Abstract
Cytokine and proto-oncogene messenger RNAs (mRNAs) are rapidly degraded through AU-rich elements in the 3' untranslated region. Rapid decay involves AU-rich binding protein AUF1, which complexes with heat shock proteins hsc70-hsp70, translation initiation factor eIF4G, and poly(A) binding protein. AU-rich mRNA decay is associated with displacement of eIF4G from AUF1, ubiquitination of AUF1, and degradation of AUF1 by proteasomes. Induction of hsp70 by heat shock, down-regulation of the ubiquitin-proteasome network, or inactivation of ubiquitinating enzyme E1 all result in hsp70 sequestration of AUF1 in the perinucleus-nucleus, and all three processes block decay of AU-rich mRNAs and AUF1 protein. These results link the rapid degradation of cytokine mRNAs to the ubiquitin-proteasome pathway.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3' Untranslated Regions
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Carrier Proteins / metabolism
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Cell Nucleus / metabolism
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Cysteine Endopeptidases / metabolism*
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Cysteine Proteinase Inhibitors / pharmacology
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Cytoplasm / metabolism
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Eukaryotic Initiation Factor-4G
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Granulocyte-Macrophage Colony-Stimulating Factor / genetics*
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HSC70 Heat-Shock Proteins
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HSP70 Heat-Shock Proteins / metabolism*
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HeLa Cells
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Heat-Shock Response*
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Heterogeneous Nuclear Ribonucleoprotein D0
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Heterogeneous-Nuclear Ribonucleoprotein D*
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Humans
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Leupeptins / pharmacology
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Multienzyme Complexes / metabolism*
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Peptide Initiation Factors / metabolism
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Poly(A)-Binding Proteins
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Proteasome Endopeptidase Complex
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Protein Binding
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Proto-Oncogene Mas
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RNA, Messenger / genetics
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RNA, Messenger / metabolism*
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RNA-Binding Proteins / metabolism*
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Transfection
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Ubiquitins / metabolism*
Substances
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3' Untranslated Regions
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Carrier Proteins
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Cysteine Proteinase Inhibitors
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Eukaryotic Initiation Factor-4G
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HNRNPD protein, human
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HSC70 Heat-Shock Proteins
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HSP70 Heat-Shock Proteins
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HSPA8 protein, human
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Heterogeneous Nuclear Ribonucleoprotein D0
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Heterogeneous-Nuclear Ribonucleoprotein D
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Leupeptins
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MAS1 protein, human
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Multienzyme Complexes
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Peptide Initiation Factors
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Poly(A)-Binding Proteins
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Proto-Oncogene Mas
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RNA, Messenger
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RNA-Binding Proteins
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Ubiquitins
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Granulocyte-Macrophage Colony-Stimulating Factor
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde