ERK Dephosphorylation through MKP1 Deacetylation by SIRT1 Attenuates RAS-Driven Tumorigenesis
The role of Situin 1 (SIRT1) in tumorigenesis is still controversial due to its wide range of substrates, including both oncoproteins and tumor suppressors. A recent study has demonstrated that SIRT1 interferes in the Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven activation of the Raf-mit...
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MDPI AG
2020-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/4/909 |
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| author | Ok-Seon Kwon Haeseung Lee Yun-Jeong Kim Hyuk-Jin Cha Na-Young Song Mi-Ok Lee |
| author_facet | Ok-Seon Kwon Haeseung Lee Yun-Jeong Kim Hyuk-Jin Cha Na-Young Song Mi-Ok Lee |
| author_sort | Ok-Seon Kwon |
| collection | DOAJ |
| description | The role of Situin 1 (SIRT1) in tumorigenesis is still controversial due to its wide range of substrates, including both oncoproteins and tumor suppressors. A recent study has demonstrated that SIRT1 interferes in the Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven activation of the Raf-mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway, thereby inhibiting tumorigenesis. However, the molecular mechanism of SIRT1 as a tumor suppressor in RAS-driven tumorigenesis has been less clearly determined. This study presents evidence that the ectopic expression of SIRT1 attenuates RAS- or MEK-driven ERK activation and reduces cellular proliferation and transformation in vitro. The attenuation of ERK activation by SIRT1 results from prompt dephosphorylation of ERK, while MEK activity remains unchanged. We identified that MKP1, a dual specific phosphatase for MAPK, was deacetylated by SIRT1. Deacetylation of MKP1 by direct interaction with SIRT1 increased the binding affinity to ERK which in turn facilitated inactivation of ERK. Taken together, these results suggest that SIRT1 would act as a tumor suppressor by modulating RAS-driven ERK activity through MKP1 deacetylation. |
| first_indexed | 2024-03-10T20:35:31Z |
| format | Article |
| id | doaj.art-1528759014744cf19ec0f92aad5a8da6 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T20:35:31Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-1528759014744cf19ec0f92aad5a8da62023-11-19T21:01:57ZengMDPI AGCancers2072-66942020-04-0112490910.3390/cancers12040909ERK Dephosphorylation through MKP1 Deacetylation by SIRT1 Attenuates RAS-Driven TumorigenesisOk-Seon Kwon0Haeseung Lee1Yun-Jeong Kim2Hyuk-Jin Cha3Na-Young Song4Mi-Ok Lee5Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaIntellectual Information Team, Future Medicine Division, Korea Institute of Oriental Medicine, Daejeon 34054, KoreaCollege of Pharmacy, Seoul National University, Seoul 08826, KoreaCollege of Pharmacy, Seoul National University, Seoul 08826, KoreaDepartment of Oral Biology, Yonsei University College of Dentistry, Seoul 03722, KoreaStem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaThe role of Situin 1 (SIRT1) in tumorigenesis is still controversial due to its wide range of substrates, including both oncoproteins and tumor suppressors. A recent study has demonstrated that SIRT1 interferes in the Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven activation of the Raf-mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway, thereby inhibiting tumorigenesis. However, the molecular mechanism of SIRT1 as a tumor suppressor in RAS-driven tumorigenesis has been less clearly determined. This study presents evidence that the ectopic expression of SIRT1 attenuates RAS- or MEK-driven ERK activation and reduces cellular proliferation and transformation in vitro. The attenuation of ERK activation by SIRT1 results from prompt dephosphorylation of ERK, while MEK activity remains unchanged. We identified that MKP1, a dual specific phosphatase for MAPK, was deacetylated by SIRT1. Deacetylation of MKP1 by direct interaction with SIRT1 increased the binding affinity to ERK which in turn facilitated inactivation of ERK. Taken together, these results suggest that SIRT1 would act as a tumor suppressor by modulating RAS-driven ERK activity through MKP1 deacetylation.https://www.mdpi.com/2072-6694/12/4/909SIRT1RASERKMKP1tumorigenesisdeacetylation |
| spellingShingle | Ok-Seon Kwon Haeseung Lee Yun-Jeong Kim Hyuk-Jin Cha Na-Young Song Mi-Ok Lee ERK Dephosphorylation through MKP1 Deacetylation by SIRT1 Attenuates RAS-Driven Tumorigenesis Cancers SIRT1 RAS ERK MKP1 tumorigenesis deacetylation |
| title | ERK Dephosphorylation through MKP1 Deacetylation by SIRT1 Attenuates RAS-Driven Tumorigenesis |
| title_full | ERK Dephosphorylation through MKP1 Deacetylation by SIRT1 Attenuates RAS-Driven Tumorigenesis |
| title_fullStr | ERK Dephosphorylation through MKP1 Deacetylation by SIRT1 Attenuates RAS-Driven Tumorigenesis |
| title_full_unstemmed | ERK Dephosphorylation through MKP1 Deacetylation by SIRT1 Attenuates RAS-Driven Tumorigenesis |
| title_short | ERK Dephosphorylation through MKP1 Deacetylation by SIRT1 Attenuates RAS-Driven Tumorigenesis |
| title_sort | erk dephosphorylation through mkp1 deacetylation by sirt1 attenuates ras driven tumorigenesis |
| topic | SIRT1 RAS ERK MKP1 tumorigenesis deacetylation |
| url | https://www.mdpi.com/2072-6694/12/4/909 |
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