Cell Cycle Control Flashcards
1
Q
cell survival and proliferation regulation
A
- In higher eukaryotes, cell survival & proliferation are tightly regulated
- Integrated controls continually evaluate the state of the cell & environment.
- Regulation of somatic cell number = homeostasis (maintains organism’s physiology within normal limits).
- Normal cell proliferation is modulated by regulation of the cell cycle - checkpoints
2
Q
apoptosis and necrosis
A
- Apoptosis = programmed cell death; eliminates damaged cells & cells needed only temporarily during development.
- Necrosis = another form of cell death – but uncontrolled and damages the surrounding tissue –> leads to inflammation
3
Q
balance between cell loss and cell proliferation
A
- Adult tissues composed mostly of differentiated cells
- Constant low-level turnover of these cells
o Cells die & they are replaced - Some cell loss is accidental other cell loss is through programmed cell death (apoptosis)
o Cell is abnormal in some way eg dividing too rapidly or infected by virus. - Cell loss not a problem as long as cell population is replenished.
- One role of apoptosis is to survey for cellular abnormalities & DNA damage & execute self-destruct mechanism when detected.
4
Q
cell cycle control
A
- Precise control during development & growth is crucial - determines size & shape of organs/tissues
- Cell division - controlled by complex network of signalling pathways - extracellular signals & intracellular cues
- Cell cycle regulatory mechanisms operate in the somatic cells of higher animals, including humans…well conserved (∴ important!!)
- Loss of control/disturbance in the cell cycle –> cancer (~1/6 people)
5
Q
CDK-cyklin protein
A
The CDK-cyclin protein complexes are composed of two subunits:
- Cyclin: Present only in specific phase of cell cycle
o unstable, resulting in transient activity
o Appearance of specific cyclin is the result of preceding CDK-cyclin complex - activate TF for new cyclin
- Cyclin-Dependent protein Kinase (CDK)
o substrate specificity & phosphorylation activity controlled by bound cyclin
o phosphorylate serine or threonine of target protein - Sequential activation of different CDK-cyclin complexes controls cell cycle progression.
- CDK-cyclin active at wrong time, it will cause inappropriate genes to be transcribed or switched off
6
Q
CDK-cyklin complexes
A
- The CC is controlled primarily by regulating the G1 CDK-cyclin complexes
- Extracellular growth factors (mitogens) induce synthesis of G1 cyclins
o Once the mitogens have acted, the CC proceeds
o even when the mitogens are removed - Cyclin levels change with CC progression
- CDK protein abundance remains constant, but activity varies with cell cycle phase
- Each CDK subunit can associate with various cyclins
- ∴ CDK-cyclin complexes increase & decrease in phase with the cell cycle
7
Q
CDK-cyclin activities
A
- CDK-cyclins drive CC from one step to the next
- Going to the next step in the cycle requires activation of genes whose protein products are necessary for the next phase
- CDK-cyclin activities vary throughout the cell cycle in mammalian cell.
- Widths of bands indicate the relative activities of CDK-cyclin complexes
8
Q
transcription factors and CDK-cyclin
A
Activation occurs by CDK-cyclin complexes turning on Transcription Factors (TF)
- CDK-cyclin complexes active in G1 takes cells into S phase
- The G1 CDK-cyclin complexes activate multiple cellular components:
- TF turns on genes encoding:
o DNA polymerase
o Enzymes ≈ produce dNTPs
o Proteins involved in duplication of chromosomes
o Subunits of the next CDK-cyclin complex
9
Q
phosphorylation/de-phosphorylation of CDKs (G1/S cyclins vs G2/M cyclins)
A
ontrol their ability to regulate the cell cycle in complexes with cyclins
- G1/S cyclins – essential for the control of the cell cycle at the G1/S transition
- Cyclin E–CDK2, (also Cyclin D–CDK4, & Cyclin D–CDK6), regulate transition from G1 to S phase
- Cyclin A–CDK2 is active in S phase.
- G2/M cyclins – essential for the control of the cell cycle at the G2/M transition (mitosis).
- G2/M cyclins accumulate steadily during G2 -abruptly destroyed as cells exit from mitosis (at end of M-phase).
- Cyclin B–CDK1 regulates progression from G2 to M phase
10
Q
CDKs - cyclin dependent
A
- cyclin dependent because each CDK must be attached to a cyclin to function.
- Cyclin tethers target protein so that CDK can phosphorylate it.
- CDKs are present throughout cell cycle so activity of the complex is a function of which cyclin is present. As different cyclins present at different stages of cell cycle, each phase is characterised by phosphorylation of different target proteins.
- Target protein binds to cyclin part of active CDK-cyclin complex placing target phosphorylation sites close to active site of CDK.
11
Q
CDK Targets
A
- How does the phosphorylation of some target proteins control the cell cycle?
o Phosphorylation initiates a chain of events =>
o Activation of specific transcription factors (TFs)
o These TFs promote transcription of certain genes whose products are required for the next stage of the cell cycle
12
Q
example of CDK targets
A
Example: Connection of the appearance of cyclin to gene transcription is the Rb-E2F pathway
- Rb is target protein of Cdk2-cyclin A
- E2F is transcription factor that Rb regulates
- From late M phase through to the middle of G1, Rb & E2F are an inactive complex that does not promote transcription.
1. Late in G1, active Cdk2-cyclin A complex is produced, and phosphorylates Rb
2. Phosphorylation alters shape of Rb so it no longer binds E2F
13
Q
checkpoints: brakes on CC progression
A
- Proper progression through cell cycle is crucial to the production of progeny cells with correct number of chromosomes
o Eg attempting to condense chromosomes before DNA replication is completed could lead to production of chromosome fragments. - Proliferation is controlled by cell cycle checkpoints that prevent progression until preceding stage has been successful
14
Q
How do checkpoints act as brakes on cell cycle?
A
- they activate proteins that inhibit protein kinase activity of one CDK-cyclin complex
- Cell cycle is held in check until cell is properly prepared to proceed to next phase of cycle.
- Checkpoint system operates by detecting damaged DNA
- If DNA is damaged during G1, CDK-cyclin complexes stop phosphorylating target proteins.
15
Q
process of CC brakes/blocking (1)
A
- p53 recognises DNA damage, then activates protein p21
- p21 binds to Cdk2-cyclinA complex, inhibits protein kinase activity
- Cdk2-cyclinA complex can no longer phosphorylate Rb
- Cell cycle is unable to progress from G1 –> S blocked
