Retinoblastoma Proteins, the Cell Cycle, and Cancer
The ability of cancer cells to divide and proliferate rapidly is a key feature of the disease. To do so, the cells in a tumor have corrupted the controlled mechanism of the cell cycle. Retinoblastoma protein is named for its association with retinoblastoma, but is involved in many other forms of cancer. This protein is known as a tumor suppressor because its natural function helps to restrict cell growth.
The Cell Cycle: Its Importance and Disruption
Given that the body is composed of trillions of individual living cells, you would expect there to be quite a bit of chaos and discord. Everything runs smoothly, more or less, because these cells are tightly regulated, especially when it comes to growth and cell division. Much of this regulation comes via the cell cycle, the orderly process in which our cells carry out their functions in our body, replicate their DNA, and divide. Progression through the cell cycle is overseen by a network of proteins within the cell, but the activity of these proteins is often controlled by chemical signals outside the cell called growth factors.
One of the most important controls within the cell cycle is called the restriction point. Once a cell has passed the restriction point, it begins to copy its DNA so that it can divide. While there are other checkpoints prior to the start of cell division, the restriction point is the most significant. The cellular “gatekeeper” with the critical function of preventing cells from passing the restriction point and dividing uncontrollably is pRb, the retinoblastoma protein.
Function of pRb
pRB carries out its gatekeeping function by binding E2F, a protein which triggers the cell’s DNA replication machinery. As long as pRb and E2F are bound, the cell cannot pass the restriction point and begin copying its DNA. Of course, there is a way in which pRb can lose its grip, and tumor cells are able to use this to their advantage, even without a direct mutation of pRb.
The grip between pRb and E2F, and control of DNA replication, is in turn managed by proteins known as cyclins, and their partners, called cyclin-dependent kinases (CDKs). Specifically, pRb is monitored by cyclin D1, and CDK 4 or 6. These proteins are activated as part of a chain reaction that starts when growth factors outside the cell interact with receptors on the cell surface. Once active, they cause a chemical change in pRb, caused phosphorylation, which forces it to release E2F. Then E2F is able to signal to the cell that it can copy its DNA and prepare to divide.
Tumor cells can short-circuit this process by increasing the activity of the cyclins and CDKs holding pRb in check. Common ways of doing so are by substantially increasing the cell’s production of growth factors, which in turn are taken up by the receptors. The receptors themselves may also be mutated and “stuck in the on position” without growth factors being present. However, pRb itself can also be disabled directly through mutation.
Inherited and Acquired Mutations
Rb, the gene which codes for the pRb protein, was first discovered in children suffering from retinoblastoma, a rare condition in which tumors in the eye form at a very young age. Patients suffering from retinoblastoma are also hundreds of times more likely to develop cancer later in life. The condition is caused by an inherited mutation in one copy of the Rb gene. Since we all carry two copies of each gene, this alone is not enough to disrupt the cell cycle, and eventually lead to cancer.
It does mean that for people inheriting the condition, Rb is a weak point, because all it takes is one mutation in the functional copy of Rb to completely lose pRb in the affected cells. That’s why people with the condition have such a high likelihood of cancer, and why it often develops very early in life. Nonetheless, many adult cancer patients also have mutations in both copies of Rb. These may have arisen through a natural buildup of mutations, or in already volatile pre-cancerous cells which have a much higher mutation rate than normal.
The discovery and understanding of pRb has allowed scientists to explain many of the mutations, whether inherited or acquired, which lead to cancer. There are many other tumor suppressors within the cell, and disruption of these proteins can produce similarly catastrophic results.
Weinberg, Robert A. The Biology of Cancer (2007). Chapter 7: Tumor Suppressor Genes, Chapter 8: pRb and Control of the Cell Cycle Clock.