E1A deregulates the centrosome cycle in a Ran GTPase-dependent manner.
By means of the yeast two-hybrid system, we have discovered a novel physical interaction between the adenovirus E1A oncoprotein and Ran, a small GTPase which regulates nucleocytoplasmic transport, cell cycle progression, and mitotic spindle organization. Expression of E1A elicits induction of S phase and centrosome amplification in a variety of ... rodent cell lines. The induction of supernumerary centrosomes requires functional RCC1, the nucleotide exchange factor for Ran and, hence, a functional Ran network. The E1A portion responsible for the interaction with Ran is the extreme NH(2)-terminal region (amino acids 1-36), which is also required for the induction of centrosome amplification. In an in vitro assay with recombinant proteins, wild-type E1A interferes with nucleotide exchange on Ran, whereas an E1A mutant, deleted from the extreme NH(2)-terminal region, does not. In addition, we detected an in vitro interaction between Ran and HPV-16 E7 and SV40 large T antigen, two oncoproteins functionally related to E1A. These findings suggest a common pathway of these oncoproteins in eliciting virus-induced genomic instability.
Mesh Terms:
3T3 Cells, Adenovirus E1A Proteins, Animals, Antigens, Polyomavirus Transforming, Cell Cycle Proteins, Cell Line, Centrosome, Cricetinae, Guanine Nucleotide Exchange Factors, Hela Cells, Humans, Mice, Nuclear Proteins, Oncogene Proteins, Viral, S Phase, Subcellular Fractions, Transfection, ran GTP-Binding Protein
3T3 Cells, Adenovirus E1A Proteins, Animals, Antigens, Polyomavirus Transforming, Cell Cycle Proteins, Cell Line, Centrosome, Cricetinae, Guanine Nucleotide Exchange Factors, Hela Cells, Humans, Mice, Nuclear Proteins, Oncogene Proteins, Viral, S Phase, Subcellular Fractions, Transfection, ran GTP-Binding Protein
Cancer Res.
Date: Mar. 15, 2003
PubMed ID: 12649209
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