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Ras Proteins, the Cell Cycle and Cancer

© David Olle

The cell cycle is a carefully choreographed series of events that are responsible for cell growth and division. In the normal cell, there are intricate mechanisms of signaling and control that determine when the cell cycle begins and ends. In a cancerous cell, however, a gene mutation (oncogene) results in a disruption of the control mechanism and a continuously active cell cycle. In the early 1990’s 1, scientists worked out most of the details of how ras proteins control the operation of the cell cycle. It was subsequently found that single point mutation of the ras gene can lead to the formation of an oncogene and a cancer causing ras protein. Around 90% of pancreatic cancers, 30% of lung and colorectal cancers, and 25% of acute myeloid leukemias harbor ras mutations. Aware of this knowledge, researchers have been busy at work trying to develop drugs that would inhibit the ras oncogene or its protein product.

How the ras protein affects the cell cycle

The cell cycle consists of a G1 growth phase, a S phase where the DNA of the cell is replicated (doubled), a G2 second growth phase, and finally a M (mitosis) phase where the cell divides forming a new cell. The binding of a growth factor molecule to a receptor on the cell membrane is the stimulus that begins the process. The ras protein is normally in the inactive state when it is associated with a molecule called GDP. Upon being activated by the growth factor stimulus, it switches GDP for the more active GTP. Before the ras protein can become functional, it must receive a small molecule with the aid of an enzyme called farnesyl transferase. At this point, the ras protein attaches to the cell membrane and initiates a cascade of enzymatic reactions. The reactions involve a molecular dance of cyclins and cyclin dependent kinase proteins and a chemical called phosphate. Eventually a protein enters the nucleus, where it activates a “transcription factor”, which in turn activates the cyclin D gene. The cyclin D protein that is formed stimulates the progression of the cell cycle into the S phase and through the remainder of the cycle. For more details see Cell Cycle Regulation

How the ras oncogene modifies the cell cycle

In normal cells, the ras protein reverts to the inactive state after transmitting the signal by replacing GTP to GDP. However, a mutation in the ras gene results in the formation of a ras protein that no longer has the enzyme to convert GTP to GDP. Therefore, the ras protein remains in the active state even with no stimulus from growth factors. The ras protein then sends continuous signals to keep the cell cycle running with no checks and balances. The result is excessive cell proliferation and cancer.