Question

The G1 phase of the cell cycle is particularly important for control of proliferation. Discuss, with emphasis on the genetics of the following G1 specific tumor suppressors: RB1, TP53, and CDKN2A. (MIn 2 and a half pages)

Answer 1

G1 is a phase of cell cycle which occurs between the end of cell division in mitosis and the beginning of DNA replication during S phase the intermediate phase is G1. During this time, the cell starts growing and prepares for for DNA replication. During this process centrosomes also starts replicating.

The tumor supressor genes have very important role to play in controlling abnormal growth of cells. Three fof them asked in the question are discussed below :

RB1 : RB1 is called the retinoblastoma susceptibility gene and was the first tumor suppressor gene to be defined molecularly. It produces a product Retinoblastoma protein or pRB which regulates transcription and also negatively regulates cell proliferation. pRB is a chromatin-associated protein that causes limits in the transcription of cell cycle genes. This is done by regulating E2F transcription factor. pRB also interacts with chromatin regulators. These helps pRB to create complexes to repress transcription. By suppressing transcription of E2F targets, pRB restricts cell proliferation by preventing the expression of genes that are needed for cell proliferation. Active pRB is found in quiescent cells, during G1 phase of the cell cycle, and also during checkpoint-mediated cell cycle arrest. During the process of hyperphosphorylation of pRB at the G1/S transition, there are some relief in pRB's inhibition of E2F which allows cell cycle progression. In many tumors pRB is functionally compromised either due to mutations in RB1 or mutations that causes increase in phosphorylation of pRB and also through the expression of viral oncoproteins targeting pRB. The inactivation of pRB reduces and hampers the ability of cells to exit the cell cyclecausing them to enter in a highly susceptible state to oncogenic proliferation .

TP53 : he TP53 gene instructs production of a protein called tumor protein p53 (or p53). This protein acts as a tumor suppressor, which means that it regulates cell division by keeping cells from growing and proliferating uncontrollably.

The p53 protein is located throughout the body in the nucleus of cells, where it attaches directly to DNA. When the DNA in a cell becomes damaged by agents such as toxic chemicals, radiation UV rays etc, this determines whether the DNA will be repaired or the damaged cell will self-destruct (or undergo apoptosis). If the DNA can be repaired, activation of genes to fix the damage is done by p53. If the DNA cannot be repaired, P53 prevents the cell from dividing and signals it to undergo apoptosis. p53 helps prevent the development of tumors by stopping cells from dividing if they have mutated or damaged DNA. If p53 genes are not expressed in wild type p53, G1 arrest and apoptosis stops. G1 arrest can occurs by the p53 induced expression of p21WAF1/CIP1/Sdi1. p53 also regulates BAX, a homologue of the BCL-2 gene. Bax does not trigger apoptosis, but accelerates the rate of apoptosis .P53 also down regulates the expression of cyclin A which also helps in cell cycle regulation. Because p53 is essential for regulating DNA repair and cell division, it has been nicknamed the "guardian of the genome."

CDKN2A : This gene is also known as cyclin-dependent kinase inhibitor 2A. in humans it is located at chromosome 9. It is expressed in many tissues and cell types. CDKN2A codes for two proteins, p16 (or p16INK4a) which is a INK4 family member and p14arf.   Both these proteins act as tumor suppressors by regulating the cell cycle. p16 leads to the inhibition of cyclin dependent kinases 4 and 6 (CDK4 and CDK6) and by causing this it activates the retinoblastoma (Rb) family of proteins, which block traversal from G1 to S-phase of cell cycle. The second protein p14ARF (known as p19ARF in the mouse) Activates the p53 tumor suppressor. Somatic mutations of CDKN2A are common in the majority of human cancers. After p53 , CDKN2A is the second most commonly inactivated gene in cancer patients.

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