Oh⁸dG induces G₁ arrest in a human acute leukemia cell line by upregulating P21 and blocking the RAS to ERK signaling pathway

다국어 초록 (Multilingual Abstract)

<P>We reported previously that KG-1, a human acute leukemia cell line, has mutational loss of 8-oxoguanine (8-hydroxyguanine; oh<SUP>8</SUP>Gua) glycosylase 1 (OGG1) activity and undergoes apoptotic death after treatment with 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxodeoxyguanosine, 8-hydroxydeoxyguanosine; oh<SUP>8</SUP>dG). In our present study, we further characterized the effects of oh<SUP>8</SUP>dG in KG-1 cells and found that, in addition to apoptosis, oh<SUP>8</SUP>dG induced the arrest of KG-1 at the G<SUB>1</SUB> phase. Simultaneously, oh<SUP>8</SUP>dG-treated KG-1 showed an increase in the oh<SUP>8</SUP>Gua content of DNA, upregulation of p21 (an inhibitor of cdk), and Ras inactivation. Moreover, the upregulation of p21 was followed by the inactivations of cdk4 and cdk2, the hypophosphorylation of Rb, and a marked decline in the expression of c-myc (a gene regulated by E2F that is a transcription factor whose activity is suppressed when it is bound to hypophosphorylated Rb). Ras inactivation was also followed by the inactivation of ERK kinase (MEK) and the inactivation of AP-1, a downstream target of the Ras signaling pathway. The specific MEK inhibitors, PD98059 and U0126, also induced G<SUB>1</SUB> arrest. These findings suggest that p21 upregulation and Ras inactivation contribute to G<SUB>1</SUB> arrest. An increase of oh<SUP>8</SUP>Gua content in DNA does not seem to be a principal contributor to G<SUB>1</SUB> arrest, however, because the kinetics of increases of oh<SUP>8</SUP>Gua content in DNA and of G<SUB>1</SUB> cell number did not coincide. We report that oh<SUP>8</SUP>dG induces the arrest of KG-1 growth at the G<SUB>1</SUB> phase mainly by upregulating p21 and inactivating Ras. © 2005 Wiley-Liss, Inc.</P>