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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Ser46 phosphorylation regulates p53-dependent apoptosis and replicative senescence
Lijin Feng1, Monica Hollstein, Yang Xu
1Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093-0322, USA.
Cell Cycle (Georgetown, Tex.)
|December 19, 2006
Summary
Phosphorylation of p53 at Serine 46 (Ser46) is crucial for activating apoptosis and senescence in response to cellular stress. This study demonstrates that mutating Ser46 impairs these critical p53 functions.
Area of Science:
- Molecular Biology
- Cellular Biology
- Genetics
Background:
- Posttranslational modifications, like phosphorylation, are key regulators of p53 activity.
- Serine 46 (Ser46) phosphorylation of p53 is linked to p53-mediated apoptosis.
- The physiological significance of Ser46 phosphorylation in vivo remains to be fully elucidated.
Purpose of the Study:
- To investigate the physiological role of p53 Ser46 phosphorylation in response to DNA damage and oncogenic stress.
- To determine the impact of Ser46 phosphorylation on p53 stabilization, apoptosis, and senescence.
- To analyze the effects of a Ser46 to Alanine (S46A) missense mutation on p53 function in a mouse model.
Main Methods:
- Utilized homologous recombination and LoxP/Cre-mediated deletion to create a p53 knock-in mouse model (p53hki(S46A)) with a Ser46 to Ala missense mutation.
- Assessed p53 stabilization, apoptosis, and gene transcription in various cell types (ES cells, MEFs, thymocytes) from p53hki(S46A) mice.
- Evaluated proliferation, senescence, and immortalization potential of p53hki(S46A) mouse embryonic fibroblasts (MEFs).
Main Results:
- p53 stabilization was modestly reduced in p53hki(S46A) cells and tissues following DNA damage.
- p53-dependent apoptosis was partially impaired in thymocytes and E1A/Ras-expressing MEFs from p53hki(S46A) mice.
- Transcription of p53 target apoptotic genes was preferentially affected by the S46A mutation.
- p53hki(S46A) MEFs showed increased susceptibility to spontaneous immortalization and escape from Ras-induced senescence.
Conclusions:
- p53 Ser46 phosphorylation is essential for activating p53-dependent apoptosis induced by DNA damage.
- Ser46 phosphorylation also plays a critical role in inducing cellular senescence in response to oncogenic stress.
- The S46A mutation compromises key tumor suppressor functions of p53, impacting apoptosis and senescence pathways.
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