Regulation of ERK1 gene expression by coactivator proteins

Abstract

RARs (retinoic acid receptors) mediate the effect of their ligand RA (retinoic acid) on gene expression. We previously showed that RA inhibited cellular proliferation in part by decreasing expression of the mitogen activated protein kinase ERK1 (extracellular signal regulated kinase 1). However, the mechanism by which RA regulates ERK1 expression is largely uncharacterized. The present study characterizes coactivator-mediated regulation of RA target gene expression by analysing ERK1 promoter activation. CBP (CREB-binding protein) and PCAF (p300/CBP associated factor) are transcriptional coactivators that interact with nuclear hormone receptors such as RARs. CBP and PCAF differentially regulated ERK1 expression in stable clones. CBP clones expressed higher ERK1 protein levels, proliferated faster in culture and were resistant to RA-mediated growth inhibition. PCAF clones expressed lower levels of ERK1 protein and cells grew more slowly than controls. CBP and PCAF regulation of the ERK1 promoter was dependent on two Sp1 (specificity protein 1) sites located between -86 and -115 bp. Immunoprecipitation and yeast two-hybrid analysis revealed that PCAF interacted with Sp1 via CBP. A putative p53 binding site at -360 bp functioned as a major repressor of ERK1 promoter activity even in the absence of exogenous p53 expression. CBP and PCAF occupancy of the proximal ERK1 promoter was dramatically decreased by RA treatment. PCAF mediated inhibition of ERK1 expression was due to decreased stability of the kinase mRNA. We conclude that CBP and PCAF coactivators mediate ERK1 gene expression at both the transcriptional and post-transcriptional level.

Phosphoproteomic Analysis of Human Embryonic Stem Cells

“…AKT (Table S5A) phosphorylates CREBBP, increasing CREBBP acetyltransferase activity, promoting NF-κB-mediated transcription and enhanced cell survival (Liu et al, 2006). Furthermore, CREBBP increases ERK1 expression (Chu et al, 2005). ERK1 activity contributes to hESC self-renewal in the presence of bFGF (Li et al, 2007).…”

Epigenetic Regulation during B Cell Differentiation Controls CIITA Promoter Accessibility

“…70) and belongs to a large family of factors known to bind GC-rich sequences. Sp1 as well as other Sp1 like molecules have been shown to interact with CBP/p300 coactivators (71,72) as well as TFIID (73). In addition to Sp1, the factors CREB, PU.1, and E47 are also known to recruit CBP/p300 (74 -76), basal transcriptional machinery (77), and RNA polymerase II (78) to promoters.…”

Effect of ret/PTC 1 rearrangement on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model

“…P300/CBP- associated factor (PCAF) was one such gene and is a co- activator of the tumour suppressor p53. PCAF was found to be induced by p53 in breast cancer cell lines and indirectly regulated ERK1 effecting cellular proliferation [35]. …”