Cell Growth And Differentiation Flashcards
What are the three main groups of disease?
Developmental conditions, neoplasia and others
What are developmental conditions?
Related to cell growth or differentiation
What are neoplasia (and metaplasia)?
Cancers and tumours
What are the two main groups of cell growth?
Hypertrophy and hyperplasia
What is hypertrophy?
Bigger cells (more proteins and membrane)
What drives hypertrophy?
Elevated protein synthesis
What is hyperplasia?
More cells
What is hyperplasia caused by?
Cell division or proliferation
What does cell differentiation begin with?
Exit from the cell cycle
What are the three broad classes of extracellular signals?
Paracrine, autocrine, endocrine
What do paracrine signals do?
Stimulate proliferation of a different cell type that has the appropriate cell surface receptor
Where are paracrine factors produced?
Locally
What are autocrine signals produced by?
Cell that also expresses the appropriate cell surface receptor
How do endocrine signals work?
Released systematically for distant effects
What are the type of proteins used in cell growth and differentiation?
Proteins that:
Stimulate proliferation and promote survival
induce differentiation and inhibit proliferation
Induce apoptosis
What do mitogens do?
Stimulate proliferation and promote survival
What are the phases of the cell cycle?
Mitosis, G1, S phase, G2
What are quiescent cells and what phase are they in?
Cells that have left the cell cycle- G0
Can quiescent cells rejoin the cell cycle?
Yes
What is FACS used to measure?
DNA content of every cell in a population
What are the controls of the cell cycle checkpoints?
Specific protein kinases and phosphatases
What do the controls of the cell cycle checkpoints ensure?
Strict alteration of mitosis and DNA replication
What are the three cell cycle checkpoints (and when do they happen)?
Restriction point (end of G1) G2/M phase checkpoint Mitotic checkpoint
What is checked at the restriction point?
DNA not damaged
Cell size
Metabolite/nutrient stores
What does the G2/M checkpoint check?
DNA completely replicated
DNA not damaged
What is colchicine used for?
Immune supression
What is checked at the mitotic checkpoint?
Chromosomes aligned on the spindle
When do extrinsic factors act on the cell cycle?
G1
What does CDK stand for?
Cyclin dependent kinases
What does CDK do?
Catalytic subunit
What does cyclin do?
Regulatory subunit
What is cyclin expression induced by?
Growth factors
What does an active cyclin-CDK complex do?
Phosphorylates specific substrates
What destroys the cyclin-CDK complex?
Proteasomes
What does post-translational phosphorylation result in?
Activation, inhibition or destruction
What is the retinoblastoma protein (RB)?
Key substrate of G1 and G1/S cyclin dependent kinases
How does RB normally work?
Unphosphorylated RB binds E2F transcription factor preventing its stimulation of S-phase protein expression
- > RB is phosphorylated and E2F dissociates in the presence of cyclin D-CDK4 and cyclin E-CDK2
- > E2F stimulates expression of more cyclin E and S phase proteins
- > DNA replication starts
What are some cyclin E and S phase promoters?
DNA polymerase, thymidine kinase, PCNA
What are some sequential activites in the cell cycle?
Mitogens in G1 phase signal to the nucleus
- > drives early gene expression
- > encode delayed genes
- > cyclin D able to form active complexes with CDK4/6
- > hypophosphorylates RB
- > allows some cyclin E expression which causes hyperphorphorylation of RB
- > activation of E2F responsive genes
- > cyclin E and CDK 2 phosphorylates and activates cyclin A and CDK 1
- > same happens to cyclin B and CDK1
- > RB dephosphorylation mediated by PP1
What does DNA damage trigger?
Cell cycle arrest or apoptosis
What is stopping of the cell cycle driven by?
CDKI genes
What things attempt DNA repair?
Nucleotide or base excision enzymes, mismatch repair etc
What causes programmed cell death?
BCL2 family or caspases
What happens if the cell senses DNA damage?
Cell cycle stops, DNA repair attempted, if not possible -> programmes cell death
What happens to TP53 in the normal cell?
Completely and continously destroyed by a proteasome
What happens to TP53 if there is DNA damage?
Kinases are activated
- > phosphorylates TP53
- > phosphorylated TP53 can’t be destroyed by proteasome
- > phosphorylated TP53 then accumulates
What are the functions of TP53?
Expression of CKI causing cell cycle arrest
DNA repair - if not possible it causes apoptosis
What mutations are the most frequent in cancer?
TP53 loss of function
What are the ways in which TP53 loss of function mutations cause cancer?
Prevent cell cycle arrest, apoptosis and DNA repair
How does the prevention of DNA repair lead to cancer?
More mutations -> more heterogenity -> more adaptation -> cancer progression
What are the types of chemo drugs?
S phase, M phase and colchicine
What do S phase drugs do?
DNA damage
What do M phase drugs do?
Mess up the mitotic spindle
What are the types of M phase drugs?
Vinca alkaloids, paclitaxel
What do vinca alkaloids do?
Stabalise free tubulin
Prevent microtubule polymerisation
Arrest cells in mitosis
What does paclitaxel do?
Stabalise microtubules
Prevents depolymerisation
Arrest cell in mitosis
What are the two types of S phase drugs?
5-fluorouracil and cisplatin
How does 5-fluorouracil work?
Prevents synthesis of thymidine
How does cisplatin work?
Binds to DNA causing damage and blocking repair
