Tumour-suppression activity of the proapoptotic regulator Par4.
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.
García-Cao
Isabel
I
Spanish National Cancer Center (CNIO), 3 Melchor Fernandez Almagro Street, Madrid 28029, Spain.
Duran
Angeles
A
Collado
Manuel
M
Carrascosa
Maria J
MJ
Martín-Caballero
Juan
J
Flores
Juana M
JM
Diaz-Meco
Maria T
MT
Moscat
Jorge
J
Serrano
Manuel
M
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
D011506:Proteins; D018179:Receptors, Thrombin; D051636:X-Linked Inhibitor of Apoptosis Protein; D002085:Butylhydroxybutylnitrosamine; D013739:Testosterone; D004958:Estradiol; C112908:protease-activated receptor 4