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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
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Crotonylation at serine 46 impairs p53 activity
Peng Liao1, Nimisha Bhattarai2, Bo Cao2
1Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, 70112, USA; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA; Department of Surgery, University of Michigan of Medicine, Ann Arbor, MI, USA.
Biochemical and Biophysical Research Communications
|February 10, 2020
Summary
Scientists discovered a new modification of the tumor suppressor p53 called crotonylation, which unexpectedly reduces p53 protein levels and activity. This modification, unique to human p53, may impact early colorectal cancer development.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Post-translational modifications (PTMs) regulate tumor suppressor p53 stability and activity.
- p53 is a critical factor in cellular responses to stress, including DNA damage and metabolic changes.
Purpose of the Study:
- To investigate the effects of short-chain fatty acid modification on p53.
- To identify the specific site and consequences of p53 crotonylation in human cells.
Main Methods:
- Treatment of human cells with crotonic acid (CA).
- Detection of p53 crotonylation using TCEP-probe labeling and anti-crotonylated peptide antibodies.
- Site-directed mutagenesis of serine 46 to alanine.
- Assessment of p53 protein and mRNA levels, p53 activity, and glycolytic activity.
Main Results:
- CA treatment induced p53 crotonylation, targeting serine 46, a site unique to human p53.
- Crotonylation reduced p53 protein levels and inhibited its activity, without affecting mRNA levels.
- Substitution of serine 46 with alanine abolished p53 crotonylation.
- CA treatment increased p53-dependent glycolytic activity and augmented cancer cell proliferation.
Conclusions:
- A novel PTM, p53 crotonylation at serine 46, impairs human p53 activity in response to CA.
- This modification, potentially influenced by gut microbiome-produced CA, may contribute to early colorectal neoplasia by inhibiting p53 without mutation.
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