The stimulation of cells with physiological concentrations of insulin induces a variety of responses, e.g. an increase in glucose uptake, induction of glycogen and protein synthesis, and gene expression. One of the determinants regulating insulin-mediated gene expression may be activating transcription factor 2 (ATF2). Insulin activates ATF2 by phosphorylation of Thr69 and Thr71 via a two-step mechanism, in which ATF2-Thr71 phosphorylation precedes the induction of ATF2-Thr69+71 phosphorylation by several minutes. We previously found that in c-Jun N-terminal kinase (JNK)-/- fibroblasts, cooperation of the ERK1/2 and p38 pathways is required for two-step ATF2-Thr69+71 phosphorylation in response to growth factors. Because JNK is also capable of phosphorylating ATF2, we assessed the involvement of JNK, ERK1/2 and p38 in the insulin-induced two-step ATF2 phosphorylation in JNK-expressing A14 fibroblasts and 3T3L1-adipocytes. The induction of ATF2-Thr71 phosphorylation was sensitive to MAPK kinase (MEK) 1/2-inhibition with U0126, and this phosphorylation coincided with nuclear translocation of phosphorylated ERK1/2. Use of the JNK inhibitor SP600125 or expression of dominant-negative JNK-activator SAPK kinase (SEK1) prevented the induction of ATF2-Thr69+71, but not ATF2-Thr71 phosphorylation by insulin. ATF2-dependent transcription was also sensitive to SP-treatment. Abrogation of p38 activation with SB203580 or expression of dominant-negative MKK6 had no inhibitory effect on these events. In agreement with this, the onset of ATF2-Thr69+71 phosphorylation coincided with the nuclear translocation of phosphorylated JNK. Finally, in vitro kinase assays using nuclear extracts indicated that ERK1/2 preceded JNK translocation. We conclude that sequential activation and nuclear appearance of ERK1/2 and JNK, rather than p38, underlies the two-step insulin-induced ATF2 phosphorylation in JNK-expressing cells.

Download full-text PDF

Source
http://dx.doi.org/10.1210/me.2005-0289DOI Listing

Publication Analysis

Top Keywords

atf2 phosphorylation
12
atf2-thr71 phosphorylation
12
atf2-thr69+71 phosphorylation
12
phosphorylation
11
c-jun n-terminal
8
n-terminal kinase
8
thr69 thr71
8
activating transcription
8
transcription factor
8
gene expression
8

Similar Publications

NEK2 (NIMA-related kinase 2) has recently gained attention for its potential role in osteoarthritis (OA) chondrocytes, however, its specific involvement remains unclear. This study aimed to investigate the role of NEK2 in OA progression and the underlying molecular mechanisms. Primary mouse knee chondrocytes were stimulated with IL-1β to establish an in vitro OA model, followed by the knockdown of NEK2 or ATF2.

View Article and Find Full Text PDF

Neprilysin is a skin wrinkle-inducing membrane bound elastase that is expressed abundantly in UV-exposed and in aged dermal fibroblasts. The overexpression of neprilysin is closely associated with enhanced epithelial-mesenchymal cytokine interactions mainly via interleukin (IL)-1α, which has the distinct potential to stimulate the expression of neprilysin by human dermal fibroblasts (HDFs). The over-expression of neprilysin also accelerates the formation of wrinkles, accompanied by disruptions of the three-dimensional architecture of dermal elastic fibers that are responsible for the loss of skin elasticity.

View Article and Find Full Text PDF

The study is to evaluate the effects of collagen/hyaluronic acid coating with or without puerarin and exosomes (Exos) derived from adipose stem cells (ADSCs-Exos) on pre-osteoblast proliferation and differentiation on the surface of titanium materials. Titanium materials with different coatings were prepared by layer-by-layer technique, evaluating the surface characterization. Cell functions were assessed by cell biology experiments.

View Article and Find Full Text PDF

Celastrus orbiculatus Thunb. is a vine used as a traditional Chinese medicinal herb. In this study, we focused on the anticancer cytotoxicity and underlying mechanism of previously unreported 3-oxygen-substituted isoflavone analogue (3-benzyloxychromone, 3-Boc) from the herb.

View Article and Find Full Text PDF

A class of chemical compounds enhances clustering of muscle nicotinic acetylcholine receptor in cultured myogenic cells.

Biochem Biophys Res Commun

October 2024

Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya, 466-8550, Japan; Graduate School of Nutritoinal Sciencess, Nagoya University of Arts and Sciences, 57 Takenoyama, Iwasaki, Nisshin, 470-0196, Japan. Electronic address:

Article Synopsis
  • - Neuromuscular signal transmission is disrupted in diseases like myasthenia gravis and congenital myasthenic syndromes, prompting research using an ATF2-luciferase system to find compounds that enhance AChR clustering.
  • - Four chemical compounds with similar structures significantly boosted luciferase activities, outperforming disulfiram—a known drug—while enhancing AChR clusters in muscle cells without causing toxicity up to 1 μM concentrations.
  • - Despite increased phosphorylation of MuSK by some compounds, they likely don't bind directly to MuSK or its associated proteins, indicating further exploration is needed to identify their exact targets for developing new treatments for neuromuscular junction disorders.
View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!