PMID:14634023

Citation	Melino, G, Bernassola, F, Ranalli, M, Yee, K, Zong, WX, Corazzari, M, Knight, RA, Green, DR, Thompson, C and Vousden, KH (2004) p73 Induces apoptosis via PUMA transactivation and Bax mitochondrial translocation. J. Biol. Chem. 279:8076-83
Abstract	p73, an important developmental gene, shares a high sequence homology with p53 and induces both G(1) cell cycle arrest and apoptosis. However, the molecular mechanisms through which p73 induces apoptosis are unclear. We found that p73-induced apoptosis is mediated by PUMA (p53 up-regulated modulator of apoptosis) induction, which, in turn, causes Bax mitochondrial translocation and cytochrome c release. Overexpression of p73 isoforms promotes cell death and bax promoter transactivation in a time-dependent manner. However, the kinetics of apoptosis do not correlate with the increase of Bax protein levels. Instead, p73-induced mitochondrial translocation of Bax is kinetically compatible with the induction of cell death. p73 is localized in the nucleus and remains nuclear during the induction of cell death, indicating that the effect of p73 on Bax translocation is indirect. The ability of p73 to directly transactivate PUMA and the direct effect of PUMA on Bax conformation and mitochondrial relocalization suggest a molecular link between p73 and the mitochondrial apoptotic pathway. Our data therefore indicate that PUMA-mediated Bax mitochondrial translocation, rather than its direct transactivation, correlates with cell death. Finally, human DeltaNp73, an isoform lacking the amino-terminal transactivation domain, inhibits TAp73-induced as well as p53-induced apoptosis. The DeltaNp73 isoforms seem therefore to act as dominant negatives, repressing the PUMA/Bax system and, thus, finely tuning p73-induced apoptosis. Our findings demonstrate that p73 elicits apoptosis via the mitochondrial pathway using PUMA and Bax as mediators.
Links	PubMed Online version:10.1074/jbc.M307469200
Keywords	Animals; Apoptosis/drug effects; Apoptosis Regulatory Proteins; Biological Transport/drug effects; Cell Line; Cytochromes c/secretion; Cytosol/metabolism; DNA Fragmentation; DNA-Binding Proteins/genetics; DNA-Binding Proteins/pharmacology; DNA-Binding Proteins/physiology; Gene Expression; Genes, Tumor Suppressor; HeLa Cells; Humans; Kinetics; Luciferases/genetics; Mice; Mice, Knockout; Mitochondria/metabolism; Nuclear Proteins/genetics; Nuclear Proteins/pharmacology; Nuclear Proteins/physiology; Promoter Regions, Genetic/genetics; Protein Isoforms/genetics; Proto-Oncogene Proteins/genetics; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins/physiology; Proto-Oncogene Proteins c-bcl-2; RNA Splicing; Transcriptional Activation; Transfection; Tumor Suppressor Protein p53/genetics; Tumor Suppressor Protein p53/physiology; Tumor Suppressor Proteins; bcl-2-Associated X Protein
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:P73		GO:0006915 : apoptosis	ECO:0000314:		P		Figure 6 - Bar graph showing measured levels of cell death where p73 is shown to induces apoptosis (cell death) through PUMA Transactivation.	complete CACAO 3318

References

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