P53 and Cancer
Cancer is a complex disease that kills millions of people annually, alterations in genetic and epigenetic cellular programs derail cellular controls normally responsible for maintaining homeostasis. Sequencing of human cancer genomes has identified a myriad of genomic alterations found in human cancers. The tumor suppressor P53 exerts its biological function by regulating transcription of numerous downstream target genes, which involved in cell cycle arrest, apoptosis, DNA repair, senescence and metabolism as transcription factors. P53 is also directly recruited to the mitochondria and induces apoptosis independent of its function. When P53 activity is lost, normal cells lose the abilities to control their growth and death which leading to immortalization and ultimately cancer. Over 50% of human cancers have mutations in the P53 gene, indicating the indispensability of intact P53 activity for suppressing tumor development. The mutations of P53 gene mainly occur in the DNA-binding domain, resulting in loss of function as a transcription factor and accumulation of dysfunctional P53 protein in tumors.
DNA contact (class I) mutant in which mutations are present on amino acids directly binding to the P53-responsive element in DNA, and conformational (class II) mutant in which mutations alter the structure of P53 to abolish its DNA-binding ability. Both the mutant types lose the transcriptional activity as well as have the dominant-negative (DN) activity by hetero-oligomerizing with wild-type P53. And that, mutant P53 shows oncogenic gain-of-function activities, including enhanced tumor progression, metastatic potential and drug resistance, when overexpressed even in cells lacking wild-type P53. Accumulating studies suggest that knockdown of mutant P53 significantly reduces oncogenic potential of cancer cells, indicating that malignant properties of cancer cells, at least partially, depend on the presence of mutant P53. This could be simply due to the loss of oncogenic activity of mutant P53 or cancer cells are addicted to mutant P53 for their survival and proliferation.
Figure 1. Mutant p53 and mutant p53 complexes interacts with transcriptionfactors.
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