title: MEK-ERK signaling controls Hdm2 oncoprotein expression by regulating hdm2 mRNA export to the cytoplasm.
abstract: The physical and functional interaction between the transcription factor p53 and its negative regulatory partner protein Hdm2 (Mdm2 in mouse) is a key point of convergence of multiple signaling pathways that regulates cell proliferation and survival. hdm2 mRNA transcription is induced by p53, forming the basis of an auto-regulatory feedback loop. Growth and survival factor-activated Ras-Raf-MEK-ERK signaling can also regulate Hdm2 expression independently of p53, contributing to the pro-survival effect of these factors. In murine fibroblasts, this occurs through the regulation of mdm2 mRNA transcription. Here we show that, in human breast cancer epithelial cells, MEK-dependent regulation of Hdm2 expression also occurs at a post-transcriptional level. Pharmacological blockade of MEK activity in T47D cells inhibits Hdm2 protein synthesis by 80-90%. This occurs in the absence of changes in the expression of the major hdm2-P1 mRNA transcript and only an approximately 40% reduction in hdm2-P2 transcript levels. The amounts of both transcripts that are associated with polyribosomes and are, hence, being actively translated are reduced by >80% by the MEK inhibitor, U0126. We show here that this is due to the inhibition of hdm2 mRNA export from the nucleus when MEK activity is inhibited. In MCF-7 breast cancer cells that express wild-type p53, Hdm2 is required to suppress p53-dependent transcription when MEK kinase is active. Regulation of the nuclear export of hdm2 mRNA provides, therefore, a mechanism whereby mitogen-stimulated cells avoid p53-dependent cell cycle arrest or apoptosis by maintaining the dynamic equilibrium of the Hdm2-p53 feedback loop.
authors.affiliation: Cancer Sciences Division, School of Medicine, University of Southampton, MP 824, Southampton General Hospital, Southampton SO16 6YD, United Kingdom.
authors.forename: Monika
authors.initials: M
authors.lastname: Phelps
authors.forename: Anna
authors.initials: A
authors.lastname: Phillips
authors.forename: Matthew
authors.initials: M
authors.lastname: Darley
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Blaydes
mesh_terms: D017209:Apoptosis; D002070:Butadienes / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D017403:In Situ Hybridization; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism* / Q000502:physiology*; D008954:Models, Biological; D009570:Nitriles / Q000494:pharmacology; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000378:metabolism* / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000378:metabolism* / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2; D012313:RNA / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C113580:U 0126; D012313:RNA; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases