MSK1 functions as a transcriptional coactivator of p53 in the regulation of p21 gene expression

• Published in: Experimental & molecular medicine 2018, 50(0), , pp.1-12
• Main Authors: Ahn, Jihye, Lee, Jin Gyeong, Chin, Chuevin, In, Suna, Yang, Aerin, Park, Hee-Sung, Kim, Jaehoon, Park, Jeong Hyeon
• Format: Article
• Language: English
• Subjects: 13/89; 13/95; 38; 38/109; 38/77; 631/337/100/2285; 631/337/176; 631/337/572/2102; 82/83; Binding Sites; Biomedical and Life Sciences; Biomedicine; Cell Line; Chromatin; Chromatin - genetics; Chromatin - metabolism; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Extracellular signal-regulated kinase; Gene expression; Gene Expression Regulation; Histone H3; Histones - metabolism; Humans; Hydrophobicity; Kinases; MAP kinase; Medical Biochemistry; Models, Biological; Molecular Medicine; Mutation; p53 Protein; Phosphorylation; Promoter Regions, Genetic; Protein Binding; Ribosomal Protein S6 Kinases, 90-kDa - genetics; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; Serine; Stem Cells; Transcription; Transcription Factors - metabolism; Tumor Suppressor Protein p53 - metabolism; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-018-0160-8

Mitogen- and stress-activated kinase 1 (MSK1) is a chromatin kinase that facilitates activator-dependent transcription by altering chromatin structure through histone H3 phosphorylation. The kinase activity of MSK1 is activated by intramolecular autophosphorylation, which is initially triggered by the activation of upstream mitogen-activated protein kinases (MAPKs), such as p38 and ERK1/2. MSK1 has been implicated in the expression of p21 , a p53 target gene; however, the precise connection between MSK1 and p53 has not been clearly elucidated. Here, using in vitro and cell-based transcription assays, we show that MSK1 functions as a transcriptional coactivator of p53 in p21 expression, an action associated with MAPK-dependent phosphorylation of MSK1 and elevated kinase activity. Of special significance, we show that MSK1 directly interacts with p53 and is recruited to the p21 promoter, where it phosphorylates histone H3 in a p53-dependent manner. In addition, phosphomimetic mutant analysis demonstrated that negative charges in the hydrophobic motif are critical for serine 212 phosphorylation in the N-terminal kinase domain, which renders MSK1 competent for histone kinase activity. These studies suggest that MSK1 acts through a direct interaction with p53 to function as a transcriptional coactivator and that MSK1 activation by upstream MAPK signaling is important for efficient p21 gene expression. Tumor suppression: another link in a signaling chain New drugs to fight tumors could be developed, thanks to research revealing how a protein called MSK1 interacts with and assists another protein, “p53,” which has well-established tumor-suppressing activity. Researchers led by Jeong Hyeon Park at Massey University in New Zealand and Jaehoon Kim at the Korea Advanced Institute of Science and Technology in South Korea studied the function of the MSK1 protein in cultured human cells. They uncovered details of a previously unknown direct interaction between the MSK1 and p53 proteins. This allows the MSK1-p53 combination to increase the activity of a gene that codes for another protein, p21. The p21 protein then participates in further molecular processes that can restrict cell growth and multiplication. Drugs that control MSK1 activity might offer new opportunities to combat the uncontrolled multiplication of cancer cells.