The hTERT and hTERC telomerase gene promoters are activated by the second exon of the adenoviral protein, E1A, identifying the transcriptional corepressor CtBP as a potential repressor of both genes.
Telomerase plays a role in the unlimited replicative capacity of the majority of cancer cells and provides a potential anticancer target. The regulation of telomerase is complex but transcriptional control of its two essential components, hTERC (RNA component) and hTERT (reverse transcriptase component), is of major importance. To investigate this further, we have used the adenoviral protein, E1A, as a tool to probe potential pathways involved in the control of telomerase transcription. The second exon of the adenoviral protein E1A activates both telomerase gene promoters in transient transfections. The corepressor, C terminal binding protein, is one of only two proteins known to bind to this region, and we propose that E1A activates both promoters by sequestering CtBP, thereby relieving repression. Activation by exon 2 of E1A involves the SP1 sites in both promoters, and consistent with this, SP1 and CtBP interact in coimmunoprecipitation studies. Modulation of the chromatin environment has been implicated in the regulation of hTERT transcription and appears to involve the SP1 sites. CtBP can be found within a histone-modifying complex and it is possible that a CtBP complex, associating with the SP1 sites, represses transcription from the telomerase promoters by modifying chromatin structure.
Glasspool
Rosalind M
RM
Cancer Research UK Centre for Oncology and Applied Pharmacology, University of Glasgow, Cancer Research UK Beatson Laboratories, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Burns
Sharon
S
Hoare
Stacey F
SF
Svensson
Catharina
C
Keith
W Nicol
WN
D017500:Adenovirus E1A Proteins / Q000235:genetics*; D000429:Alcohol Oxidoreductases; D015153:Blotting, Western; D002460:Cell Line; D002843:Chromatin / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D046911:Macromolecular Substances; D008957:Models, Genetic; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012313:RNA / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D019098:Telomerase / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection
D017500:Adenovirus E1A Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D010750:Phosphoproteins; D016329:Sp1 Transcription Factor; C422952:telomerase RNA; D012313:RNA; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; D008156:Luciferases; D019098:Telomerase