TEL, a putative tumor suppressor, induces apoptosis and represses transcription of Bcl-XL
Brenda J Irvin1, Lauren D Wood, Lilin Wang
1Department of Biochemistry, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Preston Research Building, 23rd and Pierce, Nashville, TN 37232, USA.
Abstract:
The ETS family transcriptional repressor TEL is frequently disrupted by chromosomal translocations, including the t(12;21) in which the second allele of TEL is deleted in up to 90% of the cases. Consistent with its role as a putative tumor suppressor, TEL expression inhibits colony formation by Ras-transformed NIH 3T3 cells and hinders proliferation of a variety of cell types. Although we observed no alteration in the cell cycle of TEL-expressing cells, we did find a marked increase in apoptosis of serum-starved TEL-expressing NIH 3T3 cells. This decrease in cell survival required the DNA binding domain of TEL, suggesting that TEL repressed an anti-apoptotic gene. These observations prompted us to search for genes regulated by ETS family proteins that regulate apoptosis. The anti-apoptotic molecule Bcl-XL contains multiple ets-factor binding sites within its promoters, and TEL repressed a Bcl-XL promoter-linked reporter gene. Moreover, the enforced expression of TEL decreased the endogenous expression of both Bcl-XL mRNA and protein. TEL-mediated repression of Bcl-XL likely affects cell survival via regulation of the apoptotic pathway.
Insights
The transcriptional repressor TEL, a tumor suppressor, inhibits cell growth and promotes apoptosis. TEL directly represses the anti-apoptotic gene Bcl-XL, impacting cell survival pathways.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- The ETS family transcriptional repressor TEL is frequently disrupted by chromosomal translocations.
- TEL functions as a putative tumor suppressor, inhibiting cell proliferation and colony formation.
Purpose of the Study:
- To investigate the role of TEL in apoptosis regulation.
- To identify genes regulated by TEL that influence cell survival.
Main Methods:
- Assessing the effect of TEL expression on NIH 3T3 cell proliferation and apoptosis.
- Investigating the mechanism of TEL-mediated apoptosis, focusing on the DNA binding domain.
- Analyzing the regulation of the anti-apoptotic gene Bcl-XL by TEL using reporter gene assays and mRNA/protein expression analysis.
Main Results:
- TEL expression inhibited colony formation and proliferation of Ras-transformed NIH 3T3 cells.
- TEL expression led to increased apoptosis in serum-starved NIH 3T3 cells, dependent on its DNA binding domain.
- TEL repressed Bcl-XL promoter activity and decreased endogenous Bcl-XL mRNA and protein levels.
Conclusions:
- TEL acts as a tumor suppressor by repressing the anti-apoptotic gene Bcl-XL.
- TEL-mediated repression of Bcl-XL impacts cell survival through the apoptotic pathway.
- These findings elucidate a novel mechanism of tumor suppression by TEL involving the regulation of apoptosis.
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