MAP kinases p38 and JNK are activated by the steroid hormone 1α,25(OH)₂‐vitamin D₃ in the C2C12 muscle cell line

Abstract

In chick skeletal muscle cell primary cultures, we previously demonstrated that 1alpha,25(OH)2-vitamin D3 [1alpha,25(OH)2D3], the hormonally active form of vitamin D, increases the phosphorylation and activity of the extracellular signal-regulated mitogen-activated protein (MAP) kinase isoforms ERK1 and ERK2, their subsequent translocation to the nucleus and involvement in DNA synthesis stimulation. In this study, we show that other members of the MAP kinase superfamily are also activated by the hormone. Using the muscle cell line C2C12 we found that 1alpha,25(OH)2D3 within 1 min phosphorylates and increases the activity of p38 MAPK. The immediately upstream mitogen-activated protein kinase kinases 3/6 (MKK3/MKK6) were also phosphorylated by the hormone suggesting their participation in p38 activation. 1Alpha,25(OH)2D3 was able to dephosphorylate/activate the ubiquitous cytosolic tyrosine kinase c-Src in C2C12 cells and studies with specific inhibitors imply that Src participates in hormone induced-p38 activation. Of relevance, 1alpha,25(OH)2D3 induced in the C2C12 line the stimulation of mitogen-activated protein kinase activating protein kinase 2 (MAPKAP-kinase 2) and subsequent phosphorylation of heat shock protein 27 (HSP27) in a p38 kinase activation-dependent manner. Treatment with the p38 inhibitor, SB203580, blocked p38 phosphorylation caused by the hormone and inhibited the phosphorylation of its downstrean substrates. 1Alpha,25(OH)2D3 also promotes the phosphorylation of c-jun N-terminal protein kinases (JNK 1/2), the response is fast (0.5-1 min) and maximal phosphorylation of the enzyme is observed at physiological doses of 1alpha,25(OH)2D3 (1 nM). The relative contribution of ERK-1/2, p38, and JNK-1/2 and their interrelationships in hormonal regulation of muscle cell proliferation and differentiation remain to be established.

MAPK‐pathway activity, Lrrk2 G2019S, and Parkinson's disease

“…Changes observed are not restricted to a particular pathway, perhaps as there is considerable interaction between secondary messenger cascades, both up and downstream (Bitar and Patil, 2004;Buitrago et al, 2006). Oxidative stress occurs early in the progression of Alzheimer disease, and may be the result of the activation of stress-activated protein kinase pathways (Zhu et al, 2002).…”

1α,25-Dihydroxyvitamin D3 Regulates Mitochondrial Oxygen Consumption and Dynamics in Human Skeletal Muscle Cells

“…The differentially expressed mRNAs encode proteins that play significant roles in multiple biochemical pathways involved in muscle contraction and relaxation; extracellular matrix-cell receptor interactions; actin cytoskeleton remodeling; and JAK-STAT, insulin-like (17) 0.014 Reactome p53 pathway (16) 0.014 Panther Interferon-signaling (11) 0.017 Panther Muscle contraction (9) 0.022 Reactome Terpenoid backbone biosynthesis (6) 0.028 KEGG Cell adhesion molecules (24) 0.048 KEGG (27), which showed that treatment of vitamin D-deficient humans with cholecalciferol improves muscle phosphocreatine recovery after exercise, suggesting an effect of 1␣,25(OH) 2 D 3 on the formation of high energy phosphorylated intermediates and mitochondrial function. The increase in the numbers of mitochondria could also account for the increase in cellular OCR.…”

Raf‐1 signaling is required for the later stages of 1,25‐dihydroxyvitamin D3‐induced differentiation of HL60 cells but is not mediated by the MEK/ERK module

“…For instance, we and others have shown that in HL60 cells ERK1/2 is activated in the early phase of 1,25D-induced differentiation, and this can be accentuated by serum starving the cells prior to exposure to 1,25D (Marcinkowska et al, 1997;Marcinkowska, 2001;Wang and Studzinski, 2001a). Other studies have implicated JNK (Ji et al, 2002;Wang et al, 2003;Buitrago et al, 2006), p38 (Wang and Studzinski, 2001a,b;Ji et al, 2002) and AKT (Zhang et al, 2006) pathways in the transmission of the 1,25D-generated signals to the transcriptional machinery in the nucleus. However, the Raf-MEK-ERK pathways remains firmly established as a principal all-purpose signaling cascade (Chang et al, 2003), and as such deserve additional attention regarding its role in the induction of differentiation.…”

“…These findings support the thesis that Raf-1 signals cell proliferation and cell differentiation through different intermediary proteins Involvement of mitogen-activated protein kinases (MAPKs) in signaling of monocyte/ macrophage differentiation induced by 1,25-dihydroxyvitamin D 3 (1,25D) has been well documented (e.g., Wang et al, 2000;Marcinkowska, 2001;Wang and Studzinski, 2001a;Kim et al, 2002;Studzinski et al, 2005), but the exact sequence of signaling steps has not been precisely elucidated. Early studies described MAPK activity as the basis of rapid, membranerelated effects of 1,25D on human acute promyelocytic leukemia NB4 cells (Song et al, 1998) and other cell types (Buitrago et al, 2006). These effects occurred in the time frame of seconds and minutes, but have not been universally observed in other cell types.…”

“…Early studies described MAPK activity as the basis of rapid, membranerelated effects of 1,25D on human acute promyelocytic leukemia NB4 cells (Song et al, 1998) and other cell types (Buitrago et al, 2006). These effects occurred in the time frame of seconds and minutes, but have not been universally observed in other cell types.…”