FUN Cancer Flashcards
What are the 3 types of extracellular signals that regulate cell proliferation/cell death?
And
What are the 3 stimulation factors? Define each
- Endocrine signaling: Hormones
- Autocrine: Targets sites on the same cell
- Paracrine signaling: signaling from adjacent cells
Mitogens: Stimulate cell division by relieving intracellular negative controls that block the cell cycle progress
Growth factors: Stimulate cell growth by promoting synthesis of proteins/macromolecules and by inhibiting their degradation
Survival factors: Promote cell survival by suppressing apoptosis
What are the 4 types of cyclins? What do each do?
G1 cyclins: help promote passage through the restriction point in late G1
G1/S-cyclins bind Cdks at the end of G1 and commit the cell to DNA replication
S-cyclins: bind Cdks during S phase and are required for the initiation of DNA replication
M-cyclins: promote the events of mitosis
What are cyclins? State their role
cyclins are regulatory subunits that increase and decrease during the cell cycle. They act as a substrate for CDK enzymes switching on kinase activity
True or false:
CDK activity requires substrate binding to function
True
What is the substrate for CDKs and when bound, what are they called?
Cyclins are the substrate
When bound they are known as the cyclin dependent kinase complex or CDKC
Briefly state how the levels of CDK and cyclin change during the cell cycle
Levels of CDK are at a steady state
Levels of cyclin proteins fluctuate during the cell cycle
How are cyclins degraded?
Cyclins are degraded through ubiquitylation as it is more target-specific
Discuss and explain the processes that occur in the mid-G1 Cyclin/CDK checkpoint. Give an example of a cancer that can result from compromising the checkpoint’s integrity.
Cyclin D1 is responsible for this checkpoint
In a non-proliferating cell, p16 inhibits the formation of an active CDK4/Cyclin D1 complex.
Active RBC protein inhibits the entry into the cell-division cycle. Active RBC is bound to E2F which is a transcription factor. When bound, it halts cell division machinery.
When p16 is inactive or absent, kinase activity phosphorylates RB leading to its inactivation. This encourages cell division.
Over-activity of Cdk4 or cyclin D1 encourages unregulated cell division. An example of this is Mantle Cell Lymphoma:
Expression of cyclin D1 is placed under the control of the IgH promoter. As a result of chromosomal translocation, the upregulation of cyclin D1 is induced. When bound, it activates the transcription factor E2F, releasing it from negative regulation by the tumor suppressor Rb.
Discuss p53 as a key regulator of cell proliferation
P53 is a transcription factor that is activated by DNA damage. It stops cell replication. It’s mutation is the main cause in many cancers.
DNA damage sensors launch a cascade of signaling events which induce the phosphorylation and activation of p53. p53 is a tumor suppressor that, when induced, causes cell cycle arrest.
P53 induces p21 which inhibits the activity of the cyclin-CDK complex such that Rb is not phosphorylated, remaining bound to E2F. This leads to the S phase genes turned off.
If DNA is repaired p53 levels drop, p21 decreases, and the process continues normally. If not, then p53 remains high and the cell undergoes programmed cell death.
Briefly differentiate between apoptosis and necrosis
Apoptosis is the programmed process of cell death which protects the organism from damaged cells. Necrosis is cell death through an external force such as poison and injury which leads to the random degradation of DNA
Briefly describe the 2 mechanisms of apoptosis
External signals activate the cell membranous death receptors
Internal signals trigger the release of cytochrome c from the mitochondrion
Both pathways converge with the activation of caspases 3,6, and 7 which ultimately leads to apoptosis
Which apoptotic mechanism leads to changes in mitochondrial function?
Intrinsic pathway
List the steps involved in the extrinsic signaling pathway leading to apoptosis
- A pro-apoptotic ligand binds to transmembrane death receptors
- Trimerisation of receptor
- Activation of pro-caspase 8
- Activates caspases 3,6, and 7 leading to apoptosis with death fragmentation
List the steps involved in the intrinsic signaling pathway leading to apoptosis
Cytoplasmic p53 responds to cell damage and induces mitochondrial outer-membrane permeabilization
This leads to cytochrome c leakage from mitochondria into cytoplasm
Cytochrome c binds to Apaf1 (apoptotic protease activating factor)
Cytochrome c-Apaf1 complex binds to initiator caspase 9 and activates it forming the apoptosome
Apoptosome activates other caspases ultimately leading to apoptosis
Explain the common stage between intrinsic and extrinsic pathways.
Initiator caspases such as caspase 8 and 9 are cleaved in response to activation signals from other proteins. They then activate the executioner (effector) caspases.
This leads to DNA fragmentation by endonuclease activity, loss of cell shape, and organelle breakdown.
Apoptotic bodies are then phagocytosed by macrophages
How can a cancer cell bypass apoptosis? Explain using the 2 mechanisms
- Over-ride intrinsic pathway: An example of which is p53 mutations. In this case, DNA is not repaired and mutagenic lesions accumulate.
Another example is the upregulation of anti-apoptotic proteins which lead to the overexpression of BCL2 in numerous forms of leukemia
- Do not respond to extrinsic signals. This is done through decoy receptors which bind the death ligands but do not transduce the signal.
What are the two types of neoplasms? Define each
Benign: localized growth. They grow by expansion, compression, or displacing surrounding normal tissue. They often have a capsule
Malignant: Capable of invasion and/or metastasis. They grow by local infiltration, destroying the tissue through which they invade
What are the types of cancers classified according to their origin? Which one contains the majority of cancers
Carcinomas: Epithelial cells (majority)
Sarcomas: Mesodermal origin
Lymphoma/Leukemia: Circulating cells of blood and lymph
Briefly describe the two models for tumor propagation. Are these two models mutually exclusive?
- Clinal evolution model: mutant tumor cells with a growth advantage are selected and expanded. => first mutation is the growth advantage and second mutation is the resistance to apoptosis. Natural selection
- Cancer Stem Cell Model: Refers to a rare subset of Tumor cells that have the ability to self-renew and generate diverse tumor cells. A hier by exists where there is:
Self renewing stem cells that are essential for initiation and long-term maintenance of tumor
Transit-amplifying cells: Responsible for expansion of the tumor but are incapable of long term maintenance
Population: May or may not be capable of proliferation. Incapable of maintaining the tumor. May be differentiated
No they are not mutually exclusive
What are the three classes of genes that can cause cancer? Briefly explain each with their normal function
Proto oncogenes: Normal activity is to promote cell proliferation. The mutant form is the oncogene. Gain of function mutations create forms that are excessively active
Tumor suppressor genes: Normal activity is to inhibit cell proliferation or promote apoptosis. Includes genes that prevent inappropriate cell cycle progression and promote apoptosis of damaged cells
Caretaker genes: Ensure accurate replication, repair, and segregation of DNA. Mutations of these genes leads to genomic instability
What are the 6 hallmarks of cancer?
No need for extra details
1. Growth signal autonomy: Cancer cells are not dependent on normal growth factor signaling.
- Evasion of growth inhibitory signals
- Evasion of apoptosis
- Unlimited replication potential: Maintain the length of telomeres
- Angiogenesis: Altered balance between angiogenic inducers and inhibitors can activate the angiogenic switch
- Invasion and metastasis: Mutations alter the activity of enzymes involved in invasion and alter molecules involved in cell-cell and cellular-extracellular adhesion.
What are the 4 ways that tumor suppressor genes can be inactivated?
Deletion
Point mutation
Methylation of promoter (transcriptional silencing)
MiRNAs-post-transcriptional silencing
What are the functions of proto-oncogenes?
Growth factors
Cell surface receptors
Intracellular signal transduction molecules
DNA binding proteins including transcription factors
Cell cycle proteins (cyclins, cdks, kinase inhibitors)
How can Proto-oncogenes be activated? Explain each briefly and give an example
- Point mutation or deletion:
Example: RAS oncogene controls intracellular signaling networks resulting in transcription of genes promoting cell division and inhibition of apoptosis.
Ras in the off state is bound to GDP
Ras in the on state is bound to GTP
Mutated Ras prevents GTP hydrolysis to GDP => it is continuously active
- Gene amplification: Normal protein produced in a much higher amount
Example: MYCN in neuroblastoma
MYCN is an oncogenic transcription factor that alters expression of 100s of genes. MYCN amplification is a marker of poor prognosis which is important in determining optimal therapy - Chromosome rearrangement (to create a new gene through fusion or placement of strong enhancer nearby causing overproduction of normal protein):
Example: Chronic myeloid leukemia (CML)
Translocation creating Philadelphia chromosome which has a hybrid gene made up of 2 genes. Bar-Abl fusion protein has constitutively active tyrosine kinase
Genomic instability is an almost universal feature of tumor cells. What are the two forms of this instability?
Micro-satellite instability: DNA level instability
Chromosomal instability (CIN): Abnormal karyotypes => chromosomal level instability
Define metastasis
Metastasis is the spread of tumor cells from a primary site and their establishment at distant secondary locations
Give 3 ways that tumor cells can spread through
Blood
Lymph
Within body cavities