Week 6 - Cell Proliferation & Growth Flashcards
What is the G phase?
Gap Phase
- monitor internal and external environment
- ensure suitable conditions
- G1 length can vary
- depending on external conditions
- and extracellular signals
- unfavourable conditions can delay progress
- or enter G0
- restriction point near end
- is a commitment point
What are the checkpoints in the cell cycle?
restriction point
- Start
- late G1
- cell commits to cell-cycle entry
G2/M transition
- early mitotic events triggered
- lead to chromosome alignment on mitotic spindle
metaphase-to-anaphase transition
- sister-chromatid seperation stimulated
- leads to mitosis and cytokinesis completion
What are Cdks?
Cyclin-Dependent Kinases
- activity rises and falls throughout
- regulated by cyclins
- bind to cyclins to activate
- cyclins undergo synthesis and degradation
- cdk levels remain constant
What are the four classes of cyclins?
G1/S
- activate cdks in late G1
- trigger progression through Start
- interact with one cdk
S
- after progression through Start
- stimulate chromosome duplication
- interact with same cdk as G1/S-cyclin
- and another cdk
M
- stimulate entry to mitosis
- at G2/M transition
- fall in mid-mitosis
- interact with same cdk as S-cyclin
G1
- in most cells
- govern activities of G1/S-cyclins
- interact with two cdks
How is CDK activity inhibited?
- phosphorylation
- at amino acid pair
- at kinase active site
- inhibits complex activity
- by Wee1 kinase
- phosphatase Cdc25 dephosphorylates
- to increase activity
- inhibition by CKIs (Cdk Inhibitor Proteins)
- by large rearrangement of active site structure upon binding
How is metaphase to anaphase transition triggered?
- protein destruction
- APC/C (*Anaphase-Promoting Complex or Cyclosome) is an ubiquitin ligase
- catalyses destruction of
securin - protects protein linkages
- holding sister-chromatid pairs together
S- M-cyclins - inactivates most cdks
- proteins that were phosphorylated by cdks are dephosphorylated
- APC/C remains active in G1 for stable cdk inactivity period
- activity changes with association to activating subunits
How is the cell cycle regulated?
mitogens
- stimulate cell division
- triggers G1/S-cdk activity
growth factors
- stimulate cell growth
- increases cell mass
- by promoting protein synthesis
- and inhibiting protein degradation
survival factors
- promote cell survival
- suppress apoptosis
What is the MAP kinase cascade?
Mitogen-Activated Protein Kinase Cascade
- increase of Myc
- transcription regulatory proteins
- increases gene expression of G1 (D) cyclins
- promotes cell-cycle entry
- G1-cdk complex activates gene regulatory factors
- E2F proteins
- bind to promoters for genes required for S-phase entry
What happens in the absence of mitogenic stimulation?
- E2F gene expression inhibited
- by E2F and RetinoBlastoma (Rb) protein interaction
- Rb phosphorylated by G1-cdk complex in mitogen presence
What is the role of E2F1 in metabolism?
- regulates PDK4 expression
- inhibits PDH activity
- blocks conversion of pyruvate to acetylene CoA
What is the role of cyclin D1 in metabolism?
- modulates transcription factor NRF-1 activity
- inhibiting OXPHOS
- facilitates HKII expression
- facilitating glycolysis
- these result in TCA intermediates accumulation
- leave TCA cycle to provide substrates for biosynthetic processes
How do metabolic demands change over the cell cycle?
G1
- high translation rates
- mitochondria fusion
S
- increased nucleotide synthesis
- dNTPs required
- maintained high translation rates
mitosis
- decreased translation rates
- mitochondrial fission
- enables allocation of organelles to both cells
- increased lipid synthesis
- to enable cytokinesis
