2: Cell cycle Flashcards
Which factors influence the speed of cell devision?
- embryonic vs. adult cell
- complexity of systems (e.g. rapid devision in yeast cells)
- Necessitiy for renewal (intestinal epithelium vs. hepatocytes)
- state of differentiation (e.g. neurons/cardiomyocytes that don’t replicate)
- Tumor cells ?? –> different mechanisms
What happens when the appropriate regulation of cell devision goes wrong?
Which factors might lead to it?
Cancer might develop that
- mutation in TSG/oncogenes (–> + aneupleudy)
- chormosome instability (loss/gain of chromosome)
- abnormal mitosis –> mistake in cell cylce regulatory proteins
- Contact inhibition of growth –> cells don’t stop growing when they reach the edges of a space
What is the cell cycle?
Orderly sequence of events in which a cell duplicates its contents and divides in two
What are the different phases in the cell cycle of an eucariotic cell?
- M Mitosis
- Interphase
- G0
- cell cycle machinery dismantled –> cell fulfils normal function
- G1
- phase (Gap) - Decision point: are specific structures (e.g. centromeres) duplicated?
- S
- DNA dublication
- G2
- phase (Gap) - Decision point
- check new DNA for mistakes
- G0
What happens during the S-phase of the cell cycle?
- DNA replication
- Replication of organelles (e.g. golgi, mitochondria, centromeres)
- Increased protein synthesis
Explain the structure of a centrosome
Consists of two centrioles (barrels of nine triplet microtubules
What is the function of the centrosome?
- microtubule organizing center (MTOC) (also in interphase!!)
- mitotic spindle
Explain the life cycle and replication of the centrosomes
Split in G1 and are fully replicated at the end of S-phase
What happens during the prophase of mitosis?
- condensation of DNA
- centrosomes migrate to opposite sides in cell
- spindels start to form
Explain the formation of the mitotic spindles
- ASTERS form (radial micturtubule arrays) around each centromer –> Microtubule organisation centre)
- Tadial arrays meet
- Polar micrutubules form (= radial microtubules that meet in middle)
What happens during the early prometaphase in the cell cycle?
- Chromosomes aligned at equator of the spindle
In the early:
- break down of nuclear membrane
- spindles are largely complete
- attach of chromosomes to the spindles via kinetochores at the centromer region of chromosome
What happens during the late prometaphase
- Microtubule from opposite pole is captured by sister kinetochore
- Chromosomes attached to each pole congress to the middle
- Chromosome slides rapidly towards center along microtubules
What happes during the anaphase in mitosis?
- Paired chromosomes separate to form two daughter chromosomes
- Cohesin holds sister chromatids together
- There is a anaphase A+ B
What happens during Anaphase A in mitosis?
- Breakdown cohesin (protein that holds togehter sister chromatids)
- Microtubules get shorter
- Daughter chromosomes pulled toward opposite spindle poles
What happens during Anaphase B?
- Daughter chromosomes migrate towards poles
- Spindle poles (centrosomes) migrate apart
- so cytokinesis does not happen too close to chormosomes and they have enough space
What happens during telophase of mitosis?
Chromosomes arrive at spindles
Nuclear envelope resembels
Assembly of contractile ring (for cytokinesis), made of actin and myosin
What happens at the transition out of metaphase before Anaphase can start?
Explain its mechanism
Spindle Assembly checkpoint
- are all chromosomes connected hthe kinetochore?
- When kinetochores are connected they stop signaling
- At the checkpoint it is waited, until there is no more signaling (i.e. all chormonsomes are connected) until Anaphase can start
What are the different factors required in the Spindle Assembly checkpoint?
(aka Mitotic Checkpoint)
- CENP-E (signals when not attached)
- BUB protein kinases (signals when attached)
BUBs dissociate from kinetochore when chromosomes are properly attached to the spindle
Explain the different things that can go wrong at the Spindle assembly checkpoint
Missatachmen of spindles to kinetochore might lead to aneupleudy
- Meroteilic attachment (2 differnt spindels attach to the same chromatid)
- one spindle attaches to both sister chromatids of one chromosomes
How might alterations in the cell cycle lead to aneupleudy?
- errors in DNA or centrosome replication
- might lead to multipolar spindles
- or in aberrant (irrtümliche) citokinesis
Explaint the exploitation of chromosome-missegregation as an anti-cancer treatment
- Inhibition of Checkpoint kinase (CHKE1 and CHKE2)
- Normally : Serine threonine kinase activation holds cells in G2 phase until all is ready
- inhibits attachment-error-correction mechanism
- inhibition leads to untimely cell transition to mitosis –> not ready yet because there is still an error
- Normally : Serine threonine kinase activation holds cells in G2 phase until all is ready
- Taxanes and vinca alkaloids
- Alters microtubule dynamics
- Produces unattached kinetochores
- Causes long-term mitotic arrest.
What if something goes wrong during the cell cycle? e.g Cell is not big enough or DNA damage
- Cell cylce arrest at checkpoints (G1+ spindle checkpoint)
- can be temporarily and resolved e.g. with DNA repair
- Apoptosis
- if DNA damage to great, chromosomal abnormalities or toxic agents
What are the different check points in the cell that drive/ control cell proliferation?
How is that important in cancer?
- G1: Checkpoint in G1 (Growth Factor dependant)
- initiate progession
- G2: Damage of DNA
- M: Sister chromatid alignment
All these checkpoints can be altered by tumors!!
Explain the concept of De-regulation of cell cycle during tumorigenesis
Tumors can inhibit entering into G0 phase where the cell just does its nomal function and promote proliveration
What are the physiological triggers that tell the cell to enter the cell cycle and devide?
Most cells in body are in G0 phase and fulfil their normal functions:
Exit from G0 highly regulated - requires growth factors and intracellular signalling cascades
Summarise the intracellular signaling cascade that takes place during aktivation of cell proliveration by a growth factor
They set of the signal cascade:
- Response to extracellular factors
- Signal amplification
- Signal integration
- Modulation by other pathways
- Regulation of divergent responses
Name examples of two growth factors
Which receptor do they bind to?
Epidermal growth factor (EGF)
Platelet-derived growth factor (PDGF)
–> both bind to Receptor Protein Tyrosine Kinase (RPTK)
Explain the process of a growth factor binding to a growth factor receptor (RPTK)
In present of a (dimeric) ligand–> growth factors
- Receptors form dimers
- auto-crossphorylation causes activation of receptor
- (phosphorylated AA in receptor)
How can phosphorylation of an Amino-Acid lead to altered protein function?
The added phosphate group (negatively charged) can alter protein function by:
- causing a change in shape (conformation) leading to change in activity (+ve or –ve)
- creating a docking site for another protein
Explain the process of phosphorylation
Exchange of Hydroxy-group for a phosphate group (ATP dependant, katalysed by Kinase)
Only 3 AA can be phosphorylated:
- Serine
- Threonine
- Tyrosine
What does the auto-phosphorylation in the tyrosine kinase domain of a growth factor receptor cause?
It causes receptor activation leading to
- kinase cascade
- binding of adaptor proteins
Explain the protein kinase cascade
An activated kinase will often activate further kinases
- will lead to signal amplification
- and gives the opportunity for better regulation because
- Phosphorylation in reversible (by a phosphatase) means that individual kinases can be inactivated
What is An Amphiletic Microtubule attachment?
normal (centrosome-kinetochore1, centrosome-kinetochore2) pulled to 2 ends
What is an Syntelic attachment of microtubule to the chromosome?
Same Centrosome
2 microtubules from 1 centrosome connect to both kinetochores, pulled to one end – one cell has duplication, other has one less chromosome
What is Merotelic attachment of Mictotubule to the Chormosome?
Ripped
2 microtubules (each from different centrosome) connect to 1 kinetochore, ripped apart, both sister cells with one less chromosome
What is a Monotelic attachment of Micturubule to Chromosome?
•one microtubule attached to one kinetochore (no microtubule attached to other Kinetochore)
In which cell cycle phase does the Mitotic Checkpoint Happen?
Between Meta and Anaphase
–> Checks for Attachment of Telomeres
What happens during Metaphase of Mitosis?
Starts once MT are attached to Kinetochores
- align at equator of spindles
What is the difference in chromosome movement between Prometaphase and Metaphase?
In Prometaphase: try to bring a bit of order into the chromosomes + tries to get it at the right angle (picture)
In Metaphase: Alignment at eqator of spindle (begins once Microtubule are attached)
What is the most vulnerable phase of the cell cycle?
Why?
Mitosis because
- Cells are more easily killed (irradiation, heat shock, chemicals)
- DNA damage can not be repaired
- Gene transcription silenced
What happens to protein synthesis in S-phase of the Cell cycle?
initiation of translation and elongation increased; capacity is also increased
Explain the process of Cytokinesis
Actin myosin ring between two cells forms and contracts
- new membrane is inserted
- midbody remains (connection between the two daughter cells)
- also midbody gets seperated
Which proteins stop processing in the cell cycle if damages/ errors are present at Checkpoints?
- Checkpoint kinase (CHKE1 and CHKE2) – When kinase signals it holds the cell and stops transition into next phase
- inhibition leads to untimely cell transition to mitosis
- exploited by Vinca Alkaloids and Taxanes
