Cell Cycle Regulation And Cancer Flashcards
(29 cards)
What is cell division?
An integral part. Of the cell. Cycle, the life of a cell from formation to its own division
Eukaryotic cell divisions include…
Mitosis, the division of the genetic material in the nucleus
- This yields identical daughter cells that have two sets of chromosomes(23 pairs in humans) - Cells with two sets of chromosomes are called diploid
Cytokines, the division of the cytoplasm
Gametes are produced by a variation of cell division called meiosis
-Meiosis yields non identical daughter cells that have only one set of chromosomes, half as many as the parent cell (23 chromosomes in humans)
Contrast meiosis and mitosis
- Synapsis, Chiasma, Crossing over, tetrad, configuration
- Two cycles of cell division occur in meiosis ; there is no chromosome replication between divisions
- Meiosis results in 4 different haploid cells
- Mitosis results in 2 identical diploid cells
What are the phases of the cell cycle ?
The cell cycle consists of
Mitotic(M) phase (mitosis and cytokinesis)
Interphase (cell growth and copying of chromosomes in preparation for cell division)
Interphase (about 90% of the cell cycle can be divided into subphases
- G1 phase (“first gap”)
- S phase (“synthesis”)
- G2 phase (“second gap”)
- The cell grows during all three phases, but chromosomes are duplicated only during the S phase
Describe cell cycle control
For a cell to ensure proper replication of itself, there must be checkpoints at specific points in the cell cycle:
To ensure the previous stage was completed successfully or
To ensure that conditions are proper for the next stage 9f the cycle
G2/M checkpoint- is all DNA Replicated? Is environment favorable?-enter mitosis
Metaphase-to-anaphase: are all chromosomes attached to the spindle?-trigger anaphase and proceed to cytokinesis
Start checkpoint- is environment favorable?-enter cycle and proceed to S phase
Explain the cell cycle control system
The sequential events of the cell cycle are directed by a distinct cell cycle control system, which is similar to a clock
G1 checkpoint- cell cycle checkpoint. Apoptosis will occur if DNA is damaged and cannot be repaired. Otherwise, the cell is committed to divide
G2 checkpoint- Mitosis checkpoint. Mitosis will occur if DNA has replicated properly. Apoptosis will occur if DNA is damaged and cannot be repaired
M checkpoint- spindle assembly checkpoint. Mitosis will not continue if chromosomes are not properly aligned.
How is cell cycle controlled?
The cell cycle control is regulated by both internal and external controls
The clock has specific checkpoints where the cell cycle stops until a go-ahead signal is received
What was the contribution of Lee Hartwell, Paul Nurse, and Tim hunt?
The 2001 Nobel prize in physiology or medicine was awarded to lee hartwell, Paul nurse, and Tim hunt for their ground-breaking work on cell cycle regulation
- Hartwell used budding yeast to identify mutants that blocked specific stages of cell cycle progression
- Nurse, working on fission yeast in the 70s, went on to isolate mutants that could also speed up the cell cycle, thus focusing his attention on the original Cyclin dependent kinase gene (CDK)1, cdc2
- In the 80s, hunt identified proteins in sea urchin extracts, the levels of which varied through the cell cycle hence “cyclins”
What are the types of cell cycle regulatory proteins?
Two types of regulatory proteins are involved in cell cycle control: cyclins and cyclin-dependent kinases(Cdks)
Cdks activity fluctuates during the cell cycle because it is controlled by cyclins, so named because their concentrations vary within the cell cycle
MPF (maturation-promoting factor) is a cyclin-Cdk complex that triggers a cell’s passage past the G2 checkpoint into the M phase
Give the importance of the different cell cycle checkpoints
- G1/S-cyclin binds Cdks in G1 phase and commit the cell to DNA replication phase which is S-phase
- S-cyclins bind to Cdks during S phase and are required for the initiation of DNA replication
- M-cyclins promote the events of mitosis
- In most cells, G1-cyclins promote the passage through the restriction point in late G1 by controlling G1/S cyclins
How are activities of Cyclin dependent kinase(CDKs) is regulated by multiple mechanisms?
- Association of the CDKs with their cyclin partners-complex required for activity
- Stimulators phosphorylation sites
- sites which when phosphorylated lead to full activation
- Inhibitory phosphorylation sites
- two other sites when phosphorylated lead to inactivation
- Binding of inhibitory proteins to CDK complex-(CKIs-CDK inhibitors)
How are CDKs associates with their cyclin partners?
Complex required for activity
MPF(maturation promoting factor)- is a cyclin-CDK complex that triggers a cell’s passage past the G2 checkpoint into the M phase
What are the functions of stimulatory phosphorylation sites?
Sites which when phosphorylated lead to full activation
Full activation of Cyclin-CDK complex isn’t achieved until the cyclin dependent kinase is phosphorylated by a CDK-activating kinase (CAK)
Phosphorylarylation results in a conformational change that increases protein kinase activity
Explain the functioning of inhibitory phosphorylation sites
Two other sites when phosphorylated lead to inactivation
Phosphorylation and dephosphorylation of a different set of amino acid residues (Thr 14 and Tyr 15) of the Cdk can act to inhibit the cyclin-cdk complex (figure only shows two overlapping inhibitory phosphorylations)
Wee1 kinase can add an inhibitory phosphates
Cdc25 phosphatase can remove the inhibitory phosphate
Explain how binding of inhibitory proteins to Cdk-cyclin complex operates?
Binding of a Cdk inhibitor protein (CKIs) to the cyclin-Cdk complex can also inhibit its activity
Explain regulation of cell cycle being controlled degradation of cellular molecules
Degradation of CKI and/or Cyclin-CDK complexes is accomplished in a ubiquitin-dependent mechanism
Ubiquitin ligases transfer multiple ubiquitin groups to specific amino acids within the protein
The ubiquitination marks the protein for degradation in the proteosome
Summarize ubiquitin-proteosome degradation pathway
Proteins to be degraded are Poly ubiquitinated(ATP dependent)
Polyubiquitinated protein recognized by proteosome
Peptides cleaved to amino acids
Protein degraded to peptides(ATP dependent)
Explain the control of proteolysis by SCF
- Degradation of the CDK inhibitor protein (CKI) by the active SCF complex (which has ubiquitin ligase activity)
- Important for degradation of G1/S cyclins and some CKIs that control S-phase initiation- Arrest in G1 phase if non-dividing cell
Describe the control of proteolysis by Anaphase-promoting complex(also called the cyclosome or APC/C)?
M-cyclin is ubiquitinated by the active anaphase promoting complex (APC/C)/Cdc20 compl3x and the E1/E2 ubiquitination enzymes
Another protein is targeted by APC/C/Cdc 20
***APC/Cdc20 complex formation may be initiated by active M-Cdk. Thus, M-Cdk may facilitate its own destruction
What molecular events regulate DNA replication during S phase?
- S-Cdk activation triggers dna replication during S-phase
- M-Cdk activation- stimulates chromosome segregation
- APC/C activation and Cdk inactivation leads to assembly of new prereplicative complexes at origins
What happens in the S phase?
DNA replication is initiated once every cell cycles at S-phase
“Firing of the ORI”: The preinitiation complex (assembly of several proteins) helps recruit DNA polymerase. Unwind8ng of DNA and DNA synthesis is initiated
What happen in the activation of M-phase?
Cyclin-Cdk complex triggers mitosis
Active M-Cdk also activates APC/C & facilitates M-CDK degradation
- Gradual accumulation of M-cyclin and cyclin-M-Cdk complex
- CAK and Wee1 primes the M-Cdk for activation
- Cdc25 phosphatase is activated by phosphorylation (likely by POLO kinase and/or activated M-Cdk) causes dephosphorylation of M-Cdk thereby activating the cyclin-M-Cdk complex
Summarize control of mitosis
The activated M-Cdk induces the following cellular changes (primarily via protein phosphorylation):
- Assembly of the spindle apparatus
- Chromosome condensation
- Nuclear envelope breakdown
- Cytoskeleton changes
- Reorganization of the Golgi and ER (closely associated with nuclear envelope)
M-CDK can be considered as a master control gene for M-phase of the cell cycle
How does the APC/C trigger sister chromatid separation and the completion of Mitosis?
M-CDK has triggered the events of early mitosis
M-CDK also triggers the activation of anaphase-promoting complex (APC) initiates sister chromatid separation by ubiquitinating securin and thus activating separase
