Abstract
Programmed cell death 4 (PDCD4) is a tumour suppressor implicated in cancer development and progression and was recently identified as a repressor of cap-independent translation of specific genes involved in the regulation of apoptosis. We show that the RNA-binding protein HuR binds to the PDCD4 3'UTR to protect it from miR-21-induced silencing. However, following H2O2 treatment, PDCD4 mRNA is degraded via miR-21 binding. Importantly, we identify HuR as a novel substrate of the ERK8 kinase pathway in response to H2O2 treatment. We show that phosphorylation of HuR by ERK8 prevents it from binding to PDCD4 mRNA and allows miR-21-mediated degradation of PDCD4.
Keywords:
kinase; miRNA; tumour supressor.
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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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Binding Sites
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ELAV-Like Protein 1 / genetics
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ELAV-Like Protein 1 / metabolism*
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Enzyme Activation
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Silencing
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HeLa Cells
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Humans
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Hydrogen Peroxide / pharmacology
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Phosphorylation
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RNA Interference
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RNA Stability
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism*
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Signal Transduction
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Time Factors
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Transfection
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Uterine Cervical Neoplasms / enzymology*
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Uterine Cervical Neoplasms / genetics
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Uterine Cervical Neoplasms / pathology
Substances
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3' Untranslated Regions
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Apoptosis Regulatory Proteins
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ELAV-Like Protein 1
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ELAVL1 protein, human
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MIRN21 microRNA, human
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MicroRNAs
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PDCD4 protein, human
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RNA, Messenger
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RNA-Binding Proteins
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Hydrogen Peroxide
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Extracellular Signal-Regulated MAP Kinases
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MAPK15 protein, human