15.2 Cancer II Flashcards
(38 cards)
Cancer pathology is ultimately due to?
the accumulation of DNA mutations that negatively effect expression of tumor suppressor genes or positively effect expression of oncogenes to enhance progression through the cell cycle.
What are proto-oncogenes? what is an oncogene?
they are normal genes that promote cell growth and mitosis.
The mutated proto-oncogene that increases activity of its product protein (I.e., gain of function mutation) is called an oncogene. Effect is usually dominant and requires mutation of only a single copy of proto-oncogene.
What are examples of proto-oncogenes?
Signaling proteins:
Ras
EGF receptro
Myc
BCL2
What are tumor suppressor genes?
tumor suppressor genes inhibit cell division. They are usually either transcription factors or intermediates in signaling pathways. With a loss-of-function mutation, tumor suppressor genes drive a cell towards cancer. Effect is usually recessive and requires mutation of both gene copies to be effective.
What are examples of tumor suppressors?
retinoblastoma
BRCA
APC
p53
What are the two mechanisms that can result in cancer development?
1) genes that control growth and cell cycle progression can become mutated in such a way that there is more than a normal amount of either gene products being expressed or gene activity These genes play roles in normal development and cell function and in the absence of genetic changes, these genes are called proto-oncogenes.
2) A second set of genes that might be mutated in cancer cells are those that normally prevent uncontrolled growth and these include the tumor suppressor genes. Normally, if only one copy of these genes is normal, the cell will not become cancerous b/c enough of the protein can be expressed from the single normal gene in order to prevent uncontrolled growth of the cell. However, if both copies of a tumor suppressor are defective, the cell then becomes cancerous
Oncogenes are dominant, what does this mean?
this means only one copy of the gene needs to be mutated in order to cause a disease
How is p53 a tumor suppressor?
p53 gene product prevents the division of cells w/damaged DNA.
What is a recessive change?
When two copies of genes need to be mutated to become cancerous. Ex: tumor suppressor genes.
What mutation occurs in Ras to cause it to be a proto-oncogene?
The 12th amino acid of Ras is a glycine and when it’s mutated to valine, Ras remains in the “on” state, even if it has GDP bound to its nucleotide binding site.
Ras is mutated in such a way in about 1/4 of all cancers and has also been incorporated into the genomre of viruses, such as the Rous sarcoma virus, which also causes cancer.
Normal cells stop growing when they touch each other (contact-inhibition of cell growth), how is mutated Ras different?
Cells that have a mutated copy of Ras gene grow in an uncontrolled manner. This is the basis for one assay of for cancer-critical genes in DNA is introduced into cell cultures and the cells are then screened for cells that are capable of growing on top of each other.
How many copies of a mutated Ras oncogene are needed for cells to become cancerous?
one single copy of a mutated Ras oncongene is sufficient for a cell to become cancerous and these genes are therefore considered to have a dominant effect on cell growth.
Why are tumor suppressors said to be recessive?
Mutations in the genes that code for expression of tumor suppressors can render them non-functional. However, even if only one copy of a normal tumor suppressor gene is present, that’s usually enough to prevent uncontrolled growth of the cell and therefore, tumor suppressor mutations are recessive.
Why is retinoblastoma protein (Rb) a well studied example of a tumor suppressor gene?
Rb is defective in a rare, genetically inherited disease, that leads to frequent development of cancer cell growth in patients eye. The Rb protein is a protein that normally inactivates an E2F transcription factor in cells, unless the G1-cyclin dependent kinase is activated and that leads to cell division normally. Mutations that lead to the loss of full length Rb protein expression lead to uncontrolled progression through the cell cycle and therefore cause tumors to develop.
What are the possible scenarios that could give rise to cancer if genes for Rb protein become defective.
Normally, cells have two copies of an intact Rb gene, one on the chromosome inherited from the father and the other from the mother. Random mutation may lead to inactivation of one copy of the gene but since the other copy is still good, no tumor will result.
1) A case where someone inherits two intact copies of the Rb gene, but an occasional cell ends up having both copies of the gene defective. Only about one in thirty thousand people develop retinoblastoma through this mechanism.
The chance of mutating both copies is so small that even people who do develop retinoblastoma through this mechanism only have one tumor.
2) Case: someone who actually inherits one defective copy of the Rb geneL in this case, any mutation of the other copy in a particular cell will result in that cell becoming tumorous. These people generally develop multiple tumors in both eyes.
3) a cell can lose all copies of normal Rb genes assuming one abnormal gene is already inherited.
4) Chromosomal alterations can also lead to the loss of the nromal gene. For example, the entire normal chromosome can be lost in some sort of a mitotic nondisjunction event or a fragment of the normal chromosome containing the intact Rb gene could be lost in a chromosome deletion.
What are the three ways in which a proto-oncogene can be converted to an oncogene (obtain gain-of-function changes)
1) Mutations that cause a protein to be active when it shouldn’t. Ex: mutation of Ras glycine-12 to valine
2) Mutations that appear in the non-coding regulatory regions of the protein, such that the protein is expressed when it shouldn’t be.
3) Chromosomal reorganization can also lead to duplication of a gene, which then creates an over-expression or amplification fo that particular gene product. Chromosomal reorganization might also cause a proto-oncogene to be placed somewhere where it is under the control of the wrong promoter and that might also lead to hyper-expression.
Mutations in separate pathways lead to?
synergistic effects and might make cells more prone to develop cancer or could make individual cancers more aggressive.
Many cancer critical genes are?
transcription factors that control cell division.
Give an example of how cancer critical genes are transcription factors that control cell divsion
The retinoblastoma family of proteins plays a critical role in one of the cell cycle checkpoints
that regulates the entry of a cell into S phase.
In the presence of active Rb protein, the
transcription factor E2F is held in an inactivated condition which prevents the expression of S
phase proteins needed to replicate DNA. Rb proteins are normally inactivated when the cell
progresses through the cell cycle as part of normal cell division and this happens by the
phosphorylation of Rb by cyclin dependent kinases. The activity of cyclins in turn, is inactivated
or inhibited by cyclin inhibitors like p16. So, there are a number of ways that the inhibitory
effects of Rb on the cell cycle could be disrupted. These would include the loss of p16
expression, mutation of Rb genes that mimic the phosphorylated state or the actual loss of Rb
protein expression. In fact, the figure at the bottom of this slide shows western blots of cell
cultures obtained from different tumors, showing the expression of Rb protein and you can see
that many of the tumors are made of cells with decreased or absent Rb protein expression.
What is PTEN?
Phosphatase and Tensin homolog deleted on chromosome Ten.
This protein is a negative regulator of the PI 3-Kinase signaling pathway and it functions by removing phosphate groups on phosphorylated PIP3.
Successful cancers show alterations to which signaling pathway?
PI 3-Kinase Akt signaling pathway, which controls cell growth through the activity of the TOR family of proteins.
Half of all human cancers have mutations in which tumor suppressor gene?
the one that codes for p53.
loss of activity of p53 allows a cell to advance through the cell cycle, even if its DNA has been damaged.
What is an example of a cancer causing virus that has incorporated proteins into their genome that leads to host cell proliferation?
Human papilloma virus (HPV)
The HPV genome codes for only nine proteins, E1-E7 and L1-L2. The E6 and E7 genes are capable of causing a cell to become cancerous. These genes target two different tumor suppressor pathways.
How do E7 and E7 in HPV target suppressor pathways?
1) the E7 protein mimics the target of Rb protein. The over-expression of E7 therefore acts to decoy Rb from its normal function and that leads to the expression of cell cycle proteins that would generally be suppressed by the activity of Rb under normal circumstances.
2) the E6 protein interacts directly w/p53 and blocks its ability to drive expression of pro-apoptotic signaling proteins and cell cycle inhibitors
