Authors: 
Brown LK, Tersteege L, Burke P, Piatyszek MA, Andrews WH, Briggs LA, Wheeler J, Foster CA.
Category: 
Poster
Conference: 
Abstract: 

The inability to maintain telomere length in normal human cells lacking human telomerase (hTERT) activity results in cellular aging or replicative senescence. The identification of small molecules that induce telomerase activity in these normal cells may be useful for basic research aimed at studying telomerase regulation. Additionally, molecules found to induce hTERT expression, with high target selectivity, can possibly be used in therapeutic applications directed to alleviate or delay symptoms of aging. A high throughput screening (HTS) effort by Sierra Sciences L.L.C. of a chemical library of 312,000 small molecules resulted in the identification of several compounds that can induce hTERT transcription in normal human fibroblasts.

One of these, C0057684, was the subject of detailed evaluation in secondary assays. A critical question was to clarify if C0057684 is a specific hTERT inducer, or if it has a broader effect on transcriptional activity at Chromosome 5p15.33. To examine expression levels of genes upstream and downstream of the hTERT locus after treatment with C0057684, we used Real-Time PCR on 20 different transcripts representing all the genes in the immediate proximity of the hTERT locus. Several genes, in addition to hTERT, were found to have increased transcription levels upon treatment with C0057684. Treatment of MRC5 and BJ cells with C0057684 did not, however, result in a decrease in transcription levels of any evaluated genes. Interestingly, there was no correlation between transcriptional activity and positions or orientations of genes relative to hTERT. Though our goal was to find compounds that specifically induce expression of hTERT, our data shows that C0057684 affects expression of other genes as well.