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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
A network of p73, p53 and Egr1 is required for efficient apoptosis in tumor cells
1Burnham Institute for Medical Research, Cancer Research Center, La Jolla, CA 92037, USA.
Abstract:
p73, a transcription factor rarely mutated in cancer, regulates a subset of p53 target genes that cause cells to respond to genotoxic stress by growth arrest and apoptosis. p73 is produced in two main forms; only TAp73 reiterates the roles of p53, while DeltaNp73 can be oncogenic in character. We show that the TAp73 form produced by TP73 P1 promoter has five distinct Egr1-binding sites, each contributing to the transcriptional upregulation of TAp73 by Egr1 in several cell types. In contrast, TP73 P2 promoter transcribes DeltaNp73, is not induced by Egr1, but is induced by TAp73 and p53. Induction of TAp73 by genotoxic stress requires Egr1 in mouse in vivo. Newly discovered non-consensus p53-binding sites in p73, p53 and Egr1 promoters reveal inter-regulating networks and sustained expression by feedback loops in response to stress, resulting in prolonged expression of the p53 family of genes and efficient apoptosis.
Insights
The transcription factor p73, particularly the TAp73 form, is upregulated by Egr1 in response to genotoxic stress. This interaction, along with feedback loops, sustains p53 family gene expression for efficient apoptosis.
Area of Science:
- Molecular Biology
- Cancer Biology
- Genetics
Background:
- p73 is a transcription factor regulating p53 target genes involved in cellular responses to genotoxic stress, including growth arrest and apoptosis.
- Two main forms of p73 exist: TAp73, which mimics p53 functions, and DeltaNp73, which can be oncogenic.
Purpose of the Study:
- To investigate the regulatory mechanisms of TAp73 and DeltaNp73 expression.
- To elucidate the role of Egr1 in the transcriptional regulation of p73.
- To understand the feedback loops governing p53 family gene expression under stress.
Main Methods:
- Analysis of Egr1-binding sites on the TP73 P1 promoter.
- Investigating the induction of TAp73 and DeltaNp73 by Egr1, TAp73, and p53.
- In vivo studies in mice to assess Egr1's role in TAp73 induction by genotoxic stress.
- Identification of non-consensus p53-binding sites in p73, p53, and Egr1 promoters.
Main Results:
- The TP73 P1 promoter, producing TAp73, contains five Egr1-binding sites that upregulate TAp73 transcription.
- The TP73 P2 promoter, transcribing DeltaNp73, is not induced by Egr1 but is induced by TAp73 and p53.
- Egr1 is essential for TAp73 induction by genotoxic stress in vivo in mice.
- Novel p53-binding sites in p73, p53, and Egr1 promoters reveal complex inter-regulatory networks.
Conclusions:
- Egr1 plays a crucial role in the stress-induced upregulation of TAp73.
- Inter-regulating networks and feedback loops involving p53 family members and Egr1 ensure sustained gene expression and efficient apoptosis.
- These findings highlight a complex regulatory network essential for cellular response to DNA damage.
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