PRAD1/cyclin D1 proto-oncogene: genomic organization, 5' DNA sequence, and sequence of a tumor-specific rearrangement breakpoint.
PRAD1 (previously D11S287) is a putative proto-oncogene at 11q13, activated by overexpression through gene rearrangement or gene amplification in several types of human tumors including parathyroid adenomas, centrocytic lymphomas and other B-cell tumors with t(11;14), and breast cancers. PRAD1 (also CCND1) encodes cyclin D1, which may regulate the G1-S phase transition in the cell cycle. Here, we report the cloning and characterization of the chromosomal PRAD1/cyclin D1 gene and the sequence of its promoter region. The gene spans about 15 kb and has 5 exons; its promoter region has Sp1 binding sites and no obvious TATA box, characteristics of housekeeping genes and growth-regulating genes. Furthermore, an E2F binding motif present close to the major transcription start site may be involved in cell cycle-dependent expression of this gene. We also report the sequence of DNAs spanning joining regions of a reciprocal parathyroid hormone/PRAD1 gene rearrangement in a parathyroid adenoma. Comparison with normal sequences suggests that the rearrangement was not a simple break-and-ligate event, but rather involved multiple steps, including two microdeletions and a microinversion. Very short sequences conserved near the breakpoints and symmetrical elements in the eventually inverted DNA segment might have played a role in this illegitimate complex recombination, which may have similarities with a constitutional translocation in Duchenne muscular dystrophy.
Motokura
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T
Endocrine Unit, Massachusetts General Hospital, Boston 02114.
Arnold
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A
D000236:Adenoma / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D003001:Cloning, Molecular; D019938:Cyclin D1; D016213:Cyclins / Q000235:genetics*; D004273:DNA, Neoplasm; D015321:Gene Rearrangement; D006801:Humans; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000235:genetics*; D010281:Parathyroid Hormone / Q000235:genetics; D010282:Parathyroid Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes; D012689:Sequence Homology, Nucleic Acid
D016213:Cyclins; D004273:DNA, Neoplasm; C000715470:MAS1 protein, human; D015513:Oncogene Proteins; D010281:Parathyroid Hormone; D000090063:Proto-Oncogene Mas; D019938:Cyclin D1