Abstract
Regulation of the synthesis, function and degradation of HDM2 (Mdm2 in mouse) plays a key role in controlling the abundance and activity of the transcription factor p53, with consequent implications for the proliferation and survival of normal and cancer cells. We have previously identified the regulation of export of HDM2 mRNA from the nucleus as a novel point of control of HDM2 synthesis. This process is dependent on the activity of the growth factor-regulated MAP-kinase kinases (MEKs). Here, we provide evidence that the eIF4E kinase MNK1 is a key downstream effector of MEKs in this regulatory pathway. We show that HDM2 mRNA export in breast cancer cells is promoted by overexpressed eIF4E in a MEK- and MNK1-dependent manner, and inhibition of MNK1 suppresses endogenous HDM2 mRNA export pathways. This MNK1- and eIF4E-dependent HDM2 regulation occurs through sequences in the 3' untranslated region of HDM2 mRNA, and consequently HDM2 mRNA transcripts from both the constitutive P1 and inducible P2 promoters are regulated by this pathway. eIF4E is a known oncogene that is overexpressed in human tumours, including the majority of breast cancers. This pathway, therefore, may play an important role in the dysregulation of HDM2 oncoprotein expression that occurs in many human tumours.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions
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Active Transport, Cell Nucleus
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Cell Nucleus / metabolism
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Cytoplasm / metabolism
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Eukaryotic Initiation Factor-4E / genetics
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Eukaryotic Initiation Factor-4E / metabolism*
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Gene Expression Regulation, Neoplastic
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Luciferases / metabolism
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Mitogen-Activated Protein Kinase Kinases / genetics
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Mitogen-Activated Protein Kinase Kinases / metabolism*
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Phosphorylation
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Promoter Regions, Genetic
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins c-mdm2 / genetics*
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Proto-Oncogene Proteins c-mdm2 / metabolism
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RNA, Messenger / genetics*
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RNA, Messenger / metabolism
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Signal Transduction
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Tumor Suppressor Protein p53 / metabolism
Substances
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3' Untranslated Regions
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Eukaryotic Initiation Factor-4E
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Intracellular Signaling Peptides and Proteins
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RNA, Messenger
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Tumor Suppressor Protein p53
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Luciferases
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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MKNK1 protein, human
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinase Kinases