C-terminal p73 isoforms repress transcriptional activity of the human telomerase reverse transcriptase (hTERT) promoter.
Activation of telomerase is linked to tumorigenesis and has been observed in a variety of human tumors. Previous reports demonstrated that p53 represses human telomerase reverse transcriptase (hTERT), a key component for telomerase activity. The p73 protein displays a tumor suppressor activity similar to p53. In the present study, we examined the effect of transactivation competent p73 isoforms on hTERT expression in p53-negative human H1299 cells. Overexpression of C-terminal p73 isoforms (alpha, beta, gamma, delta) resulted in a clear down-regulation of hTERT promoter activity. The strongest inhibitory effect, comparable with p53, was observed for p73beta. Moreover, suppression of hTERT expression was also mediated by endogenous p73 after activation of E2F1 in H1299ER-E2F1 cells. Mutations in the Sp1 transcription factor-binding sites of the proximal core promoter region significantly abolished p73-induced repression, suggesting that the effect is mediated by Sp1. Finally, we demonstrate that p73 directly interacts with Sp1, suggesting that formation of a p73-Sp1 complex is the underlying mechanism for p73-triggered inhibition of hTERT expression. Our findings provide additional evidence that p73 mimics p53 in many aspects in cells lacking functional p53, thereby contributing to tumor surveillance.
Racek
Tomás
T
Department of Vectorology and Experimental Gene Therapy, University of Rostock Medical School, Schillingallee 70, 18057 Rostock, Germany.
Mise
Nikica
N
Li
Zhenpeng
Z
Stoll
Anja
A
Pützer
Brigitte M
BM
D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D008156:Luciferases / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D012326:RNA Splicing; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000502:physiology; D019098:Telomerase / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000502:physiology; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D020033:Protein Isoforms; D016329:Sp1 Transcription Factor; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D008156:Luciferases; D019098:Telomerase