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p53 is regulated by the lysine demethylase LSD1
Jing Huang1, Roopsha Sengupta, Alexsandra B Espejo
1The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA.
Nature
|September 7, 2007
Summary
The tumor suppressor p53 is regulated by lysine methylation and demethylation. The demethylase LSD1 controls p53 activity by reversing specific methylation marks, impacting gene activation and apoptosis.
Area of Science:
- Molecular Biology
- Epigenetics
- Cancer Research
Background:
- p53, a crucial tumor suppressor, is regulated by post-translational modifications like lysine methylation.
- Histone lysine methylation is known to be reversible, but reversibility for non-histone proteins was unestablished.
- The role of specific methylation marks on p53 function and its interaction with coactivators was unclear.
Purpose of the Study:
- To investigate whether the histone lysine-specific demethylase LSD1 demethylates the tumor suppressor p53.
- To determine the effect of LSD1 interaction with p53 on p53-mediated transcriptional activation and apoptosis.
- To elucidate the distinct roles of different methylation states at K370 of p53.
Main Methods:
- In vitro and in vivo assays to study the interaction between LSD1 and p53.
- Analysis of methylation and demethylation of p53 at K370.
- Assessment of p53's transcriptional activity and apoptosis promotion in the presence of LSD1.
- Investigation of p53's association with coactivator 53BP1.
Main Results:
- LSD1 interacts with p53, repressing its transcriptional activation and apoptosis-promoting functions.
- LSD1 removes both monomethylation (K370me1) and dimethylation (K370me2) of p53 at K370 in vitro, preferring K370me2 in vivo.
- K370me1 represses p53 function, while K370me2 promotes p53 association with 53BP1.
- LSD1 inhibits p53 function by preventing its interaction with 53BP1.
Conclusions:
- p53 is dynamically regulated by lysine methylation and demethylation, similar to histones.
- The methylation status at K370 of p53 dictates distinct regulatory outcomes.
- LSD1 plays a critical role in modulating p53 activity through demethylation, offering potential therapeutic targets in cancer.
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