ERK2-mediated C-terminal serine phosphorylation of p300 is vital to the regulation of epidermal growth factor-induced keratin 16 gene expression

Department of Pharmacology, Institute of Basic Medical Sciences, College of Medicine, Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan 701, Taiwan.
Journal of Biological Chemistry (Impact Factor: 4.6). 10/2007; 282(37):27215-28. DOI: 10.1074/jbc.M700264200
Source: PubMed

ABSTRACT We previously reported that the epidermal growth factor (EGF) regulates the gene expression of keratin 16 by activating the extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling which in turn enhances the recruitment of p300 to the keratin 16 promoter. The recruited p300 functionally cooperates with Sp1 and c-Jun to regulate the gene expression of keratin 16. This study investigated in detail the molecular events incurred upon p300 whereby EGF caused an enhanced interaction between p300 and Sp1. EGF apparently induced time- and dose-dependent phosphorylation of p300, both in vitro and in vivo, through the activation of ERK2. The six potential ERK2 phosphorylation sites, including three threonine and three serine residues as revealed by sequential analysis, were first identified in vitro. Confirmation of these six sites in vivo indicated that these three serine residues (Ser-2279, Ser-2315, and Ser-2366) on the C terminus of p300 were the major signaling targets of EGF. Furthermore, the C-terminal serine phosphorylation of p300 stimulated its histone acetyltransferase activity and enhanced its interaction with Sp1. These serine phosphorylation sites on p300 controlled the p300 recruitment to the keratin 16 promoter. When all three serine residues on p300 were replaced by alanine, EGF could no longer induce the gene expression of keratin 16. Taken together, these results strongly suggested that the ERK2-mediated C-terminal serine phosphorylation of p300 was a key event in the regulation of EGF-induced keratin 16 expression. These results also constituted the first report identifying the unique p300 phosphorylation sites induced by ERK2 in vivo.

  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: Transcription factor Sp1 was, for many years, viewed as a basal transcription factor and relegated to the regulation of so-called housekeeping genes. Sp1's role in recruiting the general transcription machinery in the absence of a TATA box increased its importance in gene regulation, particularly in light of recent estimates that the majority of mammalian genes lack a TATA box. In this review, we briefly address the history of Sp1, the founding member of the Sp family of transcription factors. We review the evidence suggesting Sp1 is highly regulated by post-translational modifications that both positively and negatively affect Sp1's activity on a wide array of genes. Sp1 is overexpressed in many cancers and is associated with poor prognosis. Targeting Sp1 in cancer treatment has been suggested; however, our review of the literature on Sp1-dependent regulation of genes that contribute to the "hallmarks of cancer", described by Hanahan and Weinberg, illustrates the extreme complexity of Sp1 functions. Sp1 both activates and suppresses the expression of a number of essential oncogenes and tumor suppressors, as well as genes involved in essential cellular functions, including proliferation, differentiation, DNA damage response, apoptosis, senescence, and angiogenesis. Sp1 is also implicated in inflammation and genomic instability, as well as epigenetic silencing. Based on the seemingly opposing effects of Sp1, a more complete understanding of the function of Sp1 in cancer is needed to validate its potential as a therapeutic target. This article is protected by copyright. All rights reserved.
    FEBS Journal 11/2014; 282(2). DOI:10.1111/febs.13148 · 3.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To date only a handful of drugs are available for the treatment of melanoma. Among them vemurafenib, a BrafV600E specific inhibitor, showed promising results in terms of response rate and increase in median survival time. However, its effectiveness is limited by development of resistance and the search for additional drugs for melanoma treatment is ongoing. The present study was performed to analyze the correlation between Braf expression and the expression of p300, a known down stream target of the mitogen activated protein kinase (MAPK) pathway, which was recently shown by us to be a prognostic marker for melanoma progression and patient survival.
    BMC Cancer 06/2014; 14(1):398. DOI:10.1186/1471-2407-14-398 · 3.32 Impact Factor
    This article is viewable in ResearchGate's enriched format


Available from