The Regulation of MAPKs in Y1 Mouse Adrenocortical Tumor Cells

Abstract

The regulation of the MAPKs, Erk(1) and Erk(2), and the MAPK kinase, Mek, were examined in the Y1 mouse adrenocortical tumor cell line and in the protein kinase A-defective mutant, Kin-8. ACTH and basic fibroblast growth factor each increased Mek phosphorylation and stimulated Mek activity in both cell lines and also activated the Erks at concentrations that paralleled their effects on Mek. The specific Mek inhibitor, PD98059, blocked the activation of the Erks by ACTH and basic fibroblast growth factor, indicating that Mek is the upstream activator of Erk. PD98059 did not block the phosphorylation of Mek, as might have been expected from previous studies; instead PD98059 inhibited the activity of the activated enzyme. In ACTH-stimulated, mutant Kin-8 cells, PD98059 paradoxically increased the amount of phosphorylated Mek, while preventing the activation of Erk. These results are interpreted as reflecting the loss of a protein kinase A-mediated inhibitory influence on Mek phosphorylation and activation.

Regulation of G Protein–Coupled Receptor Signaling: Specific Dominant-Negative Effects of Melanocortin 2 Receptor Accessory Protein 2

“…Because the ACTH-stimulated activation of mitogen-activated protein kinases (MAPKs) is largely independent of cAMP-dependent protein kinase (PKA) (26), we tested the ability of ACTH to stimulate the phosphorylation of the MAPKs extracellular signal–regulated kinases (ERKs) ERK1 and ERK2 in serum-deprived cells transfected with plasmids encoding MC2R and either MRAP or MRAP2 (Fig. 2A).…”

Study of the Signaling Function of Sulfiredoxin and Peroxiredoxin III in Isolated Adrenal Gland

“…Srx expression is known to be regulated via two distinct transcriptional factors, AP-1 and nuclear factor erythroid 2-related factor (Nrf2). ACTH activates ERK via a cAMP-dependent pathway in Y-1 mouse adrenocortical tumor cells (Le & Schimmer, 2001), and ERK activation leads to AP-1 activation. We found that injection of ACTH increased the abundance of Srx in the adrenal glands of wild-type and Nrf2 knockout (KO) mice by similar extents, whereas induction of HO-1, whose gene is a well-characterized target of Nrf2, was apparent in wild-type mice but not in Nrf2 KO mice (Kil et al, 2012).…”

ACTH Modulates ERK Phosphorylation in the Adrenal Gland in a Time‐Dependent Manner

“…This leads to an increase in the expression of steroidogenic enzymes and steroidogenesis (1,2,17,18). In recent years, the data relating ERKs and steroidogenesis has been increasing steadily (3,11,(19)(20)(21). Even so, it cannot be discarded that this activation of ERKs 1/2 is also related to proliferation of adrenal cortex cells, since ACTH also increases the expression of Proliferating Cell Nuclear Antigen (PCNA) in the adrenal gland (22).…”

“…Upon binding it activates the cAMP/PKA -signaling cascade, leading to steroidogenesis (1,2). Recently, it has been described, namely in the Y1 adrenocortical tumor cell line, that ACTH could act via other cascades such as the Mitogen Activated Protein Kinase (MAPK) cascades (3,4).…”