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Mutation in p53 Suppressor Gene Drives Tumor Development

By BiotechDaily International staff writers
Posted on 19 Nov 2018
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Image: Biomedical animation of a breast tumor (Photo courtesy of Drew Berry, Walter and Eliza Hall Institute).
Image: Biomedical animation of a breast tumor (Photo courtesy of Drew Berry, Walter and Eliza Hall Institute).
Cancer researchers have outlined a molecular mechanism that promotes tumor development and growth by interfering with the normal expression of the p53 suppressor gene.

Mutations in p53's TRP53 (transformation-related protein 53), prevalent in human cancers, have been reported to drive tumor development through dominant-negative effects over normal wild-type TRP53 function.

A mutation that leads to a mutant protein that disrupts the activity of the wild-type protein is known as a dominant-negative mutation. This mutation may arise in a human somatic cell and provide a proliferative advantage to the mutant cell, leading to its clonal expansion. For instance, a dominant-negative mutation in a gene necessary for the normal process of programmed cell death (apoptosis) in response to DNA damage can make the cell resistant to apoptosis. This will allow proliferation of the clone even when excessive DNA damage is present. Such dominant-negative mutations occur in the tumor suppressor gene p53. Dominant-negative p53 mutations occur in a number of different types of cancer and pre-cancerous lesions.

Investigators at the Walter and Eliza Hall Institute (Melbourne, Australia) reported in the November 1, 2018, issue of the journal Genes & Development that RNA sequencing of lymphatic cancers had shown that the mutant TRP53 dominant-negative effect did not globally repress wild-type TRP53 function but disproportionately impacted a subset of wild-type TRP53 target genes. Accordingly, TRP53 mutant proteins impaired pathways for DNA repair, proliferation, and metabolism in premalignant cells.

"Genetic defects in p53 are found in half of all human cancers, but exactly how these changes disrupt p53 function has long been a mystery," said senior author Dr. Gemma Kelly, a research scientist at the Walter and Eliza Hall Institute. "p53 plays a critical role in many pathways that prevent cancer, such as repairing DNA or killing cells if they have irreparable DNA damage."

"Early during cancer development, one copy of the gene may undergo a sudden and permanent change through mutation, while the other copy of the gene remains normal. This results in the cell making a mixture of normal and mutant versions of the p53 protein," said Dr. Kelly. "We found that the mutant p53 protein can bind to and "tackle" the normal p53 protein, blocking it from performing protective roles such as DNA repair. This makes the cell more likely to undergo further genetic changes that accelerate tumor development.

Established tumors have often lost the normal copy of their p53 gene and only produce mutant p53 protein. If mutant p53 acts by tackling normal p53, then it may no longer play a role in established tumors where no normal p53 is produced. This would mean that drugs that block mutant p53 would have no clinical benefit. Conversely, if mutant p53 has new, cancer-promoting activities of its own in established tumors, then a drug that specifically blocks mutant p53 could be beneficial for treating thousands of patients."

Related Links:
Walter and Eliza Hall Institute


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