HtrA2 enhances the apoptotic functions of p73 on bax.
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-alpha 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 p73alpha 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.
Marabese
M
M
Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche, Mario Negri, via La Masa 19, Milan 20156, Italy. marabese@marionegri.it
Mazzoletti
M
M
Vikhanskaya
F
F
Broggini
M
M
D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2