The topoisomerase I- and p53-binding protein topors is differentially expressed in normal and malignant human tissues and may function as a tumor suppressor.
Topors was identified recently as a human protein that binds to topoisomerase I and p53. Topors contains a highly conserved RING domain and localizes in promyelocytic leukemia nuclear bodies. Relatively little is known regarding topors expression patterns or function. We now demonstrate that topors mRNA and protein are widely expressed in normal human tissues. By contrast, topors mRNA and protein levels are decreased or undetectable in colon adenocarcinomas relative to normal colon tissue, and expression of the topors protein is not detectable in several colon cancer cell lines. The human TOPORS gene is located on chromosome 9p21, with loss of heterozygosity in this region frequently observed in several different malignancies. While we were unable to detect loss of heterozygosity of the TOPORS gene in 16 sporadic colon cancer cases, increased methylation of a CpG island in the TOPORS promoter was evident in colon adenocarcinoma specimens relative to matched normal tissues. Additional studies indicate that forced expression of topors inhibits cellular proliferation and is associated with an accumulation of cells in the G(0)/G(1) phase of the cell cycle. This effect is independent of the topors RING domain and maps to a C-terminal region of the protein. These results suggest that topors functions as a negative regulator of cell growth, and possibly as a tumor suppressor.
Saleem
Ahamed
A
Department of Pharmacology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ, USA.
Dutta
Jayeeta
J
Malegaonkar
Diptee
D
Rasheed
Farheena
F
Rasheed
Zeshaan
Z
Rajendra
Rajeev
R
Marshall
Henderson
H
Luo
Minje
M
Li
Honghua
H
Rubin
Eric H
EH
D000230:Adenocarcinoma / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis*; D002453:Cell Cycle; D002455:Cell Division; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D005434:Flow Cytometry; D016193:G1 Phase; D016147:Genes, Tumor Suppressor; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D019656:Loss of Heterozygosity; D008164:Luminescent Proteins / Q000378:metabolism; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000096:biosynthesis*; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D016192:Resting Phase, Cell Cycle; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D014157:Transcription Factors / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D020298:U937 Cells; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D008164:Luminescent Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D049452:Green Fluorescent Proteins; C120157:TOPORS protein, human; D044767:Ubiquitin-Protein Ligases; D013936:Thymidine