The p53 gene may be the most important gene preventing human cancer. This gene i

Question

The p53 gene may be the most important gene preventing human cancer. This gene is mutated in about half of all cancers (and the pathway in which it participates is mutated in essentially all cancers). A. We can envisage two mechanisms to increase the amount of p53 protein when it is suddenly needed. First,

transcription and translation of the p53 gene might be low in the absence of a stimulus and markedly increased after stimulation. Second, transcription and translation of the p53 gene might be high at all times, but the protein amount is normally low as a result of proteolytic degradation; after stimulation, degradation is inhibited and consequently the protein amount increases. The latter mechanism is actually used by cells. Suggest the most important advantage of this mechanism.

B. List two of the four major classes of stimuli that evoke increased p53 amounts in normal human cells.

C. A defect in p53 increases the likelihood of amplification of proto-oncogenes and loss of tumor suppressor genes. Describe the two ways in which p53 normally works to prevent these outcomes. Describe the sequence of steps that can lead to these outcomes in the absence of p53.

Explanation / Answer

a). p53 is a tumour suppressor gene. During mutations, cells turn on this gene to avoid becoming cancerous. In normal cells, transcription and translation of the p53 gene is high at all times, but the protein amount is normally low as a result of proteolytic degradation. After stimulation, degradation is inhibited and consequently the protein amount increases. This mechanism is most favoured because cells can readily make available the p53 proteins, which can immediately interfere with the cell division, whereas transcriptional activation of gene after receiving the signal of impaired cell division takes time.

b). The two (of four) classes of stimuli that evoke increased p53 amounts in normal human cells include (i) cellular UV damage, (ii) stress signals.

c). The two ways in which p53 normally works to prevent these outcomes include cell cycle arrest and apoptosis. Active p53 enhances transcription of a cyclin-dependent kinase inhibitor (p21), stalling the cell cycle. p53 activity increases upon phosphorylation by a kinase, active p53 enhances transcription of genes that promote apoptosis. The p53 mutations are most often occur in residues that are involved in DNA binding, which would result in uncontrolled cell division and decreased celluar apoptosis that lead to tumour growth. The mutations of p53 gene is most common in many cancer types including breast cancer, endometrial cancer, oropharyngeal cancer, colorectal cancer, cervical cancer, etc.

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