ELL targets c-Myc for proteasomal degradation and suppresses tumour growth
Abstract Increasing evidence supports that ELL (eleven–nineteen lysine-rich leukaemia) is a key regulator of transcriptional elongation, but the physiological function of Ell in mammals remains elusive. Here we show that ELL functions as an E3 ubiquitin ligase and targets c-Myc for proteasomal degra...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2016-03-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/ncomms11057 |
| _version_ | 1797827426055618560 |
|---|---|
| author | Yu Chen Chi Zhou Wei Ji Zhichao Mei Bo Hu Wei Zhang Dawei Zhang Jing Wang Xing Liu Gang Ouyang Jiangang Zhou Wuhan Xiao |
| author_facet | Yu Chen Chi Zhou Wei Ji Zhichao Mei Bo Hu Wei Zhang Dawei Zhang Jing Wang Xing Liu Gang Ouyang Jiangang Zhou Wuhan Xiao |
| author_sort | Yu Chen |
| collection | DOAJ |
| description | Abstract Increasing evidence supports that ELL (eleven–nineteen lysine-rich leukaemia) is a key regulator of transcriptional elongation, but the physiological function of Ell in mammals remains elusive. Here we show that ELL functions as an E3 ubiquitin ligase and targets c-Myc for proteasomal degradation. In addition, we identify that UbcH8 serves as a ubiquitin-conjugating enzyme in this pathway. Cysteine 595 of ELL is an active site of the enzyme; its mutation to alanine (C595A) renders the protein unable to promote the ubiquitination and degradation of c-Myc. ELL-mediated c-Myc degradation inhibits c-Myc-dependent transcriptional activity and cell proliferation, and also suppresses c-Myc-dependent xenograft tumour growth. In contrast, the ELL(C595A) mutant not only loses the ability to inhibit cell proliferation and xenograft tumour growth, but also promotes tumour metastasis. Thus, our work reveals a previously unrecognized function for ELL as an E3 ubiquitin ligase for c-Myc and a potential tumour suppressor. |
| first_indexed | 2024-04-09T12:48:06Z |
| format | Article |
| id | doaj.art-2167e5b4fc6f436d93e5b23325c17d9c |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-09T12:48:06Z |
| publishDate | 2016-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-2167e5b4fc6f436d93e5b23325c17d9c2023-05-14T11:20:42ZengNature PortfolioNature Communications2041-17232016-03-017111510.1038/ncomms11057ELL targets c-Myc for proteasomal degradation and suppresses tumour growthYu Chen0Chi Zhou1Wei Ji2Zhichao Mei3Bo Hu4Wei Zhang5Dawei Zhang6Jing Wang7Xing Liu8Gang Ouyang9Jiangang Zhou10Wuhan Xiao11The Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of SciencesThe Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of SciencesThe Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of SciencesThe Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of SciencesThe Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of SciencesThe Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of SciencesThe Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of SciencesThe Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of SciencesThe Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of SciencesThe Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of SciencesThe Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of SciencesThe Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of SciencesAbstract Increasing evidence supports that ELL (eleven–nineteen lysine-rich leukaemia) is a key regulator of transcriptional elongation, but the physiological function of Ell in mammals remains elusive. Here we show that ELL functions as an E3 ubiquitin ligase and targets c-Myc for proteasomal degradation. In addition, we identify that UbcH8 serves as a ubiquitin-conjugating enzyme in this pathway. Cysteine 595 of ELL is an active site of the enzyme; its mutation to alanine (C595A) renders the protein unable to promote the ubiquitination and degradation of c-Myc. ELL-mediated c-Myc degradation inhibits c-Myc-dependent transcriptional activity and cell proliferation, and also suppresses c-Myc-dependent xenograft tumour growth. In contrast, the ELL(C595A) mutant not only loses the ability to inhibit cell proliferation and xenograft tumour growth, but also promotes tumour metastasis. Thus, our work reveals a previously unrecognized function for ELL as an E3 ubiquitin ligase for c-Myc and a potential tumour suppressor.https://doi.org/10.1038/ncomms11057 |
| spellingShingle | Yu Chen Chi Zhou Wei Ji Zhichao Mei Bo Hu Wei Zhang Dawei Zhang Jing Wang Xing Liu Gang Ouyang Jiangang Zhou Wuhan Xiao ELL targets c-Myc for proteasomal degradation and suppresses tumour growth Nature Communications |
| title | ELL targets c-Myc for proteasomal degradation and suppresses tumour growth |
| title_full | ELL targets c-Myc for proteasomal degradation and suppresses tumour growth |
| title_fullStr | ELL targets c-Myc for proteasomal degradation and suppresses tumour growth |
| title_full_unstemmed | ELL targets c-Myc for proteasomal degradation and suppresses tumour growth |
| title_short | ELL targets c-Myc for proteasomal degradation and suppresses tumour growth |
| title_sort | ell targets c myc for proteasomal degradation and suppresses tumour growth |
| url | https://doi.org/10.1038/ncomms11057 |
| work_keys_str_mv | AT yuchen elltargetscmycforproteasomaldegradationandsuppressestumourgrowth AT chizhou elltargetscmycforproteasomaldegradationandsuppressestumourgrowth AT weiji elltargetscmycforproteasomaldegradationandsuppressestumourgrowth AT zhichaomei elltargetscmycforproteasomaldegradationandsuppressestumourgrowth AT bohu elltargetscmycforproteasomaldegradationandsuppressestumourgrowth AT weizhang elltargetscmycforproteasomaldegradationandsuppressestumourgrowth AT daweizhang elltargetscmycforproteasomaldegradationandsuppressestumourgrowth AT jingwang elltargetscmycforproteasomaldegradationandsuppressestumourgrowth AT xingliu elltargetscmycforproteasomaldegradationandsuppressestumourgrowth AT gangouyang elltargetscmycforproteasomaldegradationandsuppressestumourgrowth AT jiangangzhou elltargetscmycforproteasomaldegradationandsuppressestumourgrowth AT wuhanxiao elltargetscmycforproteasomaldegradationandsuppressestumourgrowth |