TEL, a putative tumor suppressor, modulates cell growth and cell morphology of Ras-transformed cells while repressing the transcription of stromelysin-1

被引:91
作者
Fenrick, R
Wang, LL
Nip, J
Amann, JM
Rooney, RJ
Walker-Daniels, J
Crawford, HC
Hulboy, DL
Kinch, MS
Matrisian, LM
Hiebert, SW
机构
[1] Vanderbilt Univ, Med Ctr, Sch Med, Vanderbilt Ingram Canc Ctr,Dept Biochem, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Med Ctr, Sch Med, Dept Cell Biol, Nashville, TN 37232 USA
[3] Duke Univ, Sch Med, Dept Genet, Durham, NC 27715 USA
[4] Purdue Univ, Dept Basic Med Sci, W Lafayette, IN 47907 USA
关键词
D O I
10.1128/MCB.20.16.5828-5839.2000
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 NM 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.
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页码:5828 / 5839
页数:12
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