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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Transcriptional regulation by p53
Rachel Beckerman1, Carol Prives
1Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Abstract:
Inactivation of p53 is critical for the formation of most tumors. Illumination of the key function(s) of p53 protein in protecting cells from becoming cancerous is therefore a worthy goal. Arguably p53's most important function is to act as a transcription factor that directly regulates perhaps several hundred of the cell's RNA polymerase II (RNAP II)-transcribed genes, and indirectly regulates thousands of others. Indeed p53 is the most well studied mammalian transcription factor. The p53 tetramer binds to its response element where it can recruit diverse transcriptional coregulators such as histone modifying enzymes, chromatin remodeling factors, subunits of the mediator complex, and components of general transcription machinery and preinitiation complex (PIC) to modulate RNAPII activity at target loci (Laptenko and Prives 2006). The p53 transcriptional program is regulated in a stimulus-specific fashion (Murray-Zmijewski et al. 2008; Vousden and Prives 2009), whereby distinct subsets of p53 target genes are induced in response to different p53-activating agents, likely allowing cells to tailor their response to different types of stress. How p53 is able to discriminate between these different loci is the subject of intense research. Here, we describe key aspects of the fundamentals of p53-mediated transcriptional regulation and target gene promoter selectivity.
Insights
The p53 protein acts as a crucial transcription factor, regulating genes to prevent cancer. Understanding how p53 selects specific gene promoters is key to its tumor-suppressing function.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Tumorigenesis is often linked to the inactivation of the p53 protein.
- The p53 protein is a critical transcription factor that regulates numerous genes involved in cellular protection.
- Understanding p53's regulatory mechanisms is essential for cancer prevention and treatment.
Purpose of the Study:
- To elucidate the fundamental mechanisms of p53-mediated transcriptional regulation.
- To investigate how p53 achieves selectivity in targeting specific gene promoters.
- To explore the role of p53 in cellular stress response and tumor suppression.
Main Methods:
- Analysis of p53 binding to response elements.
- Investigation of recruitment of transcriptional coregulators (e.g., histone modifiers, chromatin remodelers, mediator complex).
- Examination of stimulus-specific transcriptional programs regulated by p53.
Main Results:
- p53 functions as a transcription factor, regulating hundreds of RNA polymerase II (RNAP II)-transcribed genes directly and thousands indirectly.
- p53 recruits diverse transcriptional machinery, including histone-modifying enzymes and mediator complex subunits, to modulate gene activity.
- p53 exhibits stimulus-specific transcriptional regulation, activating distinct gene subsets in response to different cellular stresses.
Conclusions:
- p53's role as a transcription factor is central to its tumor-suppressive function.
- The ability of p53 to selectively target gene promoters is a key area of ongoing research.
- Understanding p53's transcriptional regulation provides insights into cancer development and potential therapeutic strategies.
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