The p53-regulated cyclin G gene promotes cell growth: p53 downstream effectors cyclin G and Gadd45 exert different effects on cisplatin chemosensitivity.
Among the p53-regulated genes that have been identified thus far, cyclin G is a relatively recent one. We conducted a series of experiments aimed at elucidating cyclin G function. Ectopic overexpression of cyclin G in human RKO colon carcinoma cells accelerated cell growth. Transfection of normal human fibroblasts with the cyclin G expression vector promoted clonal expansion. Cyclin G immune complexes isolated from the transfected cells exhibited appreciable levels of cyclin-dependent kinase activity, as evidenced using histone H1 as a substrate. The retinoblastoma protein, pRb, was detectable in cyclin G immune complexes, raising the possibility that Rb may be one mediator of cyclin G action. Cyclin G-overexpressing cells were more sensitive to cisplatin cytotoxicity than the parent cells, probably because cyclin G overexpression overrides cell cycle checkpoint(s). Overexpression of another p53-regulated gene, GADD45, by contrast, protected cells from cisplatin killing. These findings suggest that different downstream effectors of the p53 pathway may exert different effects on cellular survival after treatment with cancer chemotherapy drugs such as cisplatin.
Smith
M L
ML
Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Kontny
H U
HU
Bortnick
R
R
Fornace
A J
AJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002455:Cell Division / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology*; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D015870:Gene Expression; D016158:Genes, p53; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D000097642:GADD45 Proteins
D000970:Antineoplastic Agents; D002945:Cisplatin; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D016160:Retinoblastoma Protein; D000097642:GADD45 Proteins; C534702:CCNG1 protein, human