Oncogenes were first discovered in a tumor virus that had captured an animal's proto-oncogene, appended it to own genome, and subverted it to its own ends. Proto-oncogenes are cell growth promoters. They stimulate cell proliferation. It's no wonder that viruses use them to encourage growth of the cells that they infect. But non-virally induced cell growth has to be carefully controlled and organisms have developed wonderfully complex ways of accomplishing that mission. That's where tumor suppressors come in. Their name is something of a misnomer. Their role to make sure that normal cell growth is limited and properly regulated.
Tumor suppressor genes were first discovered in individuals that had a hereditary disposition to cancer. For example, the first tumor suppressor gene was found as a result of analyzing youngsters with familial retinoblastoma, a disease that afflicts approximately 1 in 20,000 children aged six and younger. Actually, there are two forms of the disease. In about 55% of cases, it's not hereditary – no close relatives show evidence of the disorder. In addition, most often only one eye is affected. This condition is termed "sporadic" retinoblastoma. The remaining cases exhibit a dominant pattern of inheritance and often both eyes harbor tumors. In the 1970's, the retinoblastoma gene was mapped to the 13th human chromosome. And in 1986, the gene was cloned. It was soon shown that children with the hereditary form of the disease harbor mutations in the retinoblastoma gene that renders the protein that it specifies inactive.
In order to explain these discoveries, scientists guessed that the retinoblastoma protein somehow acts to curtail cell proliferation. When it is inactivated via mutation, cells continue to divide and soon form tumors. But this hypothesis met with some difficulties. Humans have two 13th chromosomes. Analysis of the genome of affected individuals showed that only one of the two bore a defect in the retinoblastoma gene. Why wasn't the normal version of the gene making up for the deficit in the other?
The explanation was simple, but surprising. Ordinarily, DNA analysis is carried out on white blood cells from the blood because they are a convenient source of genetic material. That's how the defect in the retinoblastoma gene was detected. However, when the DNA of the tumor itself (rather than that of other cells in an affected individual) was analyzed, it was found that, in many cases, both chromosomes bore mutant copies of the retinoblastoma gene! Apparently, tumor cells somehow eliminated the normal copy of the retinoblastoma gene and replaced it on the homologous 13th chromosome with its defective partner. This phenomenon is called "loss of heterozygosity". It's caused by genetic exchange between two homologous chromosomes. Tumors use this strategy so often that it has been used to find other tumor suppressor genes. (There are other mechanisms that tumors use to eliminate or repress the normal copy of a tumor suppressor gene from a cancer. They include complete loss of the homologous chromosomes, loss of large sections of the homologous chromosome, and repression of the expression of the normal gene by the addition of methyl groups to its promoter regions).
The retinoblastoma gene is one of the most important tumor suppressors. I intend to discuss it in more detail in the next post. But in order to better explain its role in the cell and in tumorigenesis in general, I'm going to take a detour into the world of cell division. That's because the retinoblastoma protein plays a determining role in deciding whether cells should divide or not. For those of you who want a historical overview of how scientists discovered the mechanism of cell division, I recommend a short book, "The Cell Cycle" by Andrew Murray and Tim Hunt. It's 25 years old, but it remains a wonderful introduction to the subject. Professor Hunt was awarded the Nobel Prize in Physiology or Medicine in 2001.
As we've seen, growth factors are the means of some cells to tell others to proliferate through growth factor receptors that transmit information from outside the cell, through the cytoplasm, to the nucleus by a complex series of intracellular cascades. Ultimately, these various signals have to be integrated so that the cell can take one of three paths - to divide further; to stop dividing and differentiate; or to commit suicide. If a cell opts to divide, it goes through a series of steps called the cell cycle. First it must prepare for DNA synthesis. The interval between cell division and DNA replication is called "Gap1" or more commonly, "G1". In the next step, it replicates its DNA so that its daughters can each get a full complement of genetic material. The period in which DNA is being replicated is called "S" for DNA synthesis. Next there is another gap in which the cell prepares for the actual physical division of the cell. It's called "Gap2" or "G2". Finally, the cell splits in two. This process, called "M" for mitosis, ensures that each daughter is dealt the proper chromosome constitution. These series of steps are repeated each time a cell divides. In mammalian cells at body temperature, a complete round of cell division takes about a day, although the timing varies depending on the cell type.
I've drawn a cartoon of one cell division cycle and it's shown at the right. Each sector represents the time in which the cell spends in a particular stage of the cycle. In subsequent posts, I plan on adding to this figure to illustrate some of the biochemical events that drive the process
Up till about 50 years ago, cell division was carefully examined microscopically in a variety of cell types and meticulously described. But there was virtually nothing known about the biochemical events that drove the process. Most of the progress in elucidating the mechanism behind the cell cycle came from a combined biochemical and genetic attack. Again, the fascinating story of how the scientific community discovered how cell division worked is told in Murray and Hunt's book. I'll not get into the history, but will try to present what is known starting in the next post.