¹Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche, 'Mario Negri', via La Masa 19, Milan 20156, Italy

Correspondence: M Marabese, Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche 'Mario Negri', via La Masa 19, Milan 20156, Italy. Tel: +023 901 4236; Fax: +39 023 901 4734; E-mail: marabese@marionegri.it

Received 20 December 2007; Accepted 4 January 2007; Published online 8 February 2008.

Abstract

Regulation of the p73 gene is complex due to the presence of two promoters and the very complex mRNA maturation in both the N-terminal and C-terminal parts of the protein. We have found an additional regulation mechanism for the p73- form that occurs through proteolytic cleavage connected to the activity of the serine protease HtrA2. Following apoptotic stimuli, HtrA2 accumulates in the nucleus and cleaves p73 in the C-terminal portion, enabling the protein to increase its transactivation activity on the apoptotic gene bax but not on the cell-cycle regulator gene p21. In the presence of HtrA2, p73 is more prone to cause caspase activation and nuclei fragmentation: p73 needs HtrA2 to activate and enhance its apoptotic functions. This new relation between p73 and HtrA2 may help to understand the different behavior of the p73 protein in cell physiology and in the responses of cancer cells to chemotherapy.