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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
The p53 tumor suppressor: a master regulator of diverse cellular processes and therapeutic target in cancer
Marianne Farnebo1, Vladimir J N Bykov, Klas G Wiman
1Dept. of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden.
Abstract:
The tumor suppressor p53 has been implicated in a growing number of biological processes, including cell cycle arrest, senescence, apoptosis, autophagy, metabolism, and aging. Activation of p53 in response to oncogenic stress eliminates nascent tumor cells by apoptosis or senescence. p53 is regulated at the protein level by posttranslational modifications such as phosphorylation and acetylation. A p53 antisense gene, Wrap53, enhances p53 mRNA levels via the 5'UTR. Lack of Wrap53 transcripts that overlap with p53 abrogates the p53 DNA damage response. Around half of all human tumors carry p53 mutation that disrupt p53 specific DNA binding, and transcriptional transactivation of target genes. Reactivation of mutant p53 is a promising strategy for novel cancer therapy. The small molecule PRIMA-1 restores wild type conformation and DNA binding to mutant p53, induces mutant p53-dependent apoptosis, and inhibits tumor growth in vivo. The PRIMA-1 analog APR-246 is currently tested in a phase I clinical trial. Improved understanding of the p53 pathway should lead to better diagnosis and treatment of cancer in the future.
Insights
The p53 tumor suppressor is crucial for preventing cancer by inducing apoptosis and cell cycle arrest. Reactivating mutant p53 with drugs like PRIMA-1 shows promise for novel cancer therapies.
Area of Science:
- Molecular Biology
- Cancer Biology
- Genetics
Background:
- The tumor suppressor p53 plays a vital role in cellular processes like apoptosis, cell cycle arrest, and aging.
- p53 activity is regulated by posttranslational modifications and its antisense gene, Wrap53.
- Mutations in p53 are common in human cancers, impairing its tumor-suppressive functions.
Purpose of the Study:
- To explore the multifaceted roles of p53 in biological processes and cancer.
- To investigate strategies for reactivating mutant p53 for cancer therapy.
Main Methods:
- Review of p53's involvement in cell cycle arrest, senescence, apoptosis, autophagy, metabolism, and aging.
- Analysis of p53 regulation by posttranslational modifications and the Wrap53 gene.
- Evaluation of small molecules like PRIMA-1 and its analog APR-246 in restoring mutant p53 function.
Main Results:
- p53 activation eliminates nascent tumor cells through apoptosis or senescence.
- Wrap53 enhances p53 mRNA levels, and its absence impairs the DNA damage response.
- The small molecule PRIMA-1 restores wild-type p53 conformation and DNA binding, inducing apoptosis and inhibiting tumor growth.
Conclusions:
- Understanding the p53 pathway is essential for improving cancer diagnosis and treatment.
- Reactivation of mutant p53 represents a promising therapeutic strategy for cancers with p53 mutations.
- PRIMA-1 and its analog APR-246 demonstrate potential in targeting mutant p53-driven cancers.
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