpoint?
Aneuploidy - gain or loss of entire chromosomes
Why are broad spectrum CDK inhibitors ineffective?
Need to be used at higher dose (toxic)
CDKs exist that have functions outside of the cell cycle
Give examples of CDK4/6 selective inhibitors:
Palbociclib, ribociclib
How does HPV interact with Rb?
HPV produces E7 proteins that binds and inactivates Rb
