Cell Cycle Cell Death Flashcards
What are the cell cycles?
M Phase -> G1 phase -> G0 phase -> S phase -> G2 phase
What is the m phase?
mitosis
Chromosome duplication/segregation
Cytokinesis- cell division
G1 Phase?
RNA & Protein Synthesis / Cell growth
duration between completion of cell division and initiation of DNA replication
G0 Phase
No Cell division
S phase
synthesis
DNA replication
Histone Synthesis
Centrosome formed
Chromosome duplication
G2 Phase
Preparation for Mitosis
Restriction point
Discrete time point where errors are checked
Checkpoint-
Halts Cell cycle if proper synthesis does not occur
Locations of restriction point?
G1 phase (two hours prior to S phase)
Checkpoints?
G1 checkpoint,
G2 checkpoint,
Metaphase checkpoint
If growth factor signals are limiting, cells go into G0 →
Makes sure cell doesn’t grow too fast, too much, etc.
Cdk1:Cyclin B, what is it?
triggers G 2 → M transition
Cyclin A is synthesized in S and destroyed starting at prometaphase
Cyclins B are synthesized in S/G 2 and destroyed following the completion of chromosome attachment to the spindle
Cdk2: Cyclin A,E
Triggers G 1 → S transition
Cdk4, Cdk6: Cyclin D1 –D3
Phosphorylation of the retinoblastoma susceptibility protein (pRb) in G 1
Triggers passage of the restriction point and cyclin E synthesis in some cell types
How do Cyclin and CDK become activated?
have to be phosphorylated to activate it
-For the complex to be active, therefore, it must be phosphorylated on the first site, but dephosphorylated on the other two sites by the protein phosphatase cdc25
Cdk1:Cyclin B, what does it do?
triggers G 2 → M transition
Cyclins B are synthesized in S/G 2 and destroyed following the completion of chromosome attachment to the spindle
Cdk2: Cyclin A,E
Triggers G 1 → S transition
Cyclin A is synthesized in S and destroyed starting at prometaphase
Cdk4, Cdk6: Cyclin D1 –D3
Phosphorylation of the retinoblastoma susceptibility protein (pRb) in G 1
Triggers passage of the restriction point and cyclin E synthesis in some cell types
Cyclin and CDK come together, how are they activated when they come together?
-For the complex to be active, therefore, it must be phosphorylated on the first site, but dephosphorylated on the other two sites by the protein phosphatase cdc25
what do CKI do?
keep the balance, cells dont go to the next step prematurely
- inhibitor binding or phosphorylation interference
- block actions of CDK
what happens when INK4 binds?
twisting of the Cdk upper lobe blocks cyclin binding or interferes with ATP hydrolysis.
When p27 or p21 binds, what happens?
a loop insinuates into the upper lobe of the Cdk and blocks ATP binding
what does p21 do?
Induced by p53 tumor suppressor. Cell-cycle arrest after DNA damage. Binds PCNA and inhibits DNA synthesis. Promotes cell cycle arrest in senescence and terminal differentiation
what does p27 do?
Cell cycle arrest in response to growth suppressers like TGF-β and in contact inhibition and differentiation
what does p16 do?
Cooperates with the retinoblastoma susceptibility protein (pRb) in growth regulation. Cell-cycle arrest in senescence. Altered in a high percentage of human cancers
RAS proteins, what do that do?
GTPases that receive signal from catalytic receptors, induct cell proliferation
How do cells enter the S phase?
Mitogen attaches to receptor, activates MAPK, activates MYC
what is the G1/S Transition?
E-CDK2 complexes drive pRb hyperphosphorylation
Liberates E2F transcription factors from pRb control
E2F can increase transcription of genes
what does cyclin A do during s phase?
stabilizes prereplication complex
what is the G2/M transition?
- Activation of CDK1/cyclin B at the G 2 /M boundary
- CDK1/cyclin B translocate to the nucleus
- Activated anaphase promoting complex (APC) destroy
cdk1 freeing cyclin B for degradation
Checkpoints, what are they?
- Cell cycle checkpoints are cellular mechanisms, which control the order and timing of cell cycle phase transitions
- Checkpoints mostly activated by genotoxic stress mainly DNA damage
G1 checkpoint:
- After DNA damage, two parallel checkpoint pathways target the activity of Cyclin/Cdk complexes
- The slower pathway involves the stabilization of p53 and transcriptional upregulation of p21 which binds and inhibits the Cyclin/Cdk complexes
- The faster pathway acts via the activation of Chk2 and the inactivation of Cdc25
G2 checkpoint:
- After DNA damage induction, two ATM-dependent checkpoint pathways are activated
- The checkpoint kinases, Chk1/Chk2, target Cdc25 for nuclear export leading to the accumulation of the inactive CyclinB1/Cdk1 complex
- The lack of activated CyclinB1/Cdk1 interrupts the feedback loops (dotted lines), resulting in G2 arrest
Tumors?
Space occupying lesions that may or may not be neoplasms
Neoplasm?
relatively autonomous abnormal growth with abnormal gene regulation, 2 types: benign and malignant
Cancer
Malignant neoplasm (can produce metastasis)
Metastasis
Secondary growth of cancer at different - location from primary neoplasm
How to name cancer?
- Differentiation state (epithelial, non epithelial, etc)
- embryonic origin
- benign or malignant
what are the three steps of cancer?
initiation, promotion, progression
initiation of cancer?
- irreversible
- chemicals,radiation, viruses
- oncogenes can be activated
- inactivation of tumor suppressor gene
promotion of cancer?
- reversible in early stages
- threshold exists
- inhibition of cell death in affected cells
- chromosomal changes
- tumor to neoplasms
- CLONAL EXPANSION, promoting gene activation
.progression of cancer?
continuing change of unstable karyotype
what are oncogenes
drive growth, enhanced expression leads to unregulated growth
what are Tumor Suppressors?
- can inhibit cell division, loss of these leads to cell growth
- mostly recessive
- In carcinogenesis: inactivating mutations, deletions, loss of expression
-p53,rb, p16I,p14ARF
p16I, what is it?
tumor suppressor gene, inactivation of the INK4a locus on human chromosome 9p21 in human cancers
Rb, what is it?
tumor suppressor gene, retinoblastoma if inactivated?
Hallmarks of cancer?
- Acquire self-sufficiency of growth signals
- Become insensitive to growth inhibitory signals
- Evade cell death
- Acquire limitless replicative potential
- Angiogenesis
tumor microenvironment? components?
tissue environment in which cancer cells exists, that include normal cells, secretory factors, and the extracellular matrix
- Cellular components such as immune cells, fibroblasts, blood vessel cells , EMT cells
- secretory factors
- extracellular matrix: proteins + proteogycans
- promotes therapy resistance + cancer growth
Chemotherapy, what does it do?
Utilizes: alkylating agents, incalcating agent, antimetabolites
cell damage
Radiation therapy , what does it do?
- Direct deposition of energy to break DNA bonds
- Hydrolysis of water to produce powerful damaging free radicals
cell and DNA damage
surgery on cancer?
just cut it out
DNA – Immunotherapy what does it do?
receptor based treatment
When does cell death occur?
Cell death occurs when they loss of large amounts of genetic material due to DNA damage as they divide reaching a critical level of genomic instability
what is Necrosis? what happens?
uncontrolled form of cell death
- swelling cell membrane
- organelle swelling
- degradation of DNA
- failure of normal cell pathways
- Ca2+ overload, mitochondria uncoupling, ROS production
- inflammation
- in all cells
what is Apoptosis? what happens?
- Cell membrane: membrane blebbing and eventually fragmentation
- Cytoplasm: Fragmentation and shrinkage
- Nucleus : Chromatin condensation and degradation
- Cell membrane loses its asymmetry, and phosphatidylserine becomes exposed
- no inflammation
- hematopoietic cells
- ATM senses changes, P53, CD95
- Bax and Bak form pores on membrane, activated by Bcl2
what is Autophagy? what happens?
- Process responsible for degrading longlived proteins and cytoplasm organelles, the products of which are recycled to generate macromolecules and ATP so as to maintain cellular homeostasis
- Cell membrane: membrane blebbing
- Cytoplasm: accumulation of two-membrane autophagic vacuoles
- Nucleus : Partial chromatin condensation
- no inflammation
- all cells
what is Mitotic Catastrophe? what happens?
- Mitotic catastrophe is defined as a type of cell death that is caused by aberrant mitosis.
- Cell membrane: No change
- Cytoplasm: larger cytoplasm with the formation of giant cell.
- nuclear fragmentation. Premature chromosome condensation
- no inflammation
- all cells
what is Senescence? what happens?
- Permanent cell cycle arrest, reproductive death
- Cell membrane: No change
- Cytoplasm: Flattening and increased granularity
- Nucleus : Distinct heterochromatic structure
- Inflammation
- all cells
- p53-p21
- p16-rb pathways
