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Along the cell cycle, there are numerous checkpoints in which the cell “doubles check” whether or not it should proceed to the next phase. At these checkpoints the cell decides whether or not it should move to the next step in the cell cycle. Abnormalities in these checkpoints are the keys to cancer formation, as dysregulation of these control mechanisms leads to unregulated cell division. The most important of these cell checkpoints is the point where the cell determines whether or not it should move from the G1 to S phase. Cells that pass through this checkpoint generally end up going through the full cycle of division. Rb and p53 are the most important control mechanisms at this check point.
Tumor Suppressor genes are involved in preventing one of the steps in the pathway that causes cancer. Most often these genes are involved in regulating the cell cycle and causing apoptosis in abnormal cells. When tumor suppressors are functioning properly they prevent abnormal cells from passing through checkpoints (stop cell division to give the cell time to repair itself). Malfunctioning tumor suppressors are some of the most important contributing factors to cancer formation, because it allows unregulated cell division. Since Tumor Suppressors contribute to cancer through a loss of function mutation both alleles generally need to be mutated to cause cancer. Even 1 functioning allele is usually enough to regulate the cell cycle. This is an example of the “two hit hypothesis.”
p53 is the most important tumor suppressor and is found to be mutated in about half of all cancers. p53 is activated by cellular damage or mutation to the DNA. p53 is a transcription factor which works by altering the transcription of downstream genes. When active, p53 stops the cell cycle (primarily at the G1-to-S Phase checkpoint) to give the cell time to repair itself. If repair is not possible, p53 causes apoptosis of the cell.
We have already learned that cytochrome C leakage from the mitochondria into the cytosol activates caspases and leads to apoptosis. The interaction between Bcl-2 (oncogenic/anti-apoptotic) and Bax (anti-oncogenic/ apoptotic) is a key regulator of cyt C release. Bax is a protein embedded in the mitochondrial membrane with a pore that can open or close as a result of conformational shape changes. When this Bax pore is open, cyt C can flow out of the mitochondria into the cytosol and cause apoptosis. One of the actions of Bcl-2 is to close the Bax pore. Apoptosis is initiated by p53 by increasing the activity/expression of Bax and decreasing the activity/expression Bcl-2.
Rb protein is another important tumor suppressor which controls the G1-to-S Phase checkpoint that is dysfunctional in many cancers. Rb stands for retinoblastoma which is the first cancer this protein was associated with. Rb stops the cell cycle by inhibiting the action of the E2F transcription factor. E2F activates genes which transition a cell from the G1 phase to the S phase. Therefore, the inhibition of EF2 by active RB protein prevents the cells transition into the S phase. When RB is phosphorylated it is inactivated which allows the cell to progress through the checkpoint in an unregulated manner.
In HPV E6 protein is created and “flags” p53 for degradation using ubiquitin. HPV also creates protein E7 which inhibits the action of Rb. These functions inactivate these tumor suppressors and cause cancers primarily in the cervix.
BRCA1 & BRCA-2 are tumor suppressor genes that fix double strand DNA breaks and perform mismatch repair. Germline (inherited) mutations and inactivation of either of these tumor suppressors can lead to familial types of breast and ovarian cancers.
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3 авг 2024
