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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
Published on: December 27, 2016
p73 regulates DRAM-independent autophagy that does not contribute to programmed cell death
D Crighton1, J O'Prey, H S Bell
1Tumour Cell Death Laboratory, Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Garscube Estate, Glasgow, UK.
Abstract:
Evading programmed cell death is a common event in tumour development. The p53 family member, p73, is a potent inducer of death and a determinant of chemotherapeutic response, but different to p53, is rarely mutated in cancer. Understanding cell death pathways downstream of p53 and p73 is therefore pivotal to understand both the development and treatment of malignant disease. Recently, p53 has been shown to modulate autophagy--a membrane trafficking process, which degrades long-lived proteins and organelles. This requires a p53 target gene, DRAM, and both DRAM and autophagy are critical for p53-mediated death. We report here that TA-p73 also regulates DRAM and autophagy, with different TA-p73 isoforms regulating DRAM and autophagy to varying extents. RNAi knockdown of DRAM, however, revealed that p73's modulation of autophagy is DRAM-independent. Also, p73's ability to induce death, again different to p53, is neither dependent on DRAM nor autophagy. In contrast to TA-p73, deltaN-p73 is a negative regulator of p53-induced and p73-induced autophagy, but does not affect autophagy induced by amino-acid starvation. These studies, therefore, represent not only the first report that p73 modulates autophagy but also highlight important differences in the mechanism by which starvation, p53 and p73 regulate autophagy and how this contributes to programmed cell death.
Insights
The p73 protein regulates autophagy, a cellular degradation process, impacting programmed cell death differently than p53. Understanding these distinct pathways is crucial for cancer treatment development.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Tumor development often involves evading programmed cell death.
- The p53 family member, p73, induces cell death and influences chemotherapy response, yet is rarely mutated in cancer.
- Understanding p53 and p73 downstream pathways is key for cancer development and treatment.
Purpose of the Study:
- To investigate the role of p73 in regulating autophagy, a process linked to programmed cell death.
- To elucidate the relationship between p73, its target gene DRAM, and autophagy.
- To differentiate the mechanisms of autophagy regulation by p53, p73, and amino-acid starvation.
Main Methods:
- Investigated the regulation of DRAM and autophagy by different TA-p73 isoforms.
- Utilized RNA interference (RNAi) knockdown of DRAM to assess its necessity in p73-mediated autophagy.
- Examined the impact of deltaN-p73 on autophagy induced by p53, p73, and amino-acid starvation.
Main Results:
- TA-p73 isoforms differentially regulate DRAM and autophagy.
- p73-mediated autophagy modulation is DRAM-independent.
- p73-induced cell death does not rely on DRAM or autophagy.
- deltaN-p73 negatively regulates p53- and p73-induced autophagy but not starvation-induced autophagy.
Conclusions:
- This study is the first to report p73's modulation of autophagy.
- p73 regulates autophagy through mechanisms distinct from p53.
- Significant differences exist in how starvation, p53, and p73 control autophagy and programmed cell death.
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