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Molecular and Cellular Biology, December 1999, p. 8075-8082, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Axl-Gas6 Interaction Counteracts E1A-Mediated Cell Growth Suppression and Proapoptotic Activity

Wei-Ping Lee,1 Yong Liao,1 Dan Robinson,2 Hsing-Jien Kung,2 Edison T. Liu,3 and Mien-Chie Hung1,*

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 770301; The University of California-Davis Cancer Center, Sacramento, California 958172; and Division of Clinical Sciences, National Cancer Institute, Bethesda, Maryland 208923

Received 20 July 1999/Returned for modification 31 August 1999/Accepted 16 September 1999

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.

* Corresponding author. Mailing address: 1515 Holcombe Blvd., Section of Molecular Cell Biology Box 108, Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030. Phone: (713) 792-3668. Fax: (713) 794-0209. E-mail: mchung{at}notes.mdacc.tmc.edu.

Molecular and Cellular Biology, December 1999, p. 8075-8082, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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Copyright © 1999 by the American Society for Microbiology. All rights reserved.