Different cooperating effect of p21 or p27 deficiency in combination with INK4a/ARF deletion in mice.
The control exerted by the INK4a/ARF locus on cellular proliferation is crucial to restrict tumor development. In agreement with this, mice with defects in this locus are highly tumor prone. However, the potential contribution of other pathways in modulating tumorigenesis in the absence of INK4a/ARF is largely unexplored. In the present study, we investigated the consequences of the combined loss of either of two cyclin-dependent kinase inhibitors, p21 and p27, in cooperation with deletion of the INK4a/ARF locus. Our results show a clear differential effect in tumorigenesis depending on the CKI that is absent. The absence of p21 produced no overt alteration of the lifespan of the INK4a/ARF-null mice, although it modified their tumor spectrum, causing a significant increase in the incidence of fibrosarcomas and the appearance of a small number of rhabdomyosarcomas. In contrast, deficiency of p27 resulted in a significant increase in lethality due to accelerated tumor development, especially in the case of T-cell lymphomas. Finally, combined deficiency of INK4a/ARF and p27 resulted in a significant increase in the number of metastatic tumors. These results demonstrate genetically the oncogenic cooperation between defects on INK4a/ARF and p27, which are common alterations in human cancer.
Martín-Caballero
Juan
J
Molecular Oncology Program, Spanish National Cancer Center (CNIO), Melchor Fernandez Almagro 3, Madrid E-28029, Spain.
Flores
Juana M
JM
García-Palencia
Pilar
P
Collado
Manuel
M
Serrano
Manuel
M
D020727:ADP-Ribosylation Factors / Q000235:genetics*; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017384:Sequence Deletion; D025521:Tumor Suppressor Proteins / Q000235:genetics*
C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D020727:ADP-Ribosylation Factors