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p53 upregulates PLCε-IP3-Ca2+ pathway and inhibits autophagy through its target gene Rap2B
Jiehui Di1,2, Juanjuan Tang1,3, Heya Qian1
1Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, P.R. China.
Abstract:
The tumor suppressor p53 plays a pivotal role in numerous cellular responses as it regulates cell proliferation, metabolism, cellular growth, and autophagy. In order to identify novel p53 target genes, we utilized an unbiased microarray approach and identified Rap2B as a robust candidate, which belongs to the Ras-related GTP-binding protein superfamily and exhibits increased expression in various human cancers. We demonstrated that p53 increases the intracellular IP3 and Ca2+ levels and decreases the LC3 protein levels through its target gene Rap2B, suggesting that p53 can inhibit the autophagic response triggered by starvation via upregulation of the Rap2B-PLCε-IP3-Ca2+ pathway. As a confirmed target gene of p53, we believe that further investigating potential functions of Rap2B in autophagy and tumorigenesis will provide a novel strategy for cancer therapy.
Insights
The tumor suppressor p53 regulates cell functions and inhibits autophagy by upregulating its target gene, Rap2B. This discovery offers a potential new strategy for cancer therapy.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- The tumor suppressor p53 is crucial for regulating cellular processes including proliferation, metabolism, growth, and autophagy.
- Identifying novel p53 target genes is essential for understanding its multifaceted roles in cellular regulation and disease.
Purpose of the Study:
- To identify novel target genes of p53 using an unbiased approach.
- To investigate the role of the identified gene, Rap2B, in p53-mediated cellular responses, particularly autophagy.
Main Methods:
- Utilized an unbiased microarray approach to screen for novel p53 target genes.
- Quantified intracellular levels of inositol trisphosphate (IP3) and calcium ions (Ca2+).
- Measured levels of microtubule-associated protein 1A/1B-light chain 3 (LC3) protein to assess autophagy.
Main Results:
- Identified Rap2B, a member of the Ras-related GTP-binding protein superfamily, as a novel p53 target gene with increased expression in human cancers.
- Demonstrated that p53 upregulates Rap2B, leading to increased intracellular IP3 and Ca2+ levels.
- Showed that p53, via Rap2B, decreases LC3 protein levels, indicating inhibition of autophagy.
Conclusions:
- p53 inhibits starvation-induced autophagy through the Rap2B-Phospholipase C epsilon (PLCε)-IP3-Ca2+ pathway.
- Rap2B is a confirmed target gene of p53 and plays a role in regulating autophagy.
- Further research into Rap2B's functions in autophagy and tumorigenesis may yield novel cancer therapeutic strategies.