Extracellular Signal-Regulated Kinase 2 and CHOP Restrict the Expression of the Growth Arrest-Specific p20K Lipocalin Gene to G₀

Abstract

The activation of the growth arrest-specific (gas) p20K gene depends on the interaction of C/EBP␤ with two elements of a 48-bp promoter region termed the quiescence-responsive unit (QRU). Here we identify extracellular signal-related kinase 2 (ERK2) as a transcriptional repressor of the p20K QRU in cycling chicken embryo fibroblasts (CEF). ERK2 binds to repeated GAAAG sequences overlapping the C/EBP␤ sites of the QRU. The recruitment of ERK2 and C/EBP␤ is mutually exclusive and dictates the expression of p20K. C/EBP homologous protein (CHOP) was associated with C/EBP␤ under conditions promoting endoplasmic reticulum (ER) stress and, to a lesser extent, in cycling CEF but was not detectable when C/EBP␤ was immunoprecipitated from contact-inhibited cells. During ER stress, overexpression of CHOP inhibited p20K, while its downregulation promoted p20K, indicating that CHOP is also a potent inhibitor of p20K. Transcriptome analyses revealed that hypoxia-responsive genes are strongly induced in contact-inhibited but not serum-starved CEF, and elevated levels of nitroreductase activity, a marker of hypoxia, were detected at confluence. Conditions of hypoxia (2% O 2 ) induced growth arrest in subconfluent CEF and markedly stimulated p20K expression, suggesting that the control of proliferation and gas gene expression is closely linked to limiting oxygen concentrations associated with high cell densities.

Transcription Factor C/EBP Homologous Protein in Health and Diseases

“…Nuclear CHOP can induce a transient cell cycle arrest in G 1 phase ( 20 ). During ER stress, CHOP also inhibits the growth arrest-specific p20K genes, which are a group of genes that activate reversible G 0 arrest to regulate cell proliferation ( 59 ). Generally, it is known as an important node in the transcription factor network that dominates stress-inducible regulation of specific target genes.…”

Elevation of O-GlcNAc and GFAT expression by nicotine exposure promotes epithelial‐mesenchymal transition and invasion in breast cancer cells

“…Previous studies have shown that transcription mediated by CEBPB is influenced by its heterodimerization with ER stress-related CHOP 24 . Co-IP experiments confirmed that CHOP was associated with CEBPB in MCF-7 and MDA-MB-231 cells.…”

Hypoxia promotes proliferation and inhibits myogenesis in broiler satellite cells

“…EXFABP is a stress protein that is not only physiologically necessary at the developmental stage but also appears in tissues due to oxidative stress under pathological conditions ( Descalzi Cancedda et al, 2001 ). In chicken embryonic fibroblasts, EXFABP is markedly stimulated by hypoxia-induced growth arrest, alluding that hypoxia is linked to the control of this gene expression and proliferation ( Erb et al, 2016 ). Interestingly, EXFABP is increased in the pectoralis major of both affected and high-feed efficient broilers ( Papah et al, 2018 ; Abasht et al, 2019 ).…”