Axl-gas6 interaction counteracts E1A-mediated cell growth suppression and proapoptotic activity.
The adenovirus type 5 early region 1A gene (E1A) has previously been known as an immortalization oncogene because E1A is required for transforming oncogenes, such as ras and E1B, to transform cells in primary cultures. However, E1A has also been shown to downregulate the overexpression of the Her-2/neu oncogene, resulting in suppression of transformation and tumorigenesis induced by that oncogene. In addition, E1A is able to promote apoptosis induced by anticancer drugs, irradiation, and serum deprivation. Many tyrosine kinases, such as the epidermal growth factor receptor, Her-2/Neu, Src, and Axl, are known to play a role in oncogenic signals in transformed cells. To study the mechanism underlying the E1A-mediated tumor-suppressing function, we exploited a modified tyrosine kinase profile assay (D. Robinson, F. Lee, T. Pretlow, and H.-J. Kung, Proc. Natl. Acad. Sci. USA 93:5958-5962, 1996) to identify potential tyrosine kinases regulated by E1A. Reverse transcription (RT)-PCR products were synthesized with two degenerate primers derived from the conserved motifs of various tyrosine kinases. A tyrosine kinase downregulated by E1A was identified by analyzing the AluI-digested RT-PCR products. We isolated the DNA fragment of interest and found that E1A negatively regulated the expression of the transforming receptor tyrosine kinase Axl at the transcriptional level. To study whether downregulation of the Axl receptor is involved in E1A-mediated growth suppression, we transfected axl cDNA into E1A-expressing cells (ip1-E1A) to establish cells that overexpressed Axl. The Axl ligand Gas6 triggered a greater mitogenic effect in these ip1-E1A-Axl cells than in ip1-E1A control cells and protected the Axl-expressing cells from serum deprivation-induced apoptosis. These results indicate that downregulation of the Axl receptor by E1A is involved in E1A-mediated growth suppression and E1A-induced apoptosis and thereby contributes to E1A's antitumor activities.
Lee
W P
WP
Department of Cancer Biology, Section of Molecular Cell Biology and Breast Cancer Research Program, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Liao
Y
Y
Robinson
D
D
Kung
H J
HJ
Liu
E T
ET
Hung
M C
MC
D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D002455:Cell Division; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008934:Mitogens; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
D017500:Adenovirus E1A Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008934:Mitogens; D015513:Oncogene Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C000722289:AXL protein, human