TUMOUR SUPPRESSOR GENES

Tumour suppressor genes prevent excessive growth of a cell; the most well known ones are p53 and the retinoblastoma (Rb) gene.

Retinoblastoma Gene

Retinoblastoma gene is involved in the G1 checkpoint in the following way. It binds to a family of transcription factors known as the E2F family, thereby repressing their transcription of E2F-responsive genes, such as thymidine kinase (TK), needed for DNA replication, and cyclin E and A, needed for cell cycle progression. Rb is activated when cyclin D forms a complex with CDK4/6 (cyclin D/CDK4/6, hence making it active) this in turn phosphorylates Rb, which allows E2F to be released

p53

The p53 protein is essential for protecting us against cancer. More than half of human cancers have p53 mutations and therefore no functioning p53. p53 works by sensing DNA damage and halting the cell cycle (Figure 4.2). This is essential, because if DNA is damaged but still replicated in S phase, it could eventually manifest in the form of a protein mutation. By halting the cell cycle at the G1 checkpoint, this can be prevented. So how does this process work? Again, it comes back to the involvement of CDKs. First, in response to a variety of stress signals,

for example DNA damage, p53 switches from an inactive state to an active state. It then triggers transcription of the gene for p21, which is a CDK inhibitor. Because active CDKs are needed to progress through the cell cycle, an inactive CDK will cause the cycle to halt. The p53 protein is also involved at the G2 checkpoint in cases, for example, where DNA has been synthesized incorrectly. At this checkpoint, p53 binds to E2F (see Section ‘Retinoblastoma gene’) and prevents it from triggering transcription of proto-oncogenes, for example c-myc and c-fos, which are required for mitosis Proto-oncogenes are important promoters of normal cell growth and division; however, if they become mutated they are known as oncogenes and can have a detrimental effect. A single oncogene cannot cause cancer by itself but it can cause the cell cycle to lose its inhibitory controls, thereby increasing the rate of mitosis. When a cell loses control over mitosis, it can be the beginning of the pathway leading to the development of cancer