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Professor Gerry Melino
Department of Experimental Medicine and Biochemical Sciences
University of Tor Vergata
Via Montpellier, 1 00133, Rome, Italy
Email: gerry.melino@uniroma2.it
Tel: +39-06-72596976
Fax: +39-06-20427290

We are interested in understanding the molecular mechanisms of caspase induction and activation by p73. p73, an important developmental gene, shares a high sequence homology with p53, and induces both G1 cell cycle arrest and apoptosis. However, the molecular mechanisms through which p73 induces apoptosis are unclear. By using an inducible model of p73 (isoforms alpha, beta, gamma) expressed in Saos-2 cells, we found that p73-induced apoptosis is mediated by PUMA induction, which in turn causes Bax mitochondrial translocation and cytochrome c release. In order to test whether caspases play a role during p73-induced cell death, we measured the proenzyme expression levels of caspase 6, 7, and 8 upon dox stimulation of Saos-2 p73 inducible cell lines. We found a significant reduction in procaspase 6 steady state levels (less significant for the other procaspases) 48 h after treatment of Saos-2 beta and gamma. Consistent with the p73beta and gamma-triggered processing of procaspase 6, and to a lesser extend of procaspase 8, both isoforms induced apoptosis after 48h dox stimulation. Therefore, expression of p73, in particular the isoform beta and gamma, induces cell death and caspase activation in Saos-2 cells.
Melino G, Lu X, Gasco M, Crook T, Knight RA. Functional regulation of p73 and p63:
development and cancer. Trends Biochem Sci. 2003 Dec;28:663-70. Review..

Melino G, Bernassola F, Ranalli M, Yee K, Zong WX, Corazzari M, Knight RA, Green DR,
Thompson C, Vousden KH. p73 induces apoptosis via PUMA transactivation and Bax
mitochondrial translocation. J Biol Chem. 2003 Nov 21 [Epub ahead of print]

Bourdon JC, Laurenzi VD, Melino G, Lane D. p53: 25 years of research and more
questions to answer. Cell Death Differ. 2003 Apr;10(4):397-9.

Melino G, De Laurenzi V, Vousden KH. p73: Friend or foe in tumorigenesis. Nat Rev
Cancer. 2002 Aug;2(8):605-15. Review.

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