(Transcribed from Dr. Savant’s lecture, 20 June 2000 by Brian Buschman)
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Cancer is caused by alterations in the coding for proteins which regulate cell growth. The mutations can be caused by:
1) Carcinogens
2) Radiation
3) Viruses
4) Inherited susceptibilities
It is believed that it takes 4-6 specific mutations in a given cell to cause it to become malignant.
These types of genes are called the gatekeeper genes because they function in the regulation of entry into the S or M phases of the cell cycle.
Oncogenes are genes that cause malignancy. They originate from proto-oncogenes which are normal genes that regulate the cell cycle.
Tumor suppressor genes are genes that work to naturally keep tumors in check. They are sometimes referred to as anti-oncogenes.
Caretaker genes are the genes that function to repair the damage done to DNA. They are another form of anticancer gene.
As previously studied there are four phases of the cell cycle:
1) G1 – The resting phase where the cell spends most of it’s life. There are two subsets off of G1:
a. Go is when the cell is in a quiescent state which, under the proper conditions will be brought back into G1.
b. Apoptosis which is programmed cell death.
2) The S phase is where DNA synthesis happens.
3) G2 is a second resting phase.
4) The M phase is when the cell undergoes mitosis.
The control of the cell cycle is by the G1 and G2 checkpoints. These two points are where the cell commits itself to go through the S phase or M phase. This is what regulates how quickly a cell divides.
There are group of molecules called cyclins which are present in different concentrations at different points in the cell life cycle. The presence of the cyclins have a lot to do with when they actually cross the checkpoints.
1) Cyclin D is around through the whole life cycle.
2) Cyclin E is what triggers the passage of the G1 checkpoint.
3) Cyclin A is around as the cell passes from the S phase into G2.
4) Cyclin B is what triggers the passage of the G2 checkpoint.
There is a phospho-protein called retinoblastoma (pRB) which binds to various transcription factors (like E2F/DP) and prevents the transcription of several genes that are necessary for the entry of the cell into the S phase. It regulates many proto-oncogenes.
There are a group of proteins called cyclin-dependant kinases (Cdk2, Cdk4, Cdk6) which phosphorylate pRB when they are bound to their respective cyclin. Cdk4 and Cdk6 function when bound to cyclin D (present in the whole cycle) and Cdk2 becomes functional when bound to cyclin E. The presence of cyclin E at the end of the G1 phase is what activates Cdk2.
When the cyclin-dependant kinases phosphorylate pRB then pRB will release the bound transcription factors and this is what triggers the cell to enter the S phase of the cell cycle.
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