Abstract
p62 is a multifunctional cytoplasmic protein able to noncovalently bind ubiquitin and several signaling proteins, suggesting a regulatory role connected to the ubiquitin-proteasome pathway. No studies to date have linked p62 protein expression with pathological states. Here we demonstrate the overabundance of p62 protein in malignant breast tissue relative to normal breast tissue. The proteasome inhibitor PSI increased p62 mRNA and protein; however, PSI treatment of breast epithelial cells transfected with the p62 promoter did not affect promoter activity. High levels of prostate-derived Ets factor (PDEF) mRNA have been identified in breast cancer compared to normal breast. Only the PSA and maspin promoters have been identified as targets of this transcription factor. Here we show that PDEF stimulates the p62 promoter through at least two sites, and likely acts as a coactivator. PSI treatment abrogates the PDEF-stimulated increase of p62 promoter activity by 50%. Thus, multiple mechanisms for the induction of p62 exist. We conclude that (1) p62 protein is overexpressed in breast cancer; (2) p62 mRNA and protein increase in response to PSI, with no change of basal promoter activity; (3) PDEF upregulates p62 promoter activity through at least two sites; and (4) PSI downregulates PDEF-induced p62 promoter activation through one of these sites.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetylcysteine / analogs & derivatives*
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Acetylcysteine / pharmacology
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Adaptor Proteins, Signal Transducing
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Breast / cytology
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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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Carrier Proteins / biosynthesis*
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Carrier Proteins / genetics
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Cells, Cultured / drug effects
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Cells, Cultured / metabolism
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Computer Systems
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Cysteine Endopeptidases / metabolism
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Cysteine Proteinase Inhibitors / pharmacology
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Female
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Gene Expression Regulation, Neoplastic / drug effects*
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Gene Expression Regulation, Neoplastic / genetics
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Humans
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Leupeptins / pharmacology
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Multienzyme Complexes / metabolism
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Neoplasm Proteins / biosynthesis*
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Neoplasm Proteins / genetics
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Oligopeptides / pharmacology
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Promoter Regions, Genetic / genetics
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Proteasome Endopeptidase Complex
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Proteins*
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Proto-Oncogene Proteins c-ets
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Neoplasm / biosynthesis
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RNA, Neoplasm / genetics
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Regulatory Sequences, Nucleic Acid
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Reverse Transcriptase Polymerase Chain Reaction
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Sequestosome-1 Protein
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / biosynthesis
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Transcription, Genetic
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Transfection
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / metabolism
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Ubiquitin / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Cysteine Proteinase Inhibitors
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Leupeptins
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Multienzyme Complexes
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Neoplasm Proteins
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Oligopeptides
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Proteins
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Proto-Oncogene Proteins c-ets
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RNA, Messenger
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RNA, Neoplasm
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SPDEF protein, human
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SQSTM1 protein, human
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Sequestosome-1 Protein
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Transcription Factors
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Ubiquitin
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benzyloxycarbonyl-isoleucyl-glutamyl(O-tert-butyl)-alanyl-leucinal
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lactacystin
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde
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Acetylcysteine