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.
Oncogenes are sort of the opposite of tumor suppressor genes (because they cause cancer instead of prevent it), but they work via a different mechanism. Oncogenes are proto-oncogenes that undergo a gain of function mutation becoming more active. Proto-oncogenes are normal genes that are important to cell function. They are generally involved in the signaling pathway that initiates cell division. Proto-oncogenes can be growth factors, growth factor receptors, signal transducers, or other influencers of the cell cycle. They become a problem when they are mutated to become oncogenes and therefore proto-oncogenes can be thought of as “pre-oncogenes”. When these pre-oncogenes are overexpressed the cell thinks that it is constantly getting signals to start mitosis which leads to unregulated cell division. Because oncogenes are the result of a gain of function mutation, they can contribute to cancer with only 1 allele mutated (unlike tumor suppressor genes which need two “hits”).
MYC is a gene which encodes for a transcription factor that encourages cellular division. Burkitts Lymphoma has a t(8:14) translocation that leads the C-MYC gene being placed under the control of the regulatory mechanisms for the heavy chain portion of immunoglobulin. The heavy chain gene is constitutively active which means this translocation leads to an overexpression of the C-MYC oncogene. Overexpression of MYC can also be found in Neuroblastoma & Small Cell Carcinoma of the lung.
HER2/Neu is a transmembrane tyrosine kinase epidermal growth factor. Signals that tell the cell to divide are transferred from the outside of the cell to the inside of the cell by HER2/Neu. Overexpression of HER2/Neu promotes cellular division and opposes apoptosis. This overexpression is seen about a quarter of breast cancers and correlates with poor prognosis and reoccurrence. Trastuzumab is a monoclonal antibody which intereferes with the function of the HER2/Ney receptor, slows cellular division and increases apoptosis. This treatment is used for HER2/Neu + breast cancers.
As we have already discussed, BCL-2 prevents apoptosis by closing the Bax pore in the mitochondrial membrane and preventing Cytochrome C from leaking into the cytosol. A t(14:18) translocation leads to Bcl-2 being placed under the control of the regulatory mechanisms for the heavy chain portion of immunoglobulin. The heavy chain gene is constitutively active which means this translocation leads to an overexpression of the Bcl-2 oncogene and formation of Follicular Lymphoma.
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