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In contrast to proto-oncogenes and oncogenes, tumour suppressor genes code for proteins that prevent cell proliferation and division or even initiate apoptosis (Giacinti et al., 2006). Examples includes proteins that are necessary for apoptosis initiation, inhibitors of cell cycle progression and factors required in maintenance of cell cycle checkpoints (Chow, 2010; Reisman et al., 2012). Genetic mutations in tumour suppressor genes restrict the regulatory protein from inhibiting cell proliferation leading to tumorigenesis. So far there are more than 100 dominant oncogenes and around 30 tumour suppressor genes (Table 1.5) (Naga Deepthi et al., 2011).

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Table 1.5. Tumour suppressor genes involved in human cancers and diseases (Thomas

et al., 2012).

Gene Chromosomal

location

Cellular location

Mode of action Example of cancers

Rb 13 q 14 Nucleus Transcriptional regulator

Retinoblastoma, osteosarcoma,

carcinomas of breast, prostate, bladder and lung

p53 17 p 13.1 Nucleus Transcription factor /regulator

Most human cancers, breast, brain, sarcomas, leukaemia

APC 5 q 21 Cytoplasm Unknown Carcinomas of colon,

stomach and pancreas

WT1 11 p 13 Nucleus Transcription factor Nephroblastoma

DCC 18 q 21 Membrane Cell adhesion

molecule

Carcinomas of colon and stomach

NF-1 17 q 11 Cytoplasm p21, Ras, GTPase

activator Schwannomas NF-2 22 q 12 Inner membrane Cytoskeleton membrane link Schwannomas, meningiomas

pVHL 3 p 25 Cytoplasm Inhibits transcriptional

elongation

Renal cell carcinoma Rb, retinoblastoma protein; p53, Tumour protein p53; APC, adenomatous polyposis coli; WT1, wilms tumour protein; DCC, deleted in colorectal carcinoma; NF-1, neurofibromatosis type 1; NF-2, neurofibromatosis type 2; pVHL, von Hippel-Lindau tumour suppressor.

The first tumour suppressor gene to be identified and play a critical role in cell cycle regulation was the RB1 gene that codes for retinoblastoma protein (pRb). The pRb protein have 16 potential sites of cyclin dependent kinase (Cdk) phosphorylation and is an important regulator of G1 progression. The Rb pathway is shown in figure 1.5. Initially in G1 stage, pRb is tightly bound to the E2F transcription factor and is in a hypophosphorylated state. When pRb is phosphorylated by Cdk complexes, which is a sequential process initiated by Cdk4 and Cdk6, E2F is released and the cell can start DNA synthesis. This causes the formation of active Cdk2/cyclin E complexes that help the continuation of pRb phosphorylation, which as a result promote pRb-E2F separation so that E2F can be transcriptionally active, an obligation for the cell to move from G1 into S phase. Cyclin A is expressed as cells progress into S phase and it becomes the main cyclin linked with Cdk2. Moreover, the activity of cdc2 complexed with cyclin B phosphorylates proteins regulated during mitosis, thus is a requirement for the cells to progress from G2 to mitosis. In addition, pRb phosphorylation is maintained throughout S and G2, and during mitosis pRb is rapidly dephosphorylated. Also, during G1 when pRb is hypophosphorlated, E2F is again sequestered (Thomas et al., 2012). Therefore, the function of pRb is simply to stop the expression of genes needed for progression into the S phase of the cell cycle. However, when it is inactivated often due to genetic alterations involving either

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deletions or frameshift in the RB1 gene, causing defective protein expression and premature introduction of stop codon, cells starts to divide uncontrollably. There are some instances when other components in the pathway in which pRB functions are defective such as activation of the positive component as CDKs and G1 cyclins or inactivation of negative components as p53 and CDK inhibitors (Chow, 2010; Di Fiore et al., 2013).

Figure 1.5. The Rb pathway. In the G1 phase, Rb is linked to E2F transcription factor in a

hypophosphorylated state. The phosphorylation of Rb by Cdk4 and Cdk6 causes the release of E2F from Rb to initiate DNA synthesis. The phosphorylation of Rb continuous due to the formation of Cdk2/cyclin E complexes hence causing the cells to move from G1 into S phase. As cells moves in the S phase, cyclin A is formed and becomes the main cyclin linked with Cdk2. As the cells moves from G2 to mitosis, Cdk1 complexed with cyclin B phosphorylates proteins regulated during mitosis. Moreover, throughout S and G2 phases, the phosphorylation of Rb is maintained but is rapidly dephosphorylated during mitosis (Thomas et al., 2012).

Another commonly mutated gene in human tumours is the tumour suppressor gene, p53 (Chow, 2010; Naga Deepthi et al., 2011; Rivlin et al., 2011; Lai et al., 2014). The function of the p53 protein is to inhibit proliferation and promote apoptosis in response to DNA damage in cells, hence it plays a very important role in managing the cell cycle, the G1 to S cell cycle checkpoint. The p53 protein holds the cell long enough for the DNA repair proteins to fix the damage and once the damage is fixed the cell is then allowed to continue the cell cycle. On the contrary, if the DNA damage proves to be irreparable, the p53 protein will initiate apoptosis (Chow, 2010; Naga Deepthi et al., 2011). However, the inactivation of p53 gene due to genetic changes will allow a cell to continue to divide even in the presence of DNA damage.

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Furthermore, for tumorigenesis to occur both the paternal and maternal copies of a gene coding a tumour suppressor must be modified (Chow, 2010; Buhle, 2012).

The mutation of p53 gene codes a stable p53 mutant protein that apart from losing its tumour suppressive activities has acquired oncogenic functions that help cells to grow and survive without limitations. Interestingly, it was found that when cells become cancerous during the multistep process of malignant transformation, at each phase, p53 gene mutation was shown to contribute differentially to tumour promotion, initiation, metastasis and aggressiveness (Rivlin et al., 2011).