title: ∆Np73 is capable of inducing apoptosis by co-ordinately activating several BH3-only proteins.
abstract: Inactivation of p53 is one of the most relevant events in human cancer, since it allows transformed cells to escape their own proliferation control and leave them irresponsive to drugs that aim to damage their DNA. When p53 falls, other members of its family may become targets to attack tumoural cells. p73 has shown capacity to mediate these attacks. However, its N-terminal truncated isoforms have been associated with oncogenesis due to their capacity to act as dominant negatives of p53 and the transactivation (TA) isoforms of p73. We previously found a relationship between the overexpression of N-terminus-truncated p73 isoform (∆Np73) and that of the proapoptotic gene Bcl-2-interacting killer (BIK). In the present report we demonstrate that ∆Np73-α has the capacity to induce apoptosis through the co-ordinated activation of a group of genes harbouring GC-rich elements in their regulatory regions. ∆Np73-α synergizes with specificity protein (Sp1) on these elements but the overall response of these genes probably depends on the additional presence of consensus p53 elements. We explore the domains of ∆Np73-α involved in this transactivation capacity and found divergences with the previously described functions for them. Moreover, we found that the transforming mutation V12 of HRas impairs this transactivation capacity of ∆Np73-α, further supporting the anti-tumoural function of this later. Our data add complexity to the action of p73 on the induction of apoptosis and tumourogenesis, opening new interpretations to the expression profile of p73 isoforms in different human neoplasias.
authors.affiliation: Laboratorio de Hematología Molecular, Servicio de Hematología y Hemoterapia, Hospital Universitario Marqués de Valdecilla-IDIVAL, Santander, Spain.
authors.forename: Dámaso
authors.initials: D
authors.lastname: Sánchez-Carrera
authors.affiliation: Laboratorio de Hematología Molecular, Servicio de Hematología y Hemoterapia, Hospital Universitario Marqués de Valdecilla-IDIVAL, Santander, Spain.
authors.forename: Mikel
authors.initials: M
authors.lastname: García-Puga
authors.affiliation: Laboratorio de Hematología Molecular, Servicio de Hematología y Hemoterapia, Hospital Universitario Marqués de Valdecilla-IDIVAL, Santander, Spain.
authors.forename: Lucrecia
authors.initials: L
authors.lastname: Yáñez
authors.affiliation: Laboratorio de Hematología Molecular, Servicio de Hematología y Hemoterapia, Hospital Universitario Marqués de Valdecilla-IDIVAL, Santander, Spain.
authors.forename: Íñigo
authors.initials: Í
authors.lastname: Romón
authors.affiliation: Laboratorio de Hematología Molecular, Servicio de Hematología y Hemoterapia, Hospital Universitario Marqués de Valdecilla-IDIVAL, Santander, Spain cpipaon@humv.es.
authors.forename: Carlos
authors.initials: C
authors.lastname: Pipaón
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001482:Base Composition; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000737:chemistry; D005199:Fanconi Anemia / Q000473:pathology; D005347:Fibroblasts / Q000473:pathology / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins; D009154:Mutation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000072160:Tumor Protein p73 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C096820:BIK protein, human; D003432:Cross-Linking Reagents; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; C495901:TP53 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins
keywords: BH3-only proteins; Fanconi anaemia; apoptosis; p53; specificity protein 1 (Sp1); ∆Np73