Flashcards in Cell Cycle, Apoptosis and Cancer Deck (49):
Quiescent cells (in G0)
May reenter the cell cycle at G1 after stimulation by molecules such as growth factors
Hepatocytes, epithelial cells of the kidney tubules
Senescent cells (in G0)
Never able to reenter the cell cycle and are unable to proliferate even in the presence of growth factors
Neurons-will never divide again
Never enter G0 and are constantly dividing
Gut epithelium, skin, hair follicles, bone marrow
How to fully activate CDK's
Need CDK-activating kinases (CAK)
CDK levels during cell cycle
Levels of CDKs are constant throughout the cell cycle
Cyclin levels during cell cycle
Levels of individual cyclins vary considerably during cell cycle
Phosphorylation of CDKs by CAK does what?
CAK (CDK-activating kinase) fully activates the cyclin-CDK complex
(WEE1 inactivates by phosphorylating)
Phosphorylation of CDKs by WEE1 kinase does what?
Inhibits cyclin-CDK activity
(CAK (CDK-activating kinase) activates by phosphorylation)
A phosphatase that can remove the phosphate group that was put on by WEE1.
This will reactivate the cyclin-CDK complex
Cyclin-CDK complex activities can be modulated by what?
CDK inhibitor proteins (CKIs)
2 families of CKIs
1 of 2 families of CKIs (CDK inhibitor proteins)
i.e. p27. Inhibit G1 and S phase cyclin-CDK activities by binding to the cyclin-CDK complex and altering the conformation of the active site to render CDK inactive
1 of 2 families of CKIs (CDK inhibitor proteins)
i.e. p15, p16, p18 etc. Inhibit G1 CDKs (4 and 6) by binding to them and preventing CDK4 and CDK6 from associating with cyclin D
How to terminate the activity of cyclin-CDK complexes
Degrade the transiently expressed cyclin proteins through regulated proteolysis. Targeting them for this is done via polyubiquitination and catalyzed by ubiquitin ligases.
Specific ubiquitin ligases can also ubiquitinate CKIs and target them for degradation, thereby releasing the inhibition of S phase cyclin-CDK complexes
What does p27 do?
Binds to the cyclin-CDK complex and inactivates the kinase activity of CDK
Retinoblastoma (RB) protein
Substrate of G1 and G1/S cyclin-CDK complexes
Used as a tumor-suppressor protein b/c it can arrest the cell cycle at the G1 checkpoint
Hypophosphorylated form of RB
Binds to E2F transcription factors. This sequesters E2Fs and prevents them from triggering the transcription of cyclin E (a G1/S phase cyclin) and cyclin A (an S phase cyclin)
Hyperphosphorylation of RB
Hyperphosphorylation of RB by the G1 and G1/S CDKs releases E2Fs and allow for the transcription of cyclin E to occur so that cells can transit the late G1 checkpoint and enter the S phase
What keeps RB (retinoblastoma) protein in the phosphorylated state?
S phase and M phase cyclin-CDK complexes
Degradation of these cyclins during the later stages of mitosis allows for the dephosphorylation of RB for the next round of the cell cycle
What does DNA damage do to p53?
DNA damage appears to stabilize another tumor suppressor protein known as p53
In the presence of DNA damage, p53 is _____
p53 is phosphorylated and stabilized
It can stimulate the transcription of many genes including p21 (CIP/KIP family of CKI). Inhibition of cyclin-CDKs by p21 can lead to arrest of cells in G1, S and G2 phases
If DNA damage is not fixed, then what happens?
Retinoblastoma and the RB protein
Retinoblastoma is a childhood disease.
Tumors develop due to unchecked division of precursor cells in the immature retina.
Hereditary form affects both eyes
Nonhereditary form affects one eye
In the hereditary form, one copy of the RB gene is mutated or lost in every cell, and the cells become predisposed to becoming cancerous. Cancerous cells contain different somatic mutations in the two copies of the RB gene
p53 and cancer
More than 50% of all human cancers exhibit mutations in the p53 gene
Metabolic activation of benzo(a)pyrene (in cigarette smoke) makes a potent mutagen. Activated benzopyrene causes mutations in genes such as p53 by G-->T transversion.
Aflatoxin (in moldy grain and peanuts) also induces G-->T transversions in the p53 gene
Apoptosis is caused by what?
A cascade of intracellular proteases called caspases
Initiates outside the cell
"death receptor pathway"
Triggered by binding and activation of an external death ligand (i.e. Fas ligand) to its receptor on the plasma membrane
Adaptor proteins containing death domains (i.e. Fasassociated death domain protein (FADD)) bind to intracellular regions of the activated receptor and recruit procaspase-8
Autocatalysts of procaspase-8 generates caspase-8, which then initiates a caspase cascade involving other caspases (3,6,7)
Triggers apoptosis inside the cell
Triggered by events such as growth factor withdrawal, DNA damage (which increases p53), and cell cycle defects
(Check notes/picture for pathway diagram)
These encode proteins that promote cell growth and division. Tend to be members of sell-signaling pathways, i.e. growth factors, hormone receptors, signal transducers and TF's
Such "gain of function" mutations often appear to be inherited in an autosomal dominant fashion
How are proto-oncogenes converted to oncogenes?
Via gain of function mutations
Proto-oncogenes and HER2
A point mutation that changes Val to Gln
EGF and ligand binding doma-->ocoprotein
Deletion in part of gene
How proto-oncogenes are converted to oncogenes (3 mechanisms)
1. A point mutation
2. Gene amplification
3. Chromosomal translocation: genetic rearrangement (e.g. c-MYC, ABL)
-ABL→myelogenous leukemia (CML)
Tumor suppressor genes
Even one good copy of a tumor suppressor gene is usually sufficient to provide normal regulation. Therefore, mutations in tumor suppressor genes appear to be autosomal recessive mutations, and both copies of such genes have to be damaged to make the cells prone to the onset of cancer. These mutations are known as "loss of function"
Thus, oncogenesis results when somatic mutations occur in combination with the inheritance of recessive mutations and so both alleles become dysfunctional.
Tumor suppressor gene: p53
Monitors checkpoints of cell cycle
Characteristics of Mutated Protein Product: Observed in >50% of all human tumors
Tumor suppressor gene: RB
Regulates G1 phase of cell cycle
Characteristics of Mutated Protein Product: Observed in retinoblastoma
Tumor suppressor gene: APC
Regulates cell proliferation
Early event that occurs in the progression toward colon cancer
Tumor suppressor gene: BRCA1/BRCA2
Plays a role in DNA repair and apoptosis
Inheritance of a mutated BRCA1 gene increases chance of developing breast cancer by the age of 50 by 30x
Traits that appear to be common to most tumor cells
1. Self-sufficiency in growth signals (tumor cells don't need external growth factors b/c many oncogene products mimic growth signaling)
2. Evading growth suppressors (resist growth inhibitory signals)
3. Activating invasion and metastasis (tumor masses spawn pioneer cells that invade other regions. Metastases are the cause of 90% of cancer deaths)
4. Enabling replicative immortality (cancer cells continue to express telomerase activity)
5. Inducible angiogenesis (cells in tissue need a nearby blood vessel to get their nutrients. Cancer cells can induce the development of new blood vessels)
6. Resisting cell death (cancer cells appear to be defective in both intrinsic/extrinsic pathways of apoptosis)
7. Deregulating cellular energetics (they can upregulate their GLUT1 glucose transporters)
8. Avoiding immune destruction (they appear to be invisible to the body's T and B lymphocyte immune cells)
9. Tumor promoting inflammation (ROS may accelerate mutagenesis of cancer cells)
10. Genome instability and mutation (mutations lead to faster mutations)
Metastatic colon cancer model
"Multihit" model: takes mutations in multiple genes over a period of time for the development of full-blown cancer
Development of metastatic colon carcinoma appears to involve the following events:
1. An early loss of the anaphase-promoting complex (APC) tumor suppressor gene from the long arm of chromosome 5
2. Activation of the K-RAS oncogene (with a Val 12 mutation) on the short arm of chromosome 12
3. Loss of the deleted in colorectal carcinoma (DCC) tumor suppressor gene from the long arm of chromosome 18
4. Loss of the p53 tumor suppressor gene from the short arm of chromosome 17
5. Other events (e.g. stimulated angiogenesis)
RAS and cancer
Point mutation changing Glycine → Valine
Result: RAS oncoprotein is perpetually active
Adaptor proteins such as GRB-2 and IRS-1 have special domains known as SH2 domains or PTB domains that recognize and bind to motifs on the receptor that contain phosphorylated tyrosine residues
It accidentally incorporates an adjacent host proto-oncogene into its genome
Fibrosarcomas in chickens
****Rous sarcoma retrovirus (RSV) can cause fibrosarcomas in chickens. The transforming factors introduced by the RSV was v-src, a tyrosine kinase. The v-src gene is the oncogenic form of the normal host proto-oncogene c-SRC
Targeted inhibition of Oncoproteins. What do they use in general?
They target particular oncoproteins with monoclonal antibodies or specific inhibitors
Targeted inhibition of Oncoproteins: Herceptin
For breast cancer
Monoclonal antibody (mAb) against HER2/NEU epidermal growth factor (EGF) receptors expressed in the mammary tissue
HER2/NEU are overexpressed
Targeted inhibition of Oncoproteins: Erbitux
For colorectal cancer
A monoclonal antibody (mAb) directed against the EGF receptor that is over-expressed in colorectal cancer
Targeted inhibition of Oncoproteins: Gleevec
For chronic myelogenous leukemia (CML)
An inhibitor that binds to the active site of the ABL tyrosine kinase and inhibits its activity (prevents phosphorylation). Has little effect on hurting the normal white cells in the blood. Targets an oncoprotein (BCR-ABL) that is unique to cancer cells.
G1, G2, G3
G1: fix any DNA damage
G3: ensure chromasomes are good