The gene that cods for retinoblastoma (Rb gene) is an important tumor suppressor of cancer. Retinoblastoma itself is a childhood cancer that results from the loss of function of both copies of the Rb gene (each cell has two copies of the Rb gene). People with retinoblastoma can either develop a tumor in one eye (unilateral) or in both eyes (bilateral).
Hereditary vs. Sporadic Cases:
Hereditary retinoblastoma occurs in patients who have a family history of the disease. Because they inherit one non-functional copy of the Rb gene, only one mutation is needed for total loss of function. If someone is born with one bad copy, they have an approximately 90 % chance of developing the tumor in both eyes (90 % penetrance). In other words, being born with one non-functional copy increases the likelihood that a mutation will occur in the second copy and lead to a bilateral tumor.
Sporadic retinoblastoma occurs in patients with no family history of the disease. Therefore, they are born with two good, functional copies of the Rb gene. As a result, in order for these patients to develop retinoblastoma, two mutations in the gene are needed. This only occurs in 1 out of every 350,000 live births. Sporadic retinoblastoma is unilateral, meaning that the tumor occurs in only one eye.
Both sporadic and hereditary forms of the disease require two bad copies of the Rb gene. This means that the Rb gene is still functional even if one copy is abnormal. Loss of heterozygosity at the Rb locus on chromosome 13 is one potential mechanism for the development of bilateral retinoblastoma in patients who have a family history.
Retinoblastoma as a Tumor Suppressor in Normal Cells:
The normal function of the Rb protein is to act as an assembly factory: it brings together other proteins and has multiple binding sites to accomplish this. The Rb protein binds to multiple transcription factors and can either activate or repress transcription. For example, Rb protein strongly interacts with and binds to E2F-DP, a heterodimer that includes the E2F transcription factor. When Rb is bound to E2F-DP, the protein complex then can go to promoters that are regulated by E2F. Once there, Rb can recruit histone deacetylase to repress or turn off the transcription of genes regulated by E2F. This action suppresses cell division, which is why the Rb gene is a tumor suppressor. Since cancer cells want to divide, retinoblastoma patients lack this repressive function. In addition to histone deacetylase, Rb protein can also recruit histone and DNA methyltransferases. These methyltransferases can modify and epigenetically silence the target DNA, leading to inactive heterochromatin (permanent silencing). Therefore, Rb has a two-fold function. It can either repress the transcription or epigenetically silence the DNA of genes involved in the cell cycle that promote cell division.
How Retinoblastoma Function is Turned Off in Normal Cells and Loss of Tumor Suppressor Ability in Cancer Cells:
In order for cancer cells to grow, divide, and metastasize, they need to somehow inactivate the function of key tumor suppressors, such as the Rb gene. Since the normal function of the Rb protein is to repress the cell cycle, this ability is an obstacle to cancer cell growth. Since cancer cells in a retinoblastoma patient operate with non-functional Rb genes, the tumor suppressor function of Rb is non-existent and cancer cells can proliferate uncontrollably. However, Rb function is also controlled in normal, non-cancerous cells. We require cell division to survive, so Rb function must be regulated so that the cell cycle is not always repressed. As stated above, Rb works to repress the expression of genes regulated by E2F. These genes include Cyclin A, Cyclin E, and other proteins involved in the cell cycle. Cyclin/CDK complexes regulate the progression through the cell cycle (they oppose the function of the Rb protein). Therefore, in order to do their job effectively, they phosphorylate Rb as multiple sites. This phosphorylation causes Rb to lose its ability to bring proteins together. Since it can no longer bind E2F, it cannot turn off the expression of genes that E2F regulates and the cell cycle can go on uninterrupted by Rb repression. Then, E2F can recruit histone acetylases that activate gene expression of cell cycle cyclins.