Abstract
Gene amplification is frequently present in human tumors, although specific target genes relevant to many amplified loci remain unidentified. An expression cloning assay enabled identification of a candidate oncogene derived from human chromosome 3p14.1. The cDNA retrieved from morphologically transformed cells contained the full-length protein coding region and detected an abundant transcript in the same cells. Sequence analysis revealed identity with the wild-type sequence of p44S10, a highly conserved subunit of the 26S proteasome that exhibits similarity to the Arabidopsis fus6/cop11 family of signaling molecules. p44S10 gene copy number and mRNA expression were increased in association with segmental 1.8 - 11-fold chromosomal gains in cutaneous malignant melanoma cell lines (5/13; 40%) and tumors (2/40; 5%), and in breast cancer MCF-7 cells. Likewise, malignant progression of human radial growth phase WM35 melanoma cells was associated with amplification and increased expression of endogenous p44S10, and increased expression of p44S10 was sufficient to induce proliferation of WM35 cells in vivo. The results demonstrate segmental copy number gains within chromosome 3p in cutaneous malignant melanoma and suggest that deregulation of a proteasome regulatory particle subunit may contribute to the malignant phenotype.
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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Adenosine Triphosphatases / genetics*
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Adenosine Triphosphatases / isolation & purification
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Animals
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Cell Line, Transformed
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Chromosomes, Human, Pair 17
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Chromosomes, Human, Pair 20
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Chromosomes, Human, Pair 3
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Cysteine Endopeptidases / genetics*
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Cysteine Endopeptidases / isolation & purification
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Cysteine Endopeptidases / metabolism
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Disease Progression
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Enzyme Activation / genetics
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Gene Amplification*
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Humans
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Melanoma / enzymology*
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Melanoma / genetics*
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Melanoma / pathology
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Melanoma, Experimental / enzymology
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Melanoma, Experimental / genetics
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Melanoma, Experimental / pathology
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Mice
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Mice, Nude
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Molecular Sequence Data
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Multienzyme Complexes / genetics*
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Multienzyme Complexes / isolation & purification
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Multienzyme Complexes / metabolism
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Oncogene Proteins / genetics*
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Oncogene Proteins / isolation & purification
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Oncogene Proteins / metabolism
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Peptide Hydrolases / genetics
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Peptide Hydrolases / isolation & purification
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Peptide Hydrolases / metabolism
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Proteasome Endopeptidase Complex
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Rats
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Sequence Analysis, DNA
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Skin Neoplasms / enzymology*
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Skin Neoplasms / genetics*
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Skin Neoplasms / pathology
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Tumor Cells, Cultured
Substances
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Multienzyme Complexes
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Oncogene Proteins
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Peptide Hydrolases
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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ATP dependent 26S protease
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Adenosine Triphosphatases