Human chromosome 11 band q13 is of particular importance and interest in tumor biology. 15-20% of breast and squamous cell cancers contain a DNA amplification of 11q13, but no known gene from this region is invariably amplified and expressed in these tumors. Thus, the existence of a new oncogene in 11q13 has been postulated. In addition, a subset of B-cell derived tumors possess t(11;14) or other translocations with 11q13 breakpoints at or near BCL1. The presence of a BCL1 region oncogene that is deregulated by these rearrangements has been assumed, but transcribed sequences near BCL1 have not yet been identified. We recently discovered clonal rearrangements of the parathyroid hormone (PTH) gene in a subset of parathyroid adenomas. These rearrangements juxtaposed the active regulatory region of PTH with unidentified (potentially oncogene-containing) DNA, which mapped to 11q13 and proved to contain highly conserved gene (D11S287E or PRAD1). PRAD1 is (1) dramatically overexpressed in the rearrangement-bearing parathyroid tumors; (2) consistently amplified in breast and squamous cell cancers with 11q13 amplification, and overexpressed in these tumors; (3) located near BCL1 and overexpressed in lymphomas characterized by BCL1 rearrangement; and (4) encodes a protein related to the cyclins, which are important regulators of the cell cycle. PRAD1 is thus the best existing candidate for being the long-sought BCL1 region lymphoid oncogene and the key oncogene in breast and squamous cell cancers with 11q13 DNA amplification, in addition to its apparent role in parathyroid adenomatosis. This proposal addresses the investigation of (i) the normal function of the novel PRAD1 gene and protein product, and (2) the role of PRAD1 in tumor development. The proposed investigations include: detailed analysis of PRAD1's genomic structure, including intron-exon organization and regulatory regions; identification of PRAD1 family members in the human genome and of homologous genes in other species ranging from mammals to yeast; characterization of the gene product using anti-PRAD1 antisera; functional comparisons with the cyclins eg. with regard to regulation during the mammalian cell cycle and in cell free lysates; analysis of PRAD1 overexpression in human tumors; and assessment of PRAD1's tumorigenic potential using transformation assays in cultured cells.
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