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

Abstract

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.

PKC-mediated phosphorylation and activation of the MEK/ERK pathway as a mechanism of acquired trastuzumab resistance in HER2-positive breast cancer

“…T15 also showed hyper-activation of the ribosomal protein S6 kinase α-5 protein, MSK1 (log 2 FC(pMSK1 ser376 ) = +1.9; Figure 1 ). MSK1 is directly phosphorylated by MAPKs at serine 360, threonine 581, and threonine 700, and subsequently autophosphorylates at serine 376 for protein activation ( 37 ). Seemingly conflicting roles for MSK1 in breast cancer have been described: it shows tumor suppressor functions by acting as a transcriptional coactivator of P53 and mediating phosphorylation of histone H3 in the transcriptional activation of p21 ( 37 ), but has also been associated with epithelial-mesenchymal transition (EMT) and subsequent skeletal metastasis by histone H3 acetylation and phosphorylation of Snail, which downregulates E-cadherin to promote cellular migration and invasion ( 38 ).…”

Genetic Encoding of Phosphorylated Amino Acids into Proteins

“…These results highlight the complex nature of phosphorylation and acetylation cross-talk in regulating histone function. In other work, Ahn et al 165 in 2018 showed through in vitro assays that histone phosphorylation by mitogen-and stressactivated kinase 1 (MSK1) stimulated transcription at p53dependent gene promoters. To pinpoint the phospho-sites involved, they used GCE to encode pSer at sites Ser10 and Ser28 of histone H3, and showed that while both sites enhanced p53dependent gene transcription, phosphorylation at Ser10 had a greater impact.…”

Mitogen- and stress-activated protein kinase (MSK1/2) regulated gene expression in normal and disease states

“…MSK1 and/or 2 are involved in the positive and negative regulation of gene expression. MSK1 and MSK2 are recruited to specific genes by a host of transcription factors, including p53, ELK1, NF-κB, and RARα, several of which are substrates of MSK1/2 (Ahn et al 2018). Induction of immediate-early gene expression is associated with MSK1/2 phosphorylation of histone H3 at Ser10 or Ser28.…”