MDMX regulation of p53 response to ribosomal stress.
Ribosomal stress such as disruption of rRNA biogenesis activates p53 by release of ribosomal proteins from the nucleoli, which bind to MDM2 and inhibit p53 degradation. We found that p53 activation by ribosomal stress requires degradation of MDMX in an MDM2-dependent fashion. Tumor cells overexpressing MDMX are less sensitive to actinomycin D-induced growth arrest due to formation of inactive p53-MDMX complexes. Knockdown of MDMX increases sensitivity to actinomycin D, whereas MDMX overexpression abrogates p53 activation and prevents growth arrest. Furthermore, MDMX expression promotes resistance to the chemotherapeutic agent 5-fluorouracil (5-FU), which at low concentrations activates p53 by inducing ribosomal stress without significant DNA damage signaling. Knockdown of MDMX abrogates HCT116 tumor xenograft formation in nude mice. MDMX overexpression does not accelerate tumor growth but increases resistance to 5-FU treatment in vivo. Therefore, MDMX is an important regulator of p53 response to ribosomal stress and RNA-targeting chemotherapy agents.
Gilkes
Daniele M
DM
Molecular Oncology Program, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Chen
Lihong
L
Chen
Jiandong
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage; D003609:Dactinomycin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D012335:RNA, Ribosomal / Q000187:drug effects; D012269:Ribosomal Proteins / Q000378:metabolism; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012335:RNA, Ribosomal; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C027624:ribosomal protein L11; D003609:Dactinomycin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D005472:Fluorouracil