Cell growth and proliferation Flashcards
Why are cell numbers controlled?
Loss of control can lead to diseases such as cancer
How are cell numbers controlled?
Cells divide (proliferate) when the body needs them and die when the body doesnt
Why is cell proliferation important?
Early development - required at fertilisation as a single cell proliferates into an organism with 10^14 cells
Adult life: Tissue maintenance Skin and gut cells replaced Repairing damaged wounds Replace cells when they die Adapt to the environment Fight infection
Can any cell divide?
Most mature cells lose the ability to divide on their own
Differentiated cells must be replaced from precursors (stem cells)
What are stem cells?
Present in small numbers in tissues
Precursors to mature cells which can differentiate into any somatic cell
What is the self renewal property of stem cells?
As a stem cell differentiates into a somatic cell
it divides in two where one cell is the cell becoming the new cell type and the other cell will become another stem cell
What is the self renewal property of stem cells important?
Ensures we have constant supply of stem cells
What stimulates cell proliferation?
Mitogenic signals from surrounding tissues
What properties doe growth factors posses?
Both growth and mitogenic activities
What is cell growth?
Cells increase in size and increase in cytoplasmic organelles
What is cell division?
Chromosome duplication,
Mitosis,
Cytokinesis
What is cell proliferation?
Cell growth + cell division
How do cells proliferate?
Via the cell cycle
What is interphase?
G1 + S + G2
Cells grow and the nuclear DNA is duplicated
What is mitosis and cytokinesis?
The nucleus and cytoplasm divide to form 2 daughter cells
What are the regulators of the cell cycle?
Cyclin dependent kinases (Cdks)
What are Cdks?
Heterodimeric proteins of two subunits
Catalytic subunit
Regulatory subunit
What do Cdks do?
Phosphorylate proteins important during specific cell cycle phases
When is the Cdk subunit activated?
When it is bound to a specific cyclin subunit
Different Cyclin-Cdk dimers regulate each cell cycle pass
What are the main Cdks in the cell cycle?
C1/S-Cdk - Starts G1 phase
S-Cdk - Regulates movement into S phase
M-Cdk - Regulates movement from G2 into mitosis
What are the essential steps during the cell cycle?
- Increase cell size + cytoplasmic organelles (from G1)
- Overcome the Restriction Point (G1)
- Replicate the chromosomes once, and once only (S)
- Make sure chromosomes are fully duplicated (G2)
- Separate the duplicated chromosomes (M)
- Separate the two daughter cells (cytokinesis)
What happens during G1?
Cells grow in size during interphase by growth factors stimulating protein synthesis
Organelles expand or increase in number
What is the restriction checkpoint (R) in G1?
The checkpoint which cells can only progress through if appropriately stimulated by mitogens
What is G0?
Quiescent phase where cells enter when growth factors are limiting and not stimulating progression.
What is required for cells to progress through the Restriction point of G1?
Mitogenic growth factor signalling
Once through the R point, then further signalling is no longer needed
What is the process of how cells get through the restriction point?
- Mitogenic Growth Factor signalling induces transcription of Cyclin D
- Cyclin D protein combines with Cdk4/6 to form G1-Cdk
- G1-Cdk monophosphorylates pRb
- G1/S-Cdk hyperphosphorylates pRb in a feedback loop to completely inactivate it
- Phosphorylated pRb releases E2F which induces transcription of genes required for S phase
- The cell can now pass through to S phase
Which protein is hyperphosphorylated during G1?
Retinoblastoma Protein (pRb)
What happens if pRb is not phosphorylated?
Unphosphorylated pRb binds to the E2F transcription factor to repress cell cycle gene transcription.
What is the overall role of pRb?
Acts a R checkpoint to ensure that cells duplicate their chromosomes only when they are stimulated by mitogens.
What happens in S phase?
The chromosomes are replicated once and only once.
How does S phase ensure chromosomes are only replicated once?
- Pre-replicative complexes can only form at origins in G1 when Cdk activity is low
- Each origin fires once only in S phase in response to S-Cdk
- Each chromosome is replicated once only
- Origins are re-primed for replication only after mitosis & cell division
What is the G2 checkpoint?
Ensures cells cannot enter mitosis until the chromosomes are completely replicated in S phase
Cells are held here until this happens
What occurs at the G2 checkpoint?
M-Cdk is inactive preventing cells entering mitosis
Before replication is completed in S phase, Wee1 inhibitory enzyme phosphorylates Cdk-1 inactivating it
Once all chromosomes are replicated a phosphatase is activated to remove the inhibitory phosphate group off Cdk-1 reactivating it.
This then activates Cyclin B (M-cyclin) which releases the checkpoint
What are the stages of mitosis?
Prophase/Prometaphase
Metaphase
Anaphase
Telophase
Cytokinesis
What happens during prophase?
2 sister chromosomes duplicated in S phase are held together and condense to form chromatids
Central region of chromatics forms a kinetochore
Mitotic spindles form outside the nucleus between two spindle poles
What happens during prometaphase?
breakdown of the nuclear envelope
Mitotic spindles attach to kinetochores
What happens during metaphase?
Mitotic spindles link kinetochores to spindle poles to align the chromatids
What happens during anaphase?
Chromosome separation at anaphase starts when all kinetochores have attached to spindle
When all kinetochores are attached the APC is activated and the cohesins break down
Chromosomes are pulled apart towards opposite poles
What is the mitotic checkpoint?
Sends a stop signal when chromosomes have an unattached kinetochore to prevent the onset of anaphase.
When the kinetochores are attached the APC is activated.
What happens during telophase?
Daughter chromosomes reach opposite poles of the cell
Nuclear envelope reassembles around the sets of chromosomes to from distinct nuclei
Chromosomes decondense
What happens during cytokinesis?
A cleavage furrow is formed by the action of contractile rings which contract separating the daughter cells
What happens if a cell cycle checkpoint fails?
Leads to un-ordered cell cycle progression
What happens if the R checkpoint fails?
cells would enter S phase and replicate their chromosome without appropriate mitogenic signalling
Proliferation would be uncontrolled and lead to cancer
What happens if the G2 checkpoint fails?
cells would enter mitosis with incompletely replicated genomes
Causing gene loss or mutation
What happens if the M checkpoint fails?
chromosomes would not be properly segregated into the daughter cells
Cause altered chromosome number = Aneuploidy
How are checkpoints induced?
Induced by DNA damage
What happens when there is DNA damage?
- DNA damage stabilises p53 (transcription factor)
- p53 induces transcription of p21
- p21 binds and inactivates G1/S-Cdk, S-Cdk, M-Cdk
- Cell cycle is arrested at multiple points
- Prevents damaged chromosomes from being replicated
What is p21?
Cdk inhibitor which arrests the cell cycle and prevents damaged chromosomes from being replicated
What is apoptosis?
Programmed cell death
Digestion of cellular proteins and DNA
What is Necrosis?
Accidental cell death
Why is apoptosis important in early development?
Sculpt structures during morphogenesis such as digits
Why is apoptosis important in the body?
When cells are no longer needed
When cells are dangerous (infected, autoimmunity)
Following irreversible cell damage
How does apoptosis work?
When apoptosis is induced:
Caspases are activated
Initiator caspases are activated
These activate executioner caspases by prodomain cleavage
Executioner caspases degrade nucelar and cytosolic proteins
Phagocytes remove dead cells
How are caspases activated?
Synthesised in their procaspase form
Cleavage of prodomains activates the molecule
