Transformation of normal human cells in the absence of telomerase activation

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Resistance to viral infection of super p53 mice

Induction of expression of the tumor suppressor p53 after interferon treatment has been recently demonstrated (Takaoka et al., 2003), suggesting an antiviral activity of the protein. In addition, a direct correlation between p53 levels and tumor resistance has been addressed by generating mice with an extra copy of p53 (‘super p53’ mice) (Garcia-Cao et al., 2002). Here, we show that vesicular stomatitis virus replication in mouse embryo fibroblasts derived from ‘super p53’ mice is impaired as a result of apoptosis induction via p53 activation. These findings unequivocally demonstrate an antiviral activity of p53, a process that may contribute to inhibit the spread of the virus in vivo.Work at the laboratory of M Serrano has been funded by the Spanish Ministry of Science and Technology (SAF2002-03402), and by the European Union (QLRT-2000-02084, QLRT-2000-00616 and INTACT). C Rivas laboratory work was supported by a grant from Ministerio de Ciencia y Tecnologia de España (BIO2002-02417). C Rivas is an investigator of the Ramon y Cajal Programme

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 ζPKC (atypical protein kinase)–NF‐κB (nuclear factor‐κB)–XIAP pathway. These data show that Par4 has an important role in tumour suppression, with a particular relevance in the endometrium and prostate.This work was supported by grants SAF2003‐02613 (to M.T.D.‐M.), SAF2002‐0187 (to J.M.) and SAF2002‐03402 (to M.S.) from the Spanish Ministry of Education and Science, by INTACT (to M.S.) from the European Union and by an institutional grant from Fundación Ramón Areces to the CBMSO. J.M. is the recipient of the Ayuda Investigación Juan March 2001

Inhibition of the Phosphoinositide 3-Kinase Pathway Induces a Senescence-like Arrest Mediated by p27Kip1

A senescence-like growth arrest is induced in mouse primary embryo fibroblasts by inhibitors of phosphoinositide 3-kinase (PI3K). We observed that senescence-like growth arrest is correlated with an increase in p27Kip1 but that down-regulation of other cyclin-dependent kinase (CDK) inhibitors, including p15INK4b, p16INK4a, p19 INK4d, and p21Cip1 as well as other negative cell cycle regulators such as p53 and p19ARF, implies that this senescence-related growth arrest is independent of the activity of p53, p19ARF, p16INK4a, and p21Cip1, which are associated with replicative senescence. The p27Kip1 binds to the cyclin/CDK2 complexes and causes a decrease in CDK2 kinase activity. We demonstrated that ectopic expression of p27Kip1 can induce permanent cell cycle arrest and a senescence-like phenotype in wild-type mouse embryo fibroblasts. We also obtained results suggesting that the kinase inhibitors LY294002 and Wortmannin arrest cell growth and induce a senescence-like phenotype, at least partially, through inhibition of PI3K and protein kinase B/Akt, activation of the forkhead protein AFX, and up-regulation of p27Kip1expression. In summary, these observations taken together suggest that p27Kip1 is an important mediator of the permanent cell cycle arrest induced by PI3K inhibitors. Our data suggest that repression of CDK2 activity by p27Kip1 is required for the PI3K-induced senescence, yet mouse embryo fibroblasts derived fromp27 Kip1−/− mice entered cell cycle arrest after treatment with LY294002. We show that this is due to a compensatory mechanism by which p130 functionally substitutes for the loss of p27Kip1. This is the first description that p130 may have a role in inhibiting CDK activity during senescence.Predoctoral fellows supported by the Spanish Ministry of Education and Culture (I. G.-C.) and the Department of Immunology and Oncology (M. B.). g A junior research fellow supported by the National Funds for Scientific Research, Belgium. h Supported by the Ludwig Institute for Cancer Research and the Leukemia Research Fund. k Supported by the Spanish Research Council (CSIC), the Spanish Ministry of Education and Culture, and a core grant to the Department of Immunology and Oncology from the consortium between Pharmacia and Upjohn and CSIC.Peer reviewe