Geminin functions downstream of p53 in K-ras-induced gene amplification of dihydrofolate reductase

Ling Shen, Takashi Nishioka, Jinjin Guo, Changyan Chen

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)6153-6162
Number of pages10
JournalCancer Research
Volume72
Issue number23
DOIs
Publication statusPublished - 2012 Dec 1
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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