p73 regulates DRAM-independent autophagy that does not contribute to programmed cell death.
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.
Crighton
D
D
Tumour Cell Death Laboratory, Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Garscube Estate, Glasgow, UK.
O'Prey
J
J
Bell
H S
HS
Ryan
K M
KM
D000596:Amino Acids / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001343:Autophagy / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004318:Doxycycline / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010588:Phagosomes / Q000378:metabolism / Q000648:ultrastructure; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D000596:Amino Acids; D004268:DNA-Binding Proteins; C512709:DRAM1 protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011506:Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D049452:Green Fluorescent Proteins; D004318:Doxycycline