論文 - 詳細
| RRC ID | 58893 |
|---|---|
| 著者 | Atsumi Y, Inase A, Osawa T, Sugihara E, Sakasai R, Fujimori H, Teraoka H, Saya H, Kanno M, Tashiro F, Nakagama H, Masutani M, Yoshioka K. |
| タイトル | The Arf/p53 protein module, which induces apoptosis, down-regulates histone H2AX to allow normal cells to survive in the presence of anti-cancer drugs. |
| ジャーナル | J Biol Chem |
| Abstract |
BACKGROUND:It is unclear how DNA-damaging agents target cancer cells over normal somatic cells. RESULTS:Arf/p53-dependent down-regulation of H2AX enables normal cells to survive after DNA damage. CONCLUSION:Transformed cells, which harbor mutations in either Arf or p53, are more sensitive to DNA-damaging agents. SIGNIFICANCE:Cellular transformation renders cells more susceptible to some DNA-damaging agents. Anti-cancer drugs generally target cancer cells rather than normal somatic cells. However, the factors that determine this differential sensitivity are poorly understood. Here we show that Arf/p53-dependent down-regulation of H2AX induced the selective survival of normal cells after drug treatment, resulting in the preferential targeting of cancer cells. Treatment with camptothecin, a topoisomerase I inhibitor, caused normal cells to down-regulate H2AX and become quiescent, a process mediated by both Arf and p53. In contrast, transformed cells that harbor mutations in either Arf or p53 do not down-regulate H2AX and are more sensitive to drugs unless they have developed drug resistance. Such transformation-associated changes in H2AX expression rendered cancer cells more susceptible to drug-induced damage (by two orders of magnitude). Thus, the expression of H2AX and γH2AX (phosphorylated form of H2AX at Ser-139) is a critical factor that determines drug sensitivity and should be considered when administering chemotherapy. |
| 巻・号 | 288(19) |
| ページ | 13269-77 |
| 公開日 | 2013-5-10 |
| DOI | 10.1074/jbc.M112.402560 |
| PII | S0021-9258(19)54558-6 |
| PMID | 23536184 |
| PMC | PMC3650366 |
| MeSH | Animals Antineoplastic Agents / pharmacology* Apoptosis* Camptothecin / pharmacology Cell Shape Cells, Cultured Cellular Senescence Cisplatin / pharmacology Cyclin-Dependent Kinase Inhibitor p16 / genetics Cyclin-Dependent Kinase Inhibitor p16 / metabolism* DNA Damage DNA Replication / drug effects Down-Regulation* Doxorubicin / pharmacology Drug Resistance, Neoplasm Gene Knockdown Techniques Histones / genetics Histones / metabolism* Humans Hydroxyurea / pharmacology Mice Mice, Knockout Mutation Phenanthrenes / pharmacology Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) Polymerase Inhibitors Tumor Suppressor Protein p53 / genetics Tumor Suppressor Protein p53 / metabolism* |
| IF | 4.238 |
| リソース情報 | |
| ヒト・動物細胞 | HUC-F2(RCB0436) |