Retinoblastoma Research Paper

Retinoblastoma gene

The unphosphorylated retinoblastoma protein binds and represses transcription factors from the E2F family which are responsible for transcribing genes required for DNA replication and cell division. The cells remain in the G1 phase and are prevented from passing the G1 checkpoint and moving on to the S phase as shown in figure 1. The retinoblastoma protein is phosphorylated by cyclin-dependent kinases (CDKs) and cyclins and forms a complex with them. This causes E2F to unbind and activate genes responsible for cell division and cells finally move into the S phase. The pRb protein remains phosphorylated up until the cell reaches the M phase. (Carpenter et al., 2007) Mutations in the retinoblastoma protein causes E2F to continuously

(Hinck, 2011) When a person inherits a damaged chromosome from a parent with cancer, that one chromosome has a 'hit' or mutation and if another mutation or second 'hit' occurs on the second chromosome, cancer can be caused. This second 'hit' usually occurs during the M phase in the cell cycle as can be seen in figure 1. (Knudson, 1971)

Figure 2: figure explaining the Two-Hit Theory of Cancer Causation where it is more likely for a cell which has inherited a damaged chromosome from a cancer cell, to form a tumour than when a mutation occurs in a normal chromosome. (Knudson, 2013)

Inherited retinoblastoma was found to occur at a younger age than sporadic retinoblastoma. It was also found that with inherited retinoblastoma, the disease was in both eyes. Mutations in both alleles of the retinoblastoma gene is required to show the phenotype and for the disease to advance as shown in figure 2. It has also been proved that individuals that have the inherited mutation often develop cancer in various locations. In TP53 one mutation on one allele is sufficient to cause changes in the phenotype leading to reduced tumour suppressor function. (Knudson, 1971)

Contact

(Hanahan and Weinberg, 2011) LKB1 is an epithelial polarity protein which activates a series of kinases like AMPK, to suppress tumour development when energy levels are low. When AMPK and AMPK-related kinases are triggered, proliferation of tumour cells is prevented and they preserve the cell's polarity. (Jones and Thompson, 2009)

Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat

The naked mole rat has been known to be resistant to cancer. (Tian et al., 2013) Cell cultures of these rats display growth inhibition at a much earlier stage than normal cell cultures. Therefore these rats are known to be hypersensitive to contact inhibition, which is labelled 'early contact inhibition'. The operation of p53 and Rb systems is necessary for early contact inhibition. Inactivity of these systems can reduce early contact inhibition. P27Kip1 is a protein that triggers contact inhibition in humans and mice. Since the naked mole rat goes through early contact inhibition, this is triggered by p16Ink4a. However, for transformed cells that can't undergo early contact inhibition, contact inhibition is triggered by P27Kip1. This study attempts to prove that since there are two proteins to ensure contact inhibition of cells, cancer cells don’t develop in these rats due to the double protection. It has been proved that without the regulation