Cell Cycle Control
What is the most important checkpoint in the cell cycle and what phase does it occur in?
The restriction point or "R point". This happens at the end of G1 phase before DNA is replicated in S phase. G0<G1<S<G2<M
What is p53 and what is it's main function?
p53 is a transcription factor. It binds as a tetramer when DNA damage is detected and upregulates p21 and other pro-apoptotic proteins to induce apoptosis.
Does senescence inhibit or promote cancer?
Both! Senescence is the final stage of the cell where it is not dividing; however, cells can release Senescence Associated Secretory Phenotypes (SASP) which are inflammatory and contain matrix remodeling enzymes.
A carcinogen chemically binds to a DNA base. What is the resulting structure called?
DNA adduct
What is extravasation, and why is it important for metastasis?
the process by which circulating cancer cells leave the bloodstream and enter surrounding tissue at a distant location. Cancer cells may form a microthrombus, proliferate, and cross the blood vessel basement membrane, allowing them to potentially establish secondary tumors.
How does MYC increase gene expression?
It releases paused RNA Pol II.
What is the relationship between ARF, MDM2, and p53?
ARF inhibits MDM2 which inhibits p53.
What is the difference between driver and passenger mutations?
Driver mutations occur in cancer-critical genes while passenger mutations are just "along for the ride" and will be in non-cancerous related genes. BOTH occur in tumor genotypes.
How can methylated CpG sequences contribute to mutations?
Methylated cytosines can undergo spontaneous deamination, converting 5-methylcytosine into thymine. If the resulting mismatch is not repaired, it can lead to a permanent C-to-T mutation.
What is the relationship between chronic inflammation and cancer development?
Cancer frequently arises at sites of chronic inflammation, and inflammatory cells are commonly found within tumors. Chronic inflammation can create an environment that supports tumor development and progression.
What are Cdc25 phosphotase and Wee1 Kinase and what do they do?
Cdc25 phosphotase removes inhibitory phosphates from CDK's to allow cyclin-cdk complex formation and drive cell cylce progression. Wee1 Kinase does the opposite.
What is BCL-2 and how does it work?
BCL-2 is a pro-survival protein that blocks the intrinsic apoptosis pathway. BCL-2 inhibits BAK and BAX from permeabilizing the mitochondrial membrane.
What is field cancerization and what are some characteristics of it?
Field cancerization is when a large area of tissue accumulates genetic changes, potentially making it more cancerous, but the cells will still look normal. Ex. Different cells aquire independent mutations to form multiple unique tumors.
What are nucleotide excision repair (NER) and base excision repair (BER), and what types of DNA damage do they repair?
NER repairs bulky DNA adducts by removing a segment of DNA containing the lesion. BER repairs smaller damaged or chemically altered bases, including those resulting from deamination. Both help prevent mutations from becoming permanent!
How can researchers distinguish cancer stem cells from non-stem cancer cells within a tumor?
Researchers can compare stem-cell-specific and non-stem-cell markers to identify the different populations. They can also test tumor-forming ability by transplanting a small number of isolated cells into mice. Cancer stem cells are expected to have a greater ability to initiate tumor formation, helping demonstrate their tumor-initiating potential.
How do cyclins activate CDKs? Which one is under transcriptional regulation and which one stays constant?
Cyclins activate CDKs by inducing a conformational change that exposes the T-loop which can then be phosphorylated by CAK. CDKs stay constant throughout the cell while Cyclin levels fluctuate.
Why do p53 mutations occur in the DNA binding domain and what is the preferred mutation type? Why is it dominant negative?
Cancer mutations are typically missence mutations in the DNA binding domain. p53 is a tetrameric transcription factor. If one subunit is mutant it will inhibit activity of the other remaining subunits.
Why do cell lines have to be immortalized using proteins such as SV40LtA and hTERT?
These proteins are used to immortalize cell lines. SV40LtA is used to pull down p53 (inactivation) while hTERT is the catalycitc PROTEIN subunit of telomerase to extend telomeres.
How does reduced ALDH activity affect the risk of developing esophageal cancer in individuals who regularly consume alcohol?
Reduced activity of aldehyde dehydrogenase (ALDH) causes acetaldehyde, a carcinogenic byproduct of alcohol metabolism, to accumulate. Increased acetaldehyde exposure can damage DNA and increase the risk of esophageal cancer.
How do stromal cells within the tumor microenvironment influence tumor growth?
Stromal cells are noncancerous cells surrounding or associated with tumor cells. They can provide signals and environmental support that promote cancer cell survival and proliferation. In the exam's mouse transplantation experiment, tumors form more readily when breast tumor cells are transplanted with their associated stromal cells.
What signals need to be present to promote cell cycle progression from the R point into S phase? What pathway inhibits this and how?
Signals to promote G1 to S: Cyclin D1 binds to CDK4/6 which can phosphorylate Rb. Phosphorylated Rb releases E2F to activate transcription of S-phase genes. TGF-B activates the SMAD pathway which induces transctiption of INK4 family members (CDK inhibitors) to inhibit the Cyclin-CDK complexes.
Describe the differences between the intrinsic and extrensic apoptosis pathways.
Intrinsic pathway: Apoptosome formed by Apaf-1, cytochrome C, and initiator caspace-9.
Extrensic pathway: DISC complex formed by death receptors and intiator caspace-8.
Both lead to downstream activation of executioner caspace-3.
What is a "genetic biography"? Give an example using colon cancer tumorigenesis and how do additional mutations drive it to malignancy?
A genetic biography is the chronological order of mutations a cancer aquires to reach malignancy. APC mutations are usually the first, and trap cells in the colonic crypt, preventing differentiation and allowing expansion of mutant cells. Other mutations such as Ras and TGF-B signaling, or p53 knockout can contribute to certain hallmarks of cancer leading to malignancy.
What is the difference between tumor initiation and tumor promotion, and how do these processes contribute to cancer development?
Tumor initiation involves genetic damage that produces mutations in cells. Tumor promotion involves repeated exposure to factors that stimulate the proliferation of initiated cells. For example, in the mouse skin papilloma model, DMBA acts as the initiator and TPA acts as the promoter. Initiation followed by repeated promotion can lead to tumor formation.
A mutation causes APC to lose its normal function in intestinal epithelial cells. What happens to β-catenin signaling, and how might this affect cell proliferation?
APC normally helps regulate β-catenin degradation. When APC loses its function, β-catenin accumulates and activates genes that promote cell proliferation. This can cause intestinal epithelial cells to continue proliferating rather than differentiating normally, contributing to early tumor development.