Hdm2 negatively regulates telomerase activity by functioning as an E3 ligase of hTERT
| Autor: | Andrew H. Ko, Eun-Woo Lee, Dong-Hoon Lee, Wonkyung Oh, Choi Cy, Hye Won Lee, Yong-Soo Bae, Jaewhan Song, Mi-Ran Yang, Yoon Ch |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
Telomerase Immunoprecipitation cells Ubiquitin-Protein Ligases Biology Ubiquitin Cell Line Tumor Genetics medicine Humans Post-translational regulation Telomerase reverse transcriptase neoplasms Molecular Biology Lysine Ubiquitination Proto-Oncogene Proteins c-mdm2 Molecular biology Ubiquitin ligase enzymes and coenzymes (carbohydrates) Cell culture embryonic structures Proteasome inhibitor biology.protein biological phenomena cell phenomena and immunity medicine.drug |
| Zdroj: | Oncogene. 29(28) |
| ISSN: | 1476-5594 |
| Popis: | In this study, we identified posttranslational regulation of human telomerase reverse-transcriptase (hTERT) by the E3 ligase Hdm2. The telomerase activity generated by exogenous hTERT in U2OS cells was reduced on adriamycin treatment. The overexpressed levels of hTERT were also decreased under the same conditions. These processes were reversed by treatment with a proteasome inhibitor or depletion of Hdm2. Furthermore, intrinsic telomerase activity was increased in HCT116 cells with ablation of Hdm2. Immunoprecipitation analyses showed that hTERT and Hdm2 bound to each other in multiple domains. Ubiquitination analyses showed that Hdm2 could polyubiquitinate hTERT principally at the N-terminus, which was further degraded in a proteasome-dependent manner. An hTERT mutant with all five lysine residues at the N-terminus of hTERT that mutated to arginine became resistant to Hdm2-mediated ubiquitination and degradation. In U2OS cells, depletion of Hdm2 or addition of the Hdm2-resistant hTERT mutant strengthened the cellular protective effects against apoptosis. Similar results were obtained with the Hdm2-stable H1299 cell line. These observations indicate that Hdm2 is an E3 ligase of hTERT. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|