Regulation of MDMX expression by mitogenic signaling.
MDMX is an important regulator of p53 transcriptional activity and stress response. MDMX overexpression and gene amplification are implicated in p53 inactivation and tumor development. Unlike MDM2, MDMX is not inducible by p53, and little is known about its regulation at the transcriptional level. We found that MDMX levels in tumor cell lines closely correlate with promoter activity and mRNA level. Activated K-Ras and insulin-like growth factor 1 induce MDMX expression at the transcriptional level through mechanisms that involve the mitogen-activated protein kinase and c-Ets-1 transcription factors. Pharmacological inhibition of MEK results in down-regulation of MDMX in tumor cell lines. MDMX overexpression was detected in approximately 50% of human colon tumors and showed strong correlation with increased extracellular signal-regulated kinase phosphorylation. Therefore, MDMX expression is regulated by mitogenic signaling pathways. This mechanism may protect normal proliferating cells from p53 but also hamper p53 response during tumor development.
Gilkes
Daniele M
DM
H. Lee Moffitt Cancer Center, MRC3057A, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Pan
Yu
Y
Coppola
Domenico
D
Yeatman
Timothy
T
Reuther
Gary W
GW
Chen
Jiandong
J
D001665:Binding Sites; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor / Q000166:cytology / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D011905:Genes, ras; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008938:Mitosis / Q000235:genetics*; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D050784:Proto-Oncogene Protein c-ets-1 / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D050807:ets-Domain Protein Elk-1 / Q000502:physiology
D018797:Cell Cycle Proteins; C494112:ELK1 protein, human; C482775:MDM4 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011994:Recombinant Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D050807:ets-Domain Protein Elk-1; D007334:Insulin-Like Growth Factor I; D003513:Cycloheximide