The p44(S10) locus, encoding a subunit of the proteasome regulatory particle, is amplified during progression of cutaneous malignant melanoma

Gene amplification is frequently present in human tumors, although specific target genes relevant to many amplified loci remain unidentified. An expre ssion cloning assay enabled identification of a candidate oncogene derived from human chromosome 3p14.1, The cDNA retrieved from morphologically trans formed cells contained the full-length protein coding region and detected a n abundant transcript in the same cells. Sequence analysis revealed identit y with the wild-type sequence of p44(S10), a highly conserved subunit of th e 26S proteasome that exhibits similarity to the Arabidopsis fus6/cop11 fam ily of signaling molecules. p44(S10) gene copy number and mRNA expression w ere increased in association with segmental 1.8-11-fold chromosomal gains i n cutaneous malignant melanoma cell lines (5/13; 40%) and tumors (2/40; 5%) , and in breast cancer MCF-7 cells. Likewise, malignant progression of huma n radial growth phase WM35 melanoma cells was associated with amplification and increased expression of endogenous p44(S10), and increased expression of p44(S10) was sufficient to induce proliferation of WM35 cells in vivo. T he 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.