CDK8 regulates E2F1 transcriptional activity through S375 phosphorylation
- PMID: 22945643
- DOI: 10.1038/onc.2012.364
CDK8 regulates E2F1 transcriptional activity through S375 phosphorylation
Abstract
Activation of the Wnt/β-catenin pathway is a critical step in the development of colorectal cancers. A key mediator of this activation is the recently described oncogene CDK8, which is amplified in a large number of colorectal tumors. CDK8 affects β-catenin activation by interaction of the CDK8 submodule of the mediator complex with β-catenin/TCF transcriptional complex, and by CDK8 interacting with and phosphorylating E2F1, which acts as a repressor of β-catenin/TCF transcriptional activity. The amino-acid residue in E2F1 that CDK8 phosphorylates and how this phosphorylation impacts E2F1 activity in general is not known. Here, we describe that CDK8 phosphorylates serine 375 in E2F1 both in vitro and in cells, and that phosphorylation of this residue is required for E2F1 interaction with CDK8, and that the phosphorylation is dependent on CDK8 kinase activity. The phosphorylation of S375 by CDK8 regulates E2F1 ability to repress transcription of β-catenin/TCF-dependent genes, as well as activation of E2F1-dependent genes. This regulation is due to inactivation of E2F1 transcriptional activation, and not to the interference of E2F1's ability to bind to E2F1-binding sites in various promoters or to interact with DP1.
Similar articles
-
Role of CDK8 and beta-catenin in colorectal adenocarcinoma.Oncol Rep. 2010 Jul;24(1):285-91. Oncol Rep. 2010. PMID: 20514474
-
E2F1 represses beta-catenin transcription and is antagonized by both pRB and CDK8.Nature. 2008 Sep 25;455(7212):552-6. doi: 10.1038/nature07310. Epub 2008 Sep 14. Nature. 2008. PMID: 18794899 Free PMC article.
-
E2F1 suppresses Wnt/β-catenin activity through transactivation of β-catenin interacting protein ICAT.Oncogene. 2011 Sep 15;30(37):3979-84. doi: 10.1038/onc.2011.129. Epub 2011 May 2. Oncogene. 2011. PMID: 21532622
-
The two faces of Cdk8, a positive/negative regulator of transcription.Biochimie. 2014 Feb;97:22-7. doi: 10.1016/j.biochi.2013.10.004. Epub 2013 Oct 15. Biochimie. 2014. PMID: 24139904 Review.
-
Cyclin-Dependent Kinase 8: A New Hope in Targeted Cancer Therapy?J Med Chem. 2018 Jun 28;61(12):5073-5092. doi: 10.1021/acs.jmedchem.7b00901. Epub 2018 Jan 9. J Med Chem. 2018. PMID: 29266937 Review.
Cited by
-
Knockout of ICAT in Adipose Tissue Alleviates Fibro-inflammation in Obese Mice.Inflammation. 2023 Feb;46(1):404-417. doi: 10.1007/s10753-022-01742-w. Epub 2022 Oct 1. Inflammation. 2023. PMID: 36181623
-
A Selective and Orally Bioavailable Quinoline-6-Carbonitrile-Based Inhibitor of CDK8/19 Mediator Kinase with Tumor-Enriched Pharmacokinetics.J Med Chem. 2022 Feb 24;65(4):3420-3433. doi: 10.1021/acs.jmedchem.1c01951. Epub 2022 Feb 3. J Med Chem. 2022. PMID: 35114084 Free PMC article.
-
Cdk8 Kinase Module: A Mediator of Life and Death Decisions in Times of Stress.Microorganisms. 2021 Oct 15;9(10):2152. doi: 10.3390/microorganisms9102152. Microorganisms. 2021. PMID: 34683473 Free PMC article. Review.
-
Targeting transcription cycles in cancer.Nat Rev Cancer. 2022 Jan;22(1):5-24. doi: 10.1038/s41568-021-00411-8. Epub 2021 Oct 21. Nat Rev Cancer. 2022. PMID: 34675395 Review.
-
Gene Transcription as a Therapeutic Target in Leukemia.Int J Mol Sci. 2021 Jul 8;22(14):7340. doi: 10.3390/ijms22147340. Int J Mol Sci. 2021. PMID: 34298959 Free PMC article. Review.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases