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Molecular and Cellular Biology, August 2000, p. 5828-5839, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

TEL, a Putative Tumor Suppressor, Modulates Cell Growth and Cell Morphology of Ras-Transformed Cells While Repressing the Transcription of stromelysin-1

Randy Fenrick,1,2 Lilin Wang,1,2 John Nip,1,2 Joseph M. Amann,1,2 Robert J. Rooney,3 Jennifer Walker-Daniels,4 Howard C. Crawford,2,5 Diana L. Hulboy,2,5 Michael S. Kinch,4 Lynn M. Matrisian,2,5 and Scott W. Hiebert1,2,*

Departments of Biochemistry1 and Cell Biology5 and Vanderbilt-Ingram Cancer Center,2 Vanderbilt University School of Medicine, Nashville, Tennessee 37232; Department of Genetics, Duke University Medical School, Durham, North Carolina 27715-30543; and Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana 479074

Received 8 December 1999/Returned for modification 14 February 2000/Accepted 12 May 2000

TEL is a member of the ETS family of transcription factors that interacts with the mSin3 and SMRT corepressors to regulate transcription. TEL is biallelically disrupted in acute leukemia, and loss of heterozygosity at the TEL locus has been observed in various cancers. Here we show that expression of TEL in Ras-transformed NIH 3T3 cells inhibits cell growth in soft agar and in normal cultures. Unexpectedly, cells expressing both Ras and TEL grew as aggregates. To begin to explain the morphology of Ras-plus TEL-expressing cells, we demonstrated that the endogenous matrix metalloproteinase stromelysin-1 was repressed by TEL. TEL bound sequences in the stromelysin-1 promoter and repressed the promoter in transient-expression assays, suggesting that it is a direct target for TEL-mediated regulation. Mutants of TEL that removed a binding site for the mSin3A corepressor but retained the ETS domain failed to repress stromelysin-1. When BB-94, a matrix metalloproteinase inhibitor, was added to the culture medium of Ras-expressing cells, it caused a cell aggregation phenotype similar to that caused by TEL expression. In addition, TEL inhibited the invasiveness of Ras-transformed cells in vitro and in vivo. Our results suggest that TEL acts as a tumor suppressor, in part, by transcriptional repression of stromelysin-1.

* Corresponding author. Mailing address: Department of Biochemistry, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Rm 512 Medical Research Building II, Nashville, TN 37232. Phone: (615) 936-3582. Fax: (615) 936-1790. E-mail: scott.hiebert{at}mcmail.vanderbilt.edu.

Molecular and Cellular Biology, August 2000, p. 5828-5839, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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