Oncogenic H-ras induces cyclin B1 expression in a p53-independent manner.
The role of p53 in controlling the G2 checkpoint, in part by repressing cyclin B1 transcription, has been well established. However, accumulating evidence indicate that p53-independent pathways may also play an important role. Ras proteins have been shown to regulate G1/S, but also G2/M transitions. Since cyclin B1/cdc2 complex is the key regulator controlling the G2/M checkpoint, we were interested in addressing if the H-ras oncogene could regulate cyclin B1 expression in a p53-independent manner. We observed an induction of cyclin B1 promoter activity in the presence of H-ras oncogene in SW480 cells, which contain null p53 alleles. In addition, HeLa cells known to express the HPV18 E6 oncogene that inactivates p53, exhibited increased levels of cyclin B1 mRNA and protein when transfected with the H-ras oncogene. Higher expression of cyclin B1 correlated with higher levels of cyclin B1/cdc2 complex and kinase activity that interestingly, showed no inhibition at G2/M after DNA damage. These data suggest that H-ras participates in pathways that regulate cyclin B1 expression and therefore controls the G2/M checkpoint in a p53-independent manner.
Santana
Carla
C
Department of Molecular Biology and Biotechnology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico.
Ortega
Enrique
E
García-Carrancá
Alejandro
A
D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism*; D056744:Cyclin B1; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins; D016195:G2 Phase / Q000235:genetics; D011905:Genes, ras; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000235:genetics; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D016159:Tumor Suppressor Protein p53; D016203:CDC2 Protein Kinase