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

TEL is a member of the ETS family of transcription Factors that interacts w ith the mSin3 and SMRT corepressors to regulate transcription. TEL is biall elically disrupted in acute leukemia, and loss of heterozygosity at the TEL locus has been observed in various cancers. Here we show that expression o f 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 a s aggregates. To begin to explain the morphology of Ras-plus TEL-expressing cells, we demonstrated that the endogenous matrix metalloproteinase strome lysin-1 was repressed by TEL. TEL bound sequences in the stromelysin-1 prom oter 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 do main failed to repress stromelysin-1, When BB-94, a matrix metalloproteinas e inhibitor, was added to the culture medium of Ras-expressing cells, it ca used a cell aggregation phenotype similar to that caused by TEL expression. In addition, TEL inhibited the invasiveness of Ras-transformed cells in vi tro and in vivo. Our results suggest that TEL acts as a tumor suppressor, i n part, by transcriptional repression of stromelysin-1.