Cell replication Flashcards
Which cells divide at different rates?
- Embryonic vs adult cells: frog early embryo 30 min
- Complexity of system: yeast 1.5-3 h
- Necessity for renewal: intestinal epithelial cells around 20h hepatocytes around 1 year
- State of differentiation: some cells never divide I.e. neurone and cardiac myocytes
- Tumour cells
- Appropriate regulation of cell growth rewired (i.e. contact inhibition)
What is the relevance of appropriate regulation of cell division?
- Premature, aberrant mitosis results in cell death
- In addition to mutations in oncogenes and tumour suppressor genes, most solid tumours are aneuploid (abnormal chromosome number and content).
- Various cancer cell lines show chromosome instability (loose and gain whole chromosomes during cell division)
- Perturbation of protein levels of cell cycle regulators is found in different tumours - abnormal mitosis
- Contact inhibition of growth
- Attacking the machinery that regulates chromosome segregation is one of the most successful anti-cancer strategies in clinical use
What is the cell cycle?
- Orderly sequence of events in which a cell duplicates its contents and divides in two
- Duplication, division, co-ordination
What are the different phases in cell cycle?
M phase: mitosis (division) Nuclear division Cell division (cytokinesis) Interphase: (duplication) DNA organelles protein synthesis G0 phase: cell cycle machinery dismantled G1 phase (gap): decision point S phase: synthesis of DNA/ protein G2 phase (gap): decision point
What is the S phase?
DNA replication
- Protein synthesis: imitation of translation and elongation increased as well as capacity
- Replication of organelles: centrosomes, mitochondria, Golgi etc) in case of mitochondria, needs to coordinate with replication of mitochondrial DNA
What is the centrosome?
DNA replication
- Consists of two centrioles: barrels of nine triplet microtubules
- Function: microtubules organising centre (MTOC) biotic spindle
Describe prophase 1
condensed chromosomes - each consists of 2 sister chromatids, each with a kinetochore
In prophase, chromatin is condensed down (wrapped around positively charged histones) into chromosomes
Describe prophase 2
- Replicated chromosomes condense
- Duplicated centrosomes migrate to opposite sides of the nucleus and organ size the assembly of spindle microtubules
- Mitotic spindle forms outside nucleus between the 2 centrosomes
Describe spindle formation
- Radial microtubule arrays (ASTERS) from around each centrosome (MTOC)
- Radial arrays meet
- Polar microtubules form
- Microtubules are in a DYNAMIC state
Describe metaphase
-Chromosomes aligned at equator of spindle
Describe pro-metaphase I
Early pro metaphase:
- Breakdown of nuclear membrane
- Spindle formation largely complete
- Attachment of chromosomes to spindle via kinetochores
Describe pro-metaphase II
Late pro metaphase
- Microtubules from opposite pole is captured by sister kinetochore
- Chromosomes attached to each pole congress to the middle
- Chromosome slides rapidly toward centre along microtubules
What is anaphase?
- Paired chromatids separate to form 2 daughter chromosomes
- Cohesion holds sister chromatids together
Describe Anaphase A
- Breakdown of cohesion
- Microtubules get shorter
- Daughter chromosomes pulled toward opposite spindle poles
Describe Anaphase B
Daughter chromosomes migrate towards poles Spindle poles (centrosomes) migrate apart
Describe telophase
- Daughter chromosomes arrive at spindle
- Nuclear envelope reassembles at each pole
- Assembly of contractile ring
What happens when something goes wrong in cell cycle?
E..g. cell not big enough or DNA damage
1. Cell cycle arrest
-At check points (G1 and spindle check point)
-Can be temporary (i.e. following DNA repair)
2. Programmed cell death (apoptosis)
-DNA damage too great and cannot be repaired
-Chromosomal abnormalities
-Toxic agents
Cell cycle progression aborted and cell destroyed
What triggers a cell to enter cell cycle and divide?
-In absence of stimulus, cells go into G0 (quiescent phase)
-Most cells in the body which are differentiated to perform specific functions
-Cells are not dormant but are non-dividing
Exit from G0 highly regulated: requires growth factors and intracellular signalling cascades
What is signalling through the cell like?
Signalling cascades:
- Response to extracellular factors
- Signal amplification
- Signal integration
- Modulation by other pathways
- Regulation of divergent responses
Why is mitosis most vulnerable period of cell cycle?
- Cells are more easily killed (irradiation, heat shock, chemicals)
- DNA damage can not be repaired
- Gene transcription silenced
- Metabolism?
What is replication of centrosome?
- Consists of two centrioles:
Barrels of nine triplet microtubules. - Function:
Microtubules organizing centre (MTOC)
Mitotic spindle.
What is needed for cell cycle checkpoints?
-Requires: CENP-E BUB protein kinases -BUBs dissociate from kinetochore when chromosomes are properly attached to the spindle When all dissociated, anaphase proceeds. -Monotelic (just one bonded) Syntelic (same MTOC) Amphelic (normal) Merotelic (both MTOCs to one) -Can be targeted in cancer – generate permanent checkpoint signals to halt development
What is signalling with protein kinase cascades?
- Kinases activation leads to signal amplification, diversification and opportunity for regulation
- c-Myc is an oncogene and can make a cell enter the growth phase (stimulated by cancer or GF
What are cyclin dependent kinases?
-Cdk1, Cdk2, Cdk4, Cdk6
-Present in proliferating cells throughout cell cycle
-Activity is regulated by:
Interaction with cyclins
Phosphorylation
What are cyclins?
-Cyclin A, B, D, E
-Transiently expressed at specific points in the cell cycle
-Regulated at level of expression
Synthesised, then degraded
