| First Author | Shen L | Year | 2012 |
| Journal | Cancer Res | Volume | 72 |
| Issue | 23 | Pages | 6153-62 |
| PubMed ID | 23026135 | Mgi Jnum | J:192049 |
| Mgi Id | MGI:5463853 | Doi | 10.1158/0008-5472.CAN-12-1862 |
| Citation | Shen L, et al. (2012) Geminin functions downstream of p53 in K-ras-induced gene amplification of dihydrofolate reductase. Cancer Res 72(23):6153-62 |
| abstractText | DNA strand breakage and perturbation of cell-cycle progression contribute to gene amplification events that can drive cancer. In cells lacking p53, DNA damage does not trigger an effective cell-cycle arrest and in this setting promotes gene amplification. This is also increased in cells harboring oncogenic Ras, in which cell-cycle arrest is perturbed and ROS levels that cause DNA single strand breaks are elevated. This study focused on the effects of v-K-ras and p53 on Methotrexate (MTX)-mediated DHFR amplification. Rat lung epithelial cells expressing v-K-ras or murine lung cancer LKR cells harboring active K-ras continued cell-cycle progression when treated with MTX. However, upon loss of p53, amplification of DHFR and formation of MTX-resistant colonies occurred. Expression levels of cyclin A, Geminin, and Cdt1 were increased in v-K-ras transfectants. Geminin was sufficient to prevent the occurrence of multiple replications via interaction with Cdt1 after MTX treatment, and DHFR amplification proceeded in v-K-ras transfectants that possess a functional p53 in the absence of geminin. Taken together, our findings indicate that p53 not only regulates cell-cycle progression, but also functions through geminin to prevent DHFR amplification and protect genomic integrity. |
