The Cell Cycle & Apoptosis Flashcards
What are the four coordinated processes involved in eukaryotic cell cycles?
- cell growth
- DNA replication
- distribution of the duplicated chromosomes to daughter cells
- cell division
What does mitosis (the M phase) involve?
Nuclear division and the separation of daughter chromosomes, usually ending with cell division.
What is cytokinesis?
The actual division of a cell following mitosis
What is interphase?
The period between mitoses when the chromosomes are decondensed and distributed throughout the nucleus
What happens in the G1 phase?
cell growth and making proteins for DNA replication
What happens during the S phase?
DNA replication and DNA synthesis
What happens during the G2 phase?
proteins for mitosis are made
What can reactivate cell division?
appropriate extracellular signals such as growth factors
What happens in the G0 stage?
cells remain metabolically active but no longer proliferate
What is the progression of cells through the cell cycle regulated by?
Extracellular signals from the environment and internal signals that monitor and coordinate the various processes that take place during different cell cycle phases.
What are the 2 questions that the cell is faced with before initiating mitosis and cell division?
Should I divide?
Am I capable of dividing properly?
What is the decision point in late G1 phase called in yeast cells? In animal cells?
“START” in yeast cells and the restriction site in animal cells
What are the factors determining the “START” point in yeast cells?
available nutrients, size, and mating factors
What are the factors determining the restriction site in animal cells?
extracellular growth factors
What happens when a cell passes the first decision point?
It is committed to proceed through S phase and the rest of the cell cycle (even if external factors such as growth factors are no longer present)
What are the four cell cycle checkpoints that control the “am I capable of dividing properly?” question?
- G1: ensures damaged DNA is repaired before being replicated in S phase
- S: continues monitoring DNA integrity
- G2: prevents initiation of mitosis if DNA is not completely replicated/is damaged
- M (spindle assembly checkpoint): inhibits spindle assembly if chromosomes aren’t distributed accurately to daughter cells
What happens if there is a problem at any of the 4 cell cycle checkpoints?
Cell cycle arrest will occur
What is the cell cycle of all eukaryotes controlled by?
A conserved set of protein kinases, which are responsible for triggering the major cell cycle transitions
What are cyclins?
proteins which regulate the activity of the enzymes which regulate the cell cycle
What are cyclin dependent protein kinases (Cdks)?
phosphorylating enzymes that are regulated by cyclins
What is the interaction of cyclins with Cdks responsible for?
triggering the major cell cycle transitions and for the progression of the cell cycle through its major checkpoints
What were the 3 model organisms used to identify the key molecules responsible for cell cycle regulation?
- frog oocytes
- yeast
- sea urchins
What was discovered through the study of frog oocytes?
Identified the maturation promoting factor (MPF)
What is the purpose of MPF?
MPF is a general regulator of the transition from G2 phase to M phase
What was discovered through the study of yeast?
Mutations in genes called cell division cycle mutants (cdcs) caused various cell cycle arrests, and these genes were found to encode for protein kinases.
What do protein kinases play a key role in?
In the progression of the cell cycle through its restriction point and its various checkpoints
What was discovered during the study of sea urchins?
Following fertilization, sea urchin embryos go through a series of rapid cell divisions where distinct proteins are synthesized and degraded during the cell cycle (cyclins)
What are the two key subunits of MPF?
Cdk1 (first identified in studies of yeast) and cyclin B (first identified in studies of sea urchins)
What is Leland Hartwell known for?
The “START” site in yeast and the concept of cell cycle checkpoints
What is Timothy Hunt known for?
The discovery of cyclins
What is Paul Nurse known for?
Identifying cyclin dependent kinase
What are Yoshio Masui and Dennis Smith known for?
The discovery of MPF
How is Cdk1 regulated?
Cdk1 must first undergo a number of phosphorylation and dephosphorylation events itself before it can phosphorylate other proteins to initiate entry into the M phase
How does Cdk1 regulate the cell cycle?
After Cdk1 binds to cyclin B (in G2), it is first phosphorylated in 3 positions (1 activating position and 2 inactivating positions), followed by the desphosphorylation of 2 of these positions to become an active MPF and allow the cell into the M phase.
What are the 2 families of inhibitor proteins?
- proteins that interact with monomeric Cdk and prevent association with cyclin
- proteins that inhibit activity of Cdk/cyclin dimers
What occurs during mitosis (karyokinesis)?
- chromosomes condense
- nuclear envelope breaks down
- cytoskeleton reorganizes to form the mitotic spindle
- chromosomes move to opposite poles
What occurs during cell division (cytokinesis)?
- golgi apparatus fragments
- cytoplasm divides
What regulates all aspects of karyokinesis and cytokinesis?
the Cdk1/cyclin B complex
What do aurora and polo-like kinases form with Cdk1?
a positive feedback loop
What are aurora and polo-like kinases important for?
chromatin condensation and separation, and cytokinesis
What are cohesins?
proteins that bind to DNA in the S phase and maintain the linkage between sister chromatids following DNA replication
What are condensins activated by? What do they do?
Activated by phosphorylated Cdk1, replace the cohesins, and induce chromatin condensation
What occurs during metaphase (spindle assembly checkpoint)?
- anaphase promoting complex is inactive by the mitotic checkpoint complex (MCC) that forms at the unattached kinetochores
- complex dissociates when all chromosomes are aligned on the mitotic spindle
What occurs during anaphase? What does this result in?
Anaphase activates the APC/C which results in:
- degradation of cyclin B by ubiquination
- degradation of remaining cohesion proteins allowing separation of chromatids
What is nuclear envelope breakdown driven by?
phosphorylation of nuclear lamins by Cdk1/cyclin B, which causes the lamins to depolymerize
What drives golgi apparatus fragmentation?
The golgi apparatus fragments into small vesicles at mitosis due to phosphorylation of golgi matrix proteins by Cdk1
How is dynamic instability of microtubules increased?
As the mitotic spindles are formed, microtubule associated proteins or phosphorylated by Cdk1, which results in increased dynamic instability of microtubules.
What is cytokinesis triggered by?
The inactivation of Cdk1
What is required for cyclin D synthesis to continue?
Cyclin D synthesis continues as long as growth factors activating the pathway continue to be present.
What does the continues synthesis of cyclin D allow for?
allows for continued cell division by driving cells past their restriction point
What is a tumour suppressor gene?
a gene whose inactivation leads to tumour development
What is a key substrate of Cdk4,6/cyclin D?
a tumour suppressor known as retinal blastoma (Rb)
What is retinal blastoma? What does it control?
Rb is a transcriptional regulatory protein that controls cell cycle progression
What does activated Rb maintain?
maintains a family of transcription factors (E2F) in an inactive form in either the G1 or G0 phase
What does phosphorylation of Rb by the cdk/cyclin D complex cause?
causes Rb to dissociate form the transcription factors allowing transcription of genes involved in cell cycle progression to be expressed
What is p53?
A transcription factor that is stabilized and activated by phosphorylation from both ATM (protein kinase) and Chk2 (checkpoint kinase)
What does the activation of p53 result in?
p53 induces the expression of a Cdk inhibitor which results in cell cycle arrest
What are oncogenes/
proteins such as cyclin D and Ras which induce cell proliferation
What is programmed cell death (apoptosis)?
a carefully regulated process in which damaged or non-functional cells are removed from a tissue
What is apoptosis characterized by?
cleavage of chromosomal DNA, chromatin condensation, and fragmentation of both the nucleus and the cell
Why were caenorhabditis elegans used to study apoptosis?
- relatively simple organism
- short life cycle
- transparent (individual cells can easily be viewed during development)
- has a determined cell lineage
What was identified in the study of C. elegans?
several mutations in genes that either prevented cell death in cells normally programmed to die, or caused cell death in cells that would not normally die
What are caspases?
proteases that are the “executioners of apoptosis” and initiate many of the degradative processes of apoptosis
Why were caspases given their name?
They have a cystine in the active site, and the proteases cut after an aspartate residue
