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The effects of wild-type p53 tumor suppressor activity and mutant p53 gain-of-function on cell growth
1Department of Biochemistry, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA.
Abstract:
The tumor suppressor p53 plays a central role in the protection against DNA damage and other forms of physiological stress primarily by inducing cell cycle arrest or apoptosis. Mutation of p53, which is the most frequent genetic alteration detected in human cancers, inactivates these growth regulatory functions and causes a loss of tumor suppressor activity. In some cases, mutation also confers tumor-promoting functions, such as the transcriptional activation of genes involved in cell proliferation, cell survival and angiogenesis. Consequently, cells expressing some forms of mutant p53 show enhanced tumorigenic potential with increased resistance to chemotherapy and radiation. Our current understanding of these activities is summarized in this review. By dissecting out mechanistic differences between wild-type and mutant p53 activities, it may be possible to develop therapeutics that restore tumor suppressor function to mutant p53 or that selectively inactivate mutant p53 tumor-promoting functions.
Insights
The tumor suppressor p53 guards against DNA damage but its mutation is common in cancers, leading to tumor growth and treatment resistance. Understanding these mutations may reveal new cancer therapy strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The tumor suppressor p53 protein is crucial for cellular defense against DNA damage and stress.
- Mutations in p53 are the most frequent genetic alterations in human cancers, compromising its protective functions.
- Mutant p53 can gain new, tumor-promoting activities, enhancing cancer progression.
Purpose of the Study:
- To review the current understanding of wild-type and mutant p53 functions in cancer.
- To highlight the mechanistic differences between wild-type and mutant p53.
- To explore therapeutic strategies targeting mutant p53.
Main Methods:
- This review synthesizes existing research on p53's role in cancer.
- Mechanistic insights into p53's tumor suppressor and tumor-promoting activities are discussed.
- The review examines how p53 mutations impact cellular processes.
Main Results:
- Mutant p53 loses its tumor suppressor functions, including cell cycle arrest and apoptosis induction.
- Mutant p53 can acquire oncogenic functions, promoting cell proliferation, survival, and angiogenesis.
- Cells with mutant p53 exhibit increased tumorigenic potential and resistance to therapies like chemotherapy and radiation.
Conclusions:
- Understanding the distinct mechanisms of wild-type and mutant p53 is key for cancer treatment.
- Therapeutic approaches could aim to restore wild-type p53 function or inhibit mutant p53's oncogenic activities.
- Targeting mutant p53 offers a promising avenue for novel cancer therapies.