L16. Cell Cycle I and II and cancer Flashcards
1
Q
explain the four phases of the eukaryotic cell cycle
A
- M phase (mitosis and cytokinesis)
- interphase (G1 phase, S phase, and G2 phase)
2
Q
eukaryotic cell cycle - M phase
A
- mitosis: nuclear division
- cytokinesis: cytoplasmic division
- lasts about an hour (small fraction of total cell cycle)
3
Q
eukaryotic cell cycle - interphase
A
- period between 1 m phase and the next
- cell growth
- DNA is replicated
- centrosome is duplicated
4
Q
eukaryotic cell cycle: interphase - G1 and G2 phase
A
- gap phases that flank s phase
- monitors cell’s environment
5
Q
eukaryotic cell cycle: interphase - S phase
A
synthesis and replication of DNA
6
Q
explain the cell cycle control system
A
- it ensures that key processes occur sequentially
- does this via checkpoints
- cycle may arrest or move to G0 (specialized resting state) if conditions are not met
7
Q
cell cycle control system - what is the system dependent on
A
- cyclically activating and inactivating proteins
- called cyclin-dependent kinase (Cdk) and cyclin
8
Q
cell cycle control system - explain Cdks
A
- it is regulated by phosphorylation and dephosphorylation
- Cdk is switched on by cyclins
- once activated, Cdks trigger entry into S or M phase
9
Q
cell cycle control system - explain cyclin
A
- they are regulated by transcription and proteolysis (breakdown of protein)
- they do not have enzymatic activity but are required for activation of kinase
10
Q
Cdk and cyclins - explain the relationship between Cdk activity and cyclin concentration
A
- accumulation of cyclins during mitosis, helps regulate Cdk activity
- increase in cyclins = increased activity in Cdks
11
Q
Cdks and cyclins - how are different cell cycle events triggered
A
- different Cdks associate with different cyclins
- M-cyclins associate with M-Cdks to activate M phase
- S cyclins and G1/S cyclins associate with S-Cdks and G1/S-Cdks to activate S phase
12
Q
how are Cdks activated
A
- dephosphorylation
- positive feedback
13
Q
Cdk activation - dephosphorylation
A
- Cdks have inhibitory phosphates
- to become active, they must be dephosphorylated
14
Q
Cdk activation - positive feedback
A
- once the M-Cdk is active, it propagates the activation of more M-Cdk by activating the activating phosphatase (Cdc25)
- M-Cdk will accumulate through the G2 phase and will quickly move the cell from G2 to M phase
15
Q
how is Cdk inactivated
A
- cyclin degradation via ubiquitin-tagged degradation
- use of transcriptional regulator p53
16
Q
Cdk inactivation - explain ubiquitin-tagged degradation of cyclin
A
- degradation of M cyclins are mediated by anaphase promoting complex (APC)
- this complex will tag cyclins with ubiquitin and the cyclin will be feed into a proteasome chamber for degradation
17
Q
Cdk inactivation - use of transcriptional regulator p53
A
- used in G1 checkpoint in response to DNA damage
- damage results in increased levels and function of p53
- p53 activates the gene expression of the Cdk inhibitor p21
- p21 will then bind to G1/S- and S-Cdks to cause the cycle to be arrested in G1 to repair DNA
- if the damage is too severe, p53 can induce apoptosis
18
Q
where are the checkpoints in the cell cycle located
A
- checkpoint in mitosis
- G1 checkpoint
- G2 checkpoint
19
Q
cell cycle checkpoints - checkpoint in mitosis
A
- are all chromosomes properly attached to the mitotic spindle?
- if yes, then the duplicated chromosomes are pulled apart
20
Q
cell cycle checkpoint - G1 checkpoint
A
- is the environment favorable
- if yes, the cell will enter S phase
21
Q
cell cycle checkpoint - G2 checkpoint
A
- is all DNA replicated?
- is all DNA damage repaired?
- if yes to both, the cell enters mitosis
22
Q
cell cycle checkpoint: if conditions are not met - checkpoint in mitosis
A
inhibition of anaphase promoting complex activation delays exit from mitosis
23
Q
cell cycle checkpoint: if conditions are not met - G1 checkpoint
A
- Cdks inhibitors block entry to s phase
- DNA damage causes increased levels and function of p53
24
Q
cell cycle checkpoint: if conditions are not met - G2 checkpoint
A
inhibition of activating phosphatase (Cdc25) blocks entry to mitosis
25
explain how mitogens promote cyclin production
- they elicit cell signaling and the cycling will activate G1 cyclins, G1/S cyclins, and DNA synthesis proteins
- it has a negative control retinoblastoma (Rb) that keeps transcriptional factors inactive
26
mitogens and cyclin production - what happens to Rb after Cdks are activated
- the Cdks will phosphorylate Rb and Rb will release the transcription regulators
- the regulators then activate genes required for cell proliferation
27
what are the two steps of initiating DNA replication
1. origin loaded
2. origin fired
28
initiating DNA replication - origin loaded
- happens in G1 phase
- the origin of replication serves as landing pads for proteins
- the origin recognition complex (ORC) is perched on top of the replication origin and recruits Cdc6
- DNA helicase is loaded to open up the double helix
29
initiating DNA replication - origin fired
- happens in S phase
- helicase and the ORC = replication complex
- S-Cdk activates DNA helicase and promotes replication fork formation
- and then DNA replication begins
- S-Cdk also helps prevent re-replication by phosphorylating Cdc6
30
what are cohesins
- immediately after s phase DNA replication, sister chromatids are remained tightly bound by cohesins
- defective cohesins lead to chromosomal segregation problems
31
explain the stages of mitosis
1. prophase
2. prometaphase
3. metaphase
4. anaphase
5. telophase
32
mitosis- prophase
- duplicated chromosomes condense due to condensins
- mitotic spindle assembles between two centrosomes
33
mitosis: prophase - condensins
- condensin complex formation is triggered by M-Cdk phosphorylation
- the protein complexes facilitates chromosome condensation
- this makes it easier for them to be segregated during mitosis
34
mitosis: prophase - how are mitotic spindles formed
- at the start of mitosis, stability of microtubules decrease and causes dynamic instability
- motor proteins and associated proteins cross-link the overlapping microtubules
- this interaction stabilizes the (+) ends
- M-Cdks phosphorylate microtubule proteins
- and the centrosomes act as the spindle poles
35
mitosis - prometaphase
- starts with the breakdown of the nuclear envelope via phosphorylation of nuclear pore proteins and lamins
- chromosomes attach to spindle microtubules
36
mitosis: prometaphase - how are the chromosomes attached to the mitotic spindle
- spindle microtubules attach at kinetochores
- this attachment generates tension on the kinetochores
- the tension signals to the kinetochores that they are attached correctly
- the cell cycle control system monitors this tension
37
mitosis: prometaphase - define kinetochores
protein complexes that assemble on the centromere of each condensed chromosome
38
mitosis: prometaphase - what are the three classes of microtubules that make up the mitotic spindle
1. aster microtubules
2. kinetochore microtubules
3. interpolar microtubules
39
mitosis: three classes of microtubules that make up the mitotic spindle - aster microtubules
any microtubule originating from the centrosome which does not connect to a kinetochore.
40
mitosis: three classes of microtubules that make up the mitotic spindle - kinetochore microtubules
capture each pair of sister chromatids at their kinetochores
41
mitosis: three classes of microtubules that make up the mitotic spindle - interpolar microtubules
cross-linked at overlaps throughout the spindle
42
mitosis - metaphase
- chromosomes are aligned at the metaphase plate
- kinetochore microtubules attach to opposite poles of the spindles
43
mitosis - anaphase
- begins by cohesin breakage
- sister chromatids separate
- kinetochore microtubules shorten and spindle poles move apart
44
mitosis: anaphase - what is the anaphase promoting complex (APC)
- it triggers the separation of sister chromatids by promoting cohesin destruction
- cohesin linkage is destroyed via separase
- separase is held inactive by securin
- securin is destroyed by APC via ubiquitin targeting and allows seperase to cleave cohesin
45
mitosis: anaphase - how are sister chromatids seperated
1. anaphase A
2. anaphase B
46
mitosis: anaphase - explain anaphase A
kinetochore microtubules shorten and the attached chromosomes move poleward
47
mitosis: anaphase - explain anaphase B
the spindle poles move themselves apart
48
mitosis - telophase
- chromosomes arrive at opposite poles
- nuclear envelope reassembles
- division of cytoplasm begins with assembly of contractile ring
49
mitosis: telophase - explain the reassembly of the nuclear envelope
- nuclear pore proteins and lamins are now dephosphorylated
- allows them to be reassembled
- pores pump in nuclear proteins and the nucleus expands
50
explain cytokinesis
cytoplasm is divided in two by contractile ring of actin and myosin filaments
51
cytokinesis - explain the cleavage furrow
- the first visible sign of cytokinesis
- occurs in a plane that runs perpendicular to the mitotic spindle
- this positioning ensures that the furrow cuts between the two groups of segregated chromosomes
52
cytokinesis - how does the contractile ring divide the cell
- the ring is composed of overlapping actin and myosin filaments
- it is attached to membrane-associated proteins on the cytoplasmic face of the PM
- the force of the ring is generated by the sliding of actin filaments against myosin filaments
53
what is apoptosis
- programmed cell death
- it is used for: development, organ reorganization, metamorphosis, and immunity
54
apoptosis - how is it quick and clean
- a cell that dies may swell and burst and can trigger a potentially damaging response
- to combat this, phagocytic cells (macrophages) will engulf the cell before it spills its contents
- and it allows the organic components to be recycleda
55
apoptosis - explain caspase cascades
- pro-caspases are activated in response to apoptosis signals and they are activated through cleavage and assembly
- initiator caspases cleave and activate downstream executioner caspases which may activate more executioner caspases
56
apoptosis: caspase cascades - explain the proteolytic cascade
- they cause the breakdown of key cellular proteins
- which then causes the irreversible breakdown of the nuclear lamina
- nucleases will come and break DNA
- finally, the apoptotic cell is cleaned up
57
explain intrinsic apoptosis
- mediated by the Bcl2 family which regulates caspase activation
- death promoting proteins are Bax and Bak
- the proteins are activated in response to DNA damage and they facilitate cytochrome c release from the mitochondria
58
intrinsic apoptosis - how will apoptosis be prevented or activated
- prevented: Bcl2 protein inhibits apoptosis by preventing Bax/Bak mediated cytochrome c release
- activated: cytochrome c molecules activate initiator procaspases by promoting the assembly of an apoptosome
- apoptosome then recruits a initiator procaspase that triggers apoptosis
59
explain extrinsic apoptosis
- death receptor Fas is activated by a membrane bound protein called Fas ligand
- this ligand is present on the surface of specialized immune cells called killer lymphocytes
- binding of Fas ligand to its receptor triggers assembly of a death-inducing signaling complex
- this complex then induces initiator procaspases
60
what are the three major categories of positively acting signal proteins
1. survival factors
2. mitogens
3. growth factors
61
positively acting signal proteins - survival factors
- promote cell survival by suppressing apoptosis
- limited survival factor release dictates signaling/target cell ratios
- they upregulate the expression of anti-apoptotic proteins
- Bcl2 regulation
62
positively acting signal proteins - mitogens
- stimulates cell division by overcoming cell cycle blocks
- it inhibits Rb so cell proliferation genes can be expressed
63
positively acting signal proteins - growth factors
- stimulate cell growth by promoting synthesis and inhibiting degradation of macromolecules
- not dependent on cell cycle control
- terminally differentiated cells (nerve, muscle, immune) do most of their growing after they have been differentiated and have stopped dividing
- most extracellular growth factors bind to cell surface receptors to induce events
64
explain the properties of a cancer cell
1. proliferation
2. invasion
3. metastasis
65
properties of a cancer cell - proliferation
- the cell itself and its progeny proliferate in defiance of the normal cell constraints
- can form a tumor (clustered cancer cells that form a single mass)
66
properties of a cancer cell - invasion
the cell invades and colonizes territories normally reserved for other cells
67
properties of a cancer cell - metastasis
tumor cells with invasive properties can break loose from the primary tumor and form secondary tumors (metastases)
68
what may cause genetic instability
- defects in DNA replication
- defects in DNA repair
- defects in cell-cycle checkpoint mechanisms
- mistakes in mitosis
- abnormal chromosome numbers
69
explain the process of tumorigenesis
- a single cell undergoes a mutation that enhances its ability to proliferate, survive, or both
- this cell becomes the dominant clone in the tumor
- the cell then evolves by repeated rounds of mutation, proliferation, and natural selection
70
tumorigenesis - dominant mutation
- oncogenes (Ras)
- gain of function mutation in a single copy of the proto-oncogene can drive the cell toward cancer
71
tumorigenesis - recessive mutation
- tumor suppressor genes (APC and p53)
- loss of function mutations
- both copies of the genes must be lost to drive the cell toward cancer
72
tumorigenesis: explain the paths to oncogenic mutations
- mutation in coding sequence
- gene amplification
- chromosome rearrangement
73
tumorigenesis: paths to oncogenic mutations - mutation in coding sequence
results in hyperactive protein made in normal amounts
74
tumorigenesis: paths to oncogenic mutations - gene amplification
results in a normal protein that is overproduced
75
tumorigenesis: paths to oncogenic mutations - chromosome rearrangement
- 2 results:
1. nearby regulatory DNA sequence causes normal protein to be overproduced
2. fusion to actively transcribed gene produces hyperactive fusion protein
76
tumorigenesis - how can a tumor suppressor gene be eliminated
- whole parental chromosome is lost
- region containing the normal gene is deleted
- loss of function mutation is in the parental gene
- gene activity is silenced by epigenetic changes
77
what are alterations that will result in a cancer cell
1. alterations in cell proliferation
2. alterations in DNA damage response
3. alterations in cell growth
