Cell Cycle, CA and Death Flashcards
Prophase
The cell begins to assemble the mitotic spindle, a set of microtubules extending from the centromeres which will later attach to the chromosomes
Prometaphase
The nuclear envelope disintegrates, and the microtubules of the mitotic spindle attach to the chromosomes
Metaphase
The chromosomes are aligned on the mitotic spindle. There is a pause here to allow all chromosomes to become attached
Anaphase
The cohesion proteins which bind the sister chromatids together are cleaved and the chromosomes are pulled apart by the mitotic spindle
Telophase
The nuclear membrane reconstitutes around each set of chromosomes.
G0 -phase
quiescent, intact proliferation capacity, non-cycling
G1 -phase (Gap 1):
duration between completion of cell division and initiation of DNA replication where cells start building cell mass
S-phase (Synthesis)
DNA replication
G2 -phase (Gap 2)
duration between completion of DNA replication and initiation of cell division
M phase
Mitosis
Progression vs Transition of cell cycle
“Progression” going through the cell cycle phase
“Transition” from on phase to another
Cyclins with CDK’s
CDK4/6 bind with cyclind D
CDK2: binds with cyclin E and A
CDK 1: Binds with B
Which Cyclin is found in Mitosis
B
Which cyclin is found in G1
D1, E
Which cyclin is found in S
Cyclin A
What are positive cell cycle regulators and what are negative cell cycle regulators?
- cyclins and CDK
- cyclin dependent kinase ihibitors
Describe how to activate Cyclin CDK complexes.
Cell cycle negative regulators:
- They block the action of CDKs
- Ensure tight control of the cell cycle (Balance)
- Activated upon cell cycle checkpoint activation
- ink ihibits D-CDK4/6
- kips inhibit the rest in the cell cycle
Ink4 can bind to a CDK in what ways
- bind when cyclin isnt bound so it rpevents it from binding
- or it can bind after cyclin binds preventing ATPase use
p27kip binds in what way?
Bind after cyclin binds to CDK to block ATP binding
CKI: p21 cip1/waf1
induced by p53 tumor supressor
p27 kip1
cell cycle arrest in response to growth supressers like TGF beta
ink4: p16 ink4a
cell cycle arrest in senescence
Cell cycle entry and progression
1) mitogen binds to mitogen receptor and activates RAS
2) RAS then activates map kinase
3) map kinase activates gene regulatory protein
4) goes into nucleus which then acts as a TF and makes MYC
5) MYC will then increase Cyclin D and s-CDK to phosporylate RB
5) E2F is made which will help entry to s phase
Restriction point
One way site, not coming back
point where cells comit to devide
happens between d-ckd 4/6 and e cdk 2
G1/S transition
When E–CDK2 complexes drive pRb hyperphosphorylation, this liberates E2F transcription factors from pRb control, enabling the E2Fs to trigger increased transcription of the cyclin E and E2F1 genes; this leads to the synthesis of more cyclin E protein and the formation of more E–CDK2 complexes, which function, in turn, to drive additional pRb phosphorylation. At the same time, the newly synthesized E2F1 protein drives its own expression, further amplifying its activity.
During S phase what does its cyclin do?
just stablizes the pre replication complex making sure that DNA rep will happe and will be sustanined at S phase.
G 2 to M transtition
Activation of CDK1/cyclin B at the G 2 /M boundary
- Activation of CDK1/cyclin B at the G 2 /M boundary maintained by Cdc25
- CDK1/cyclin B translocate to the nucleus
CDK1/cyclin B initiate spindle assembly
• Activated anaphasepromoting complex (APC) destroy cdk1 freeing cyclin B for degradation
Check points of cell cycle: whats the point?
Checkpoints are biochemical circuits that detect external or internal stimuli and send appropriate signals to the cell-cycle system.
• Checkpoints mostly activated by genotoxic stress mainly DNA damage.
G1 checkpoint
ATM is a sensor that is also a kinase to check on DNA damage:
2 pthways: The faster pathway acts via the activation of Chk2 and the inactivation of Cdc25. Thus, inhibitory phosphates of the CyclinE/Cdk2 complex can no longer be removed.
Slow pathway: The slower pathway involves the stabilization of p53 and transcriptional upregulation of p21 which binds and inhibits the Cyclin/Cdk complexes (d/ cdk46 and E/cdk2)
G1 Checkpoint: p16
Another pathway that if activated cells will never replicate
G2 checkpoint
2 pathways again:
- slower pathway will inhibit cycB1 CDK1 through activated p53 pathway
- fast pathway is that chk1 and chk 2 will phosporylate and inactivating it thus inactiviating the cyclin cdk complex
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)
Cancer
Malignant neoplasm (can produce metastasis)
Metastasis
Secondary growth of cancer at different - location from primary neoplasm
Stages of Carcinogenesis
Initiation • Simple mutation in one or more genes that control key regulatory pathways of the cell (change in DNA sequence)
Promotion • Selective functional enhancement of signal transduction pathways that were induced by initiator by continuous exposure (involving changes in gene regulation)
Progression • Continuing change of the basically unstable karyotype (further changes in karyotype)
Initiation
- rreversible
- no threshold
- Genotoxic agents include chemicals, radiation, reactive oxygen species, and viruses
- Involves sequence change in cellular DNA
- Single gene mutation, chromosomal translocation, and gene amplification
- Can be a result of the activation of oncogenes or the inactivation of tumor suppressor genes
Promotion
- Promotion occurs over a long period of time
- Reversible in its early stages
- Involves gene activation or repression such that the latent phenotype of the initiated cell becomes expressed through cellular selection and clonal expansion. -Threshold exists (time and dose)
progression
- involves further complex gene changes and irreversible changes to gene experssion which will cause karyotypic instability
- benign tumors start turning into malignant neoplasms
Oncogenes
Expression of these genes is tightly control under normal circumstances. Loss of regulation of gene expression can lead to enhanced expression of these proteins which leads to unregulated cell division and growth.
Tumor suppressors
These are cellular genes that serve to check or inhibit cell division. Loss of expression of these proteins leads to cell growth or cell division.
What are the 3 ways you can find an oncogene
Cellular proto-oncogenes that have been captured by retroviruses,
Virus-specific genes that behave like cellular proto-oncogenes that have been mutated.
Cellular proto-oncogenes that have been mutated,
Type 1 transducing virus
Cellular Oncogene is carried in Retro virus
Type 2
NON Transducing virus:
cellular oncogene activated by proviral insertion and intergration
Type 3 retroviral oncogene
retroviral transactivating protien disrupts the normal regulation of the cellular transcripton
type 4 oncogenic retrovirus
inpropreate cellular signaling resulting from viral envolope/ cell receptor interactions
Name 2 oncogenes
Ras and Myc
Tumor suppressor genes
Recessive
Normal activity: repress growth
no known analogus in oncogenic viruses
examples are: Major examples are: p53, Rb, p14ARF, p16INK4A
Tumor supressor gene: P16INK4A
showed inactivation of the INK4a locus on human chromosome 9p21 in human cancers (2nd most commonly inactivated gene)
• Gene mutation • Gene deletion • CpG island methylation in promoter
normally when you have its it regulates G1 check point
Rb (Retinoblastoma)
-if mutated restriction check point is ungregulated
Tumor microenevrioments
- is the tissue environment in which cancer cells exists, that include normal cells, secretory factors, and the extracellular matrix.
- there are barriers for therapy beacuse so much is in the way
- desmoplastic rxn: to much tissue that isnt the cancer but is around the cancer thus you cant access et
- microenviroment can promote tumor progression, therapy resistance and recurrence: the cell arounds the ca cell can have mutation that produces paracince signals for other cells to devide
Radiation
effective on cells which have: repoductive activity, cells that have longer diviving future ahead and cells that are least differentated
-you break dna bonds or you use hydrolysis of water to produce powerful damaging free radicals
chemo aklylating agents
capable of denaturing certain macromolecules such as DNA macromolecules
intercalating agents
which interact with DNA and are intercalated between two bases, inducing a structural change and a functioning of this molecule– cleaving agents, capable of breaking DNA molecules.
antimetabolites
that can be structural analogues of purines or pyrimidines; they block the synthesis of the corresponding bases (5 FU), or folate analogues
mitostatic agents
s that inhibit tubulin synthesis, these being cell spindle poisons
plat derivates
which plays a role by DNA binding
Necrosis:
morphological changes
cells involved
inflammatory outcome
major biochemical features
» Describe the basic regulatory mechanisms
Morphologically characterized:
Cell membrane: Swelling and rupture. 2. Cytoplasm: Increased vacuolation, organelle degeneration, and mitochondrial swelling. 3. Nucleus : Clumping and random degradation of nuclear chromatin and DNA (karyolysis)
Cells involved: all
inflamation: yes
biological features: Extensive failure of normal physiological pathways that are essential for maintaining cellular homeostasis, such as regulation of ion transport, energy production (ATP Depletion) and pH balance.
You target: Two players are involved and target the mitochondria: 1. Receptor-interacting protein 1 (RIP1) 2. Poly [ADP-ribose] polymerase 1 (PARP-1)
Apoptosis
morphological changes
cells involved
inflammatory outcome
major biochemical features
» Describe the basic regulatory mechanisms
Also called programed cell death
• Morphologically characterized by: 1. Cell membrane: membrane blebbing and eventually fragmentation into membrane bound apoptotic bodies. 2. Cytoplasm: Fragmentation and shrinkage 3. Nucleus : Chromatin condensation and degradation via specific DNA cleavage leading to nuclear fragmentation.
Cells involved: hematopoietic cells and their malignant counterparts (liquid tumors). Apoptosis only plays a modest role in the treatment response of most solid tumors, which constitute the major part of human malignancies.
No infalmation
biochem feature: cell membrane looses assyemerty, phospatilserine is exposed, caspase and mitochodria dependent
Triggers are: DNA damage, death receptor singaling cell membrane or mitochodria dalamge
Autophagy
self eating of cell and recycling
Morphologically characterized by: 1. Cell membrane: membrane blebbing. 2. Cytoplasm: accumulation of two-membrane autophagic vacuoles. 3. Nucleus : Partial chromatin condensation No nuclear and DNA fragmentation.
- Cells involved: All cell types
- Inflammation: No.
- Biochemical features: Caspase-independent and increased lysosomal activity.
