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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Mitogen-activated protein kinase phosphatase 2: a novel transcription target of p53 in apoptosis
Wen Hong Shen1, Jianli Wang, Jingjing Wu
1Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Abstract:
The p53 tumor suppressor plays critical roles in diverse cellular responses such as cell cycle arrest, senescence, and apoptosis through transcriptional control of its target genes. Identification and characterization of new p53 target genes will advance our understanding of how p53 exerts its multiple regulatory functions. In this article, we show that mitogen-activated protein kinase phosphatase 2 (MKP2) is a novel transcription target of p53 in mediating apoptosis. Moreover, we identify a 10-bp perfect palindrome motif (CTGGCGCCAG) in the MKP2 promoter as a new binding site for p53 to activate the MKP2 gene. This GC-rich palindrome is completely different from the consensus p53 binding sequence. Induction of MKP2 is highly responsive to oxidative stress in a p53-dependent manner. Interestingly, the p53-dependent induction of MKP2 is prominent only in the cellular response to stimuli leading to apoptosis but not to cell cycle arrest. In response to oxidative stress, MKP2 is not only required for p53-mediated apoptosis, but ectopic MKP2 expression can also enhance apoptotic responses even independent of p53. These data suggest that p53 regulates distinct genes via different binding mechanisms and that MKP2 is an essential target of p53 in signaling apoptosis.
Insights
The tumor suppressor p53 (also known as TP53) targets the MKP2 gene to induce apoptosis. This discovery reveals a new p53 binding site and highlights MKP2
Area of Science:
- Molecular Biology
- Cancer Research
- Cellular Signaling
Background:
- The p53 tumor suppressor is crucial for cellular responses like apoptosis and cell cycle arrest, acting through transcriptional control of target genes.
- Understanding novel p53 target genes is essential for elucidating its diverse regulatory functions in cellular processes.
Purpose of the Study:
- To identify and characterize new p53 target genes involved in apoptosis.
- To investigate the role of mitogen-activated protein kinase phosphatase 2 (MKP2) as a novel p53 target gene in apoptosis signaling.
Main Methods:
- Identification of MKP2 as a transcription target of p53.
- Characterization of a novel p53 binding site within the MKP2 promoter.
- Analysis of MKP2 induction in response to oxidative stress and its dependence on p53.
Main Results:
- Mitogen-activated protein kinase phosphatase 2 (MKP2) is identified as a novel transcription target of p53, specifically mediating apoptosis.
- A unique 10-bp GC-rich palindrome (CTGGCGCCAG) in the MKP2 promoter serves as a novel p53 binding site, distinct from the consensus sequence.
- MKP2 induction by oxidative stress is p53-dependent and prominent in apoptosis, but not cell cycle arrest; ectopic MKP2 enhances apoptosis independently of p53.
Conclusions:
- p53 utilizes distinct binding mechanisms to regulate different target genes.
- MKP2 is an essential p53 target gene for signaling apoptosis.
- MKP2 plays a significant role in promoting apoptotic responses, highlighting its importance in cancer research and therapy.
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