RRC ID 44383
Author Horiguchi M, Koyanagi S, Hamdan AM, Kakimoto K, Matsunaga N, Yamashita C, Ohdo S.
Title Rhythmic control of the ARF-MDM2 pathway by ATF4 underlies circadian accumulation of p53 in malignant cells.
Journal Cancer Res
Abstract The sensitivity of cancer cells to chemotherapeutic agents varies according to circadian time. Most chemotherapeutic agents ultimately cause cell death through cell-intrinsic pathways as an indirect consequence of DNA damage. The p53 tumor suppressor gene (TRP53) configures the cell deaths induced by chemotherapeutic agents. In this study, we show that the transcription factor ATF4, a component of the mammalian circadian clock, functions in circadian accumulation of p53 protein in tumor cells. In murine fibroblast tumor cells, ATF4 induced the circadian expression of p19ARF (Cdkn2a). Oscillation of p19ARF interacted in a time-dependent manner with MDM2, a specific ubiquitin ligase of p53, resulting in a rhythmic prevention of its degradation by MDM2. Consequently, the half-life of p53 protein varied in a circadian time-dependent manner without variation in mRNA levels. The p53 protein accumulated during those times when the p19ARF-MDM2 interaction was facilitated. Notably, the ability of the p53 degradation inhibitor nutlin-3 to kill murine fibroblast tumor cells was enhanced when the drug was administered at those times of day during which p53 had accumulated. Taken together, these results suggested that ATF4-mediated regulation of the p19ARF-MDM2 pathway underlies the circadian accumulation of p53 protein in malignant cells. Furthermore, they suggest an explanation for how the sensitivity of cancer cells to chemotherapeutic agents is enhanced at those times of day when p53 protein has accumulated, as a result of circadian processes controlled by ATF4.
Volume 73(8)
Pages 2639-49
Published 2013-4-15
DOI 10.1158/0008-5472.CAN-12-2492
PII 0008-5472.CAN-12-2492
PMID 23580573
MeSH ADP-Ribosylation Factors / metabolism* Activating Transcription Factor 4 / genetics Activating Transcription Factor 4 / metabolism* Animals Antineoplastic Agents / pharmacology Antineoplastic Agents / toxicity Cell Line, Tumor Circadian Rhythm* / genetics Dose-Response Relationship, Drug Male Mice Mice, Knockout Neoplasms / genetics Neoplasms / metabolism* Protein Stability Proto-Oncogene Proteins c-mdm2 / metabolism* Signal Transduction* / drug effects Tumor Suppressor Protein p53 / metabolism*
IF 9.727
Times Cited 17
WOS Category ONCOLOGY
Resource
Human and Animal Cells UV·BAL-5.4G(RCB2025)