title: Tumour-suppression activity of the proapoptotic regulator Par4.
abstract: The proapoptotic protein encoded by Par4 (prostate apoptosis response 4) has been implicated in tumour suppression, particularly in the prostate. We report here that Par4-null mice are prone to develop tumours, both spontaneously and on carcinogenic treatment. The endometrium and prostate of Par4-null mice were particularly sensitive to the development of proliferative lesions. Most (80%) Par4-null females presented endometrial hyperplasia by 9 months of age, and a significant proportion (36%) developed endometrial adenocarcinomas after 1 year of age. Similarly, Par4-null males showed a high incidence of prostate hyperplasia and prostatic intraepithelial neoplasias, and were extraordinarily sensitive to testosterone-induced prostate hyperplasia. Finally, the uterus and prostate of young Par4-null mice have increased levels of the apoptosis inhibitor XIAP (X-chromosome-linked inhibitor of apoptosis), supporting the previously proposed function of Par4 as an inhibitor of the (zeta)PKC (atypical protein kinase)-NF-(kappa)B (nuclear factor-(kappa)B)-XIAP pathway. These data show that Par4 has an important role in tumour suppression, with a particular relevance in the endometrium and prostate.
authors.affiliation: Spanish National Cancer Center (CNIO), 3 Melchor Fernandez Almagro Street, Madrid 28029, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: García-Cao
authors.forename: Angeles
authors.initials: A
authors.lastname: Duran
authors.forename: Manuel
authors.initials: M
authors.lastname: Collado
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Carrascosa
authors.forename: Juan
authors.initials: J
authors.lastname: Martín-Caballero
authors.forename: Juana M
authors.initials: JM
authors.lastname: Flores
authors.forename: Maria T
authors.initials: MT
authors.lastname: Diaz-Meco
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
mesh_terms: D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002085:Butylhydroxybutylnitrosamine / Q000633:toxicity; D016889:Endometrial Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D004958:Estradiol / Q000633:toxicity; D005260:Female; D006652:Histological Techniques; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000378:metabolism*; D013739:Testosterone / Q000633:toxicity; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein
chemical_list: D011506:Proteins; D018179:Receptors, Thrombin; D051636:X-Linked Inhibitor of Apoptosis Protein; D002085:Butylhydroxybutylnitrosamine; D013739:Testosterone; D004958:Estradiol; C112908:protease-activated receptor 4