Test 2: Lecture 41 Flashcards
negative regulators of cell cycle are ___ for cancer
most common mutations
The cell cycle is a regular pattern of ____
growth, DNA replication, and cell division.
Cell cycle is a highly ___ and ___ process
evolutionarily conserved and extremely well-controlled process
The main mechanisms of control of the cell cycle are ___ and ___
checkpoints and feedback
if control mechanisms of cell cycle fail it leads to ___
cancer
The cycle works the same way in all tissues, but the ___ and ___can vary according to context and organismal needs
duration and frequency
cells can live for days or years. most cells are not actively dividing
Most tissue, differentiated cells, are actively being ___; some slowly, some quickly
renewed/ replaced
___ cells produce differentiated cells according to the needs of the tissue
Progenitor
The bone marrow produces ___ new neutrophils per day!
100 billion
Cells cannot keep growing without dividing or their ___: ___ will get too high very quickly
volume to surface area
cell likes high SA and low volume
Three stages of interphase
Gap 1 (G1): cell growth and normal functions
DNA synthesis (S): copies DNA
Gap 2 (G2): additional growth (chromatids
become replicated chromosomes)
after cell completes interphase it goes through ___ and ___ only is ___
mitosis and cytokinesis
cell is large enough and the DNA is undamaged
division of the cell cytoplasm
cytokinesis
3 major checkpoints of cell cycle
G1/S
• can DNA synthesis begin?
G2/M
• has DNA synthesis been completed
correctly?
• commitment to mitosis
spindle checkpoint
• are all chromosomes attached to spindle?
• can sister chromatids separate correctly?
what is the 1st checkpoint of cell cycle
G1/S
• can DNA synthesis begin?
what is the 2nd checkpoint of cell cycle?
G2/M
• has DNA synthesis been completed
correctly?
• commitment to mitosis
what is the 3rd checkpoint of cell cycle?
spindle checkpoint
• are all chromosomes attached to spindle?
• can sister chromatids separate correctly?
Checkpoints are based on activation and
inactivation of ___
cyclin-dependent protein
Kinases (CDKs).
CDKs are ___ until they are bound with ___ which activated the CDK.
cyclin-dependent protein
Kinases (CDKs)
inactive
cyclin
CDKs are regulated on the protein level by ___ and ___
cyclin-dependent protein
Kinases (CDKs)
CDK activating kinases(CAKs)
CDK inhibiting kinases (CIKs)
A cyclin-activated CDK has one or multiple
protein ___ target substrates
phosphorylation
Phosphorylation usually leads to destruction of the substrate (CKD and its cyclin) by \_\_\_\_
E3 ubiquitin ligase-mediated
degradation
p16, p27 work by
preventing CDK and its cyclin from binding to each other
inhibits cell cycle
Cyclins are primarily regulated on the ___ level. They are targets of transcription factors that become ___ and ___ in sequential fashion across the cell cycle
transcriptional
activated and inactivated (waves) one cyclin will lead to the activation of the next cyclin
cyclin D→ E→ A→ B
Rb-E2F
When Rb is unphosphorylated, E2F transcription factor and Rb are attached and is inactive
Phosphorylation of Rb by CDK4/6 leads release of Rb from E2F,
E2F then can attach to DND and leads to activation of transcription of proteins that carry out cell cycle progression – both structurally and regulatory (make other CDK, help with mitosis and proteins that help cell cycle)
Simplified view of role of Rb and E2F in the beginning of the cell cycle
type of pro-growth cytokine or growth factor
mitogen
External pro-division signals start with a ___ binding a surface receptor
mitogen
any type of pro-growth cytokine or growth factor
Mitogen binding activates the receptor to initiate a signal transduction cascade that leads to transcription of cell cycle regulators such as ___
cyclin D.
used in first steps of cell cycle
cyclin D is needed to bind to CDK 4 to phosphorylate Rb to make it let go of E2F which allows E2F to bind to DNA and make more proteins that lead to further steps of cell cycle
G1 checkpoint is which CDK and what inhibits this step
cyclin D/CDK 6
cyclin D/ CDK 4
p15,p18,p16,p19
cyclin E/CDK 2
p21, p27, p57
S phase is triggered by __ and inhibited by __
cyclin A/ CDK 2
p21/p27/p57
G2 is activated by ___ and inhibited by ___
cyclin A/ CKD 1
p21, p27, p57
M phase is activated by ___ and inhibited by ___
cyclin B/CDK1
p21,p27,p57
Cell cycle regulation can be simplified into the coordinated actions of three types of proteins:
___
(1) cyclins,
(2) CDKs
(3) inhibitors of cyclin-CDK complexes
____ once activated, a cell cycle regulator activates things that activate it further
positive feedback
once activated, a cell cycle regulator activates things that de-activate it
negative feedback
restriction point of the cell cycle
GI check point
all or nothing check point
before this checkpoint cell needs growth factors to move forward, after this checkpoint there is enough + and - feedback to push the cell through cell cycle
The ___ point defines a critical time in late G1 after which a cell is committed to undergo DNA replication and is no longer sensitive to growth-factor signaling.
restriction (R)
After the R point, cell cycle progression can only be ___ by conditions of cellular stress, such as DNA damage or mitotic-spindle defects.
halted
checkpoints have to fail to stop cell from dividing
Before the restriction point, the cell has a choice between cell division (growth) by continuing the cell cycle, and rest by going into ____
G0 (quiescence; not dividing indefinitely)
G0 phase
G0 (quiescence; not dividing indefinitely)
not dividing or growing cell
what CDK and cyclin are needed at each arrow?
___ is the best studied and likely the
most important negative regulator of the
cell cycle and cell survival.
p53
___ is the most commonly mutated gene
across all human cancers
p53
p53 is a transcription factor that is directly negatively regulated by ___ (sequesters p53 in the cytoplasm)
MDM2
p53 activates ___ as a critical negative feedback loop to prevent too much p53 buildup
MDM2
p53 concentrations ___ based on ___; never all on or all off.
fluctuate
p53 activated MDM2, MDM2 inactivates p53
- *Tipping this balance can tip cells toward**
- *cell division, survival, or apoptosis**
Steps of mitosis
PMAT
prophase
metaphase
anaphase
telophase
cytokinesis
DNA is replicated in ___ of interphase
S-phase
Further cellular growth in preparation for cell division occurs in ___ after DNA has been replicated
G2 phase
Prophase
1st step of mitosis
During prophase, chromosomes condense and spindle fibers form.
Metaphase
2nd step of mitosis
During metaphase, chromosomes line up in the middle of the cell.
anaphase
3rd step of mitosis
During anaphase, sister chromatids separate to opposite sides of the cell.
telophase
4th step of mitosis
During telophase, the new nuclei form and chromosomes begin to uncoil.
Cytokinesis
division of the cytoplasm into two individual cells
6 hallmarks of cancer
Sustaining proliferative signaling is caused by mutation in ___
RAS
G protein.
It is active when bound to GTP and sends pro-growth signals to the nucleus
in healthy cell: growth factors cause, GTP hydrolysis, and RAS is then inactive
cancer cells: GTP is unable to hydrolysis. RAS stays active and cell gets continuous signal to grow and divide
Evading growth suppressors by ___ mutations
PTEN
phosphatase
in health cell: PTEN will dephosphorylates PIP3 into PIP2 and stop signals to cell to divide
PIP3 activates AKT, which is a strongly pro-growth kinase that blocks expression of p27, p21 and other tumor suppressor genes.
in cancel cells: PTEN is mutated and PIP3 remains turned on and cell gets continuous signal to grow and divide
