An essential role of NFκB in tyrosine kinase signaling of p38 MAP kinase regulation of myocardial adaptation to ischemia

Abstract

We have recently demonstrated that myocardial adaptation to ischemia triggers a tyrosine kinase regulated signaling pathway leading to the translocation and activation of p38 MAP kinase and MAPKAP kinase 2. Since oxidative stress is developed during ischemic adaptation and since free radicals have recently been shown to function as an intracellular signaling agent leading to the activation of nuclear transcription factor, NFU UB, we examined whether NFU UB was involved in the ischemic adaptation process. Isolated perfused rat hearts were adapted to ischemic stress by repeated ischemia and reperfusion. Hearts were pretreated with genistein to block tyrosine kinase while SB 203580 was used to inhibit p38 MAP kinases. Ischemic adaptation was associated with the nuclear translocation and activation of NFU UB which was significantly blocked by both genistein and SB 203580. The ischemically adapted hearts were more resistant to ischemic reperfusion injury as evidenced by better function recovery and less tissue injury during postischemic reperfusion. Ischemic adaptation developed oxidative stress which was reflected by increased malonaldehyde formation. A synthetic peptide containing a cell membrane-permeable motif and nuclear sequence, SN 50, which blocked nuclear translocation of NFU UB during ischemic adaptation, significantly inhibited the beneficial effects of adaptation on functional recovery and tissue injury. In concert, SN 50 reduced the oxidative stress developed in the adapted myocardium. These results demonstrate that p38 MAP kinase might be upstream of NFU UB which plays a role in ischemic preconditioning of heart. z 1998 Federation of European Biochemical Societies.

RETRACTED: mda-9/Syntenin Regulates the Metastatic Phenotype in Human Melanoma Cells by Activating Nuclear Factor-κB

“…The functional importance of p38 MAPK in MMP-2 expression in melanoma cells was also suggested by a recent report showing that inhibition of p38 MAPK by the specific inhibitor SB203580 down-regulated MMP-2 expression resulting in reduced invasive potential of malignant melanoma cells (45). Moreover, in different cell types, the p38 MAPK-dependent pathway interferes with the transactivation properties of NF-nB (46)(47)(48). Although the mechanisms by which p38 MAPK activates NF-nB are controversial, with evidence supporting regulation of NF-nBdependent gene transcription via modulation of activation of the transcription factor IID and/or post-translational modifications, including phosphorylation and acetylation, of the RelA/p65 subunit, our data strongly suggest that mda-9/syntenin stimulates MMP-2 expression by activating MT1-MMP through the p38 MAPK and NF-nB pathways leading to melanoma cell migration and invasion.…”

p38 mitogen-activated kinase is a bidirectional regulator of human fibroblast collagenase-1 induction by three-dimensional collagen lattices

“…Because cell shrinkage caused by hypertonicity is a regulatory signal for the p38 MAPK activation [14,34], the cell size difference between fibroblasts cultured in fl-coll and att-coll might be one of the signals that activate the p38 MAPK. In fact, a number of physiological or disease processes that involve morphological alterations, such as ischaemic and hypertensive myocardial disease, also require p38 MAPK activation [12,35]. The specific activation of fibroblast p38α by fl-coll is consistent with observations that p38 MAPK mediates mitotic arrest [36] and apoptosis [37], two cellular functions associated with fibroblasts cultured in contracting collagen matrices, but not att-coll [2,38].…”

“…The inhibition of p38α by SB203580 at concentrations from 0.1 µM to 10 µM blocked transactivation activity of NF-κB in a one-way concentration-dependent manner ( Figure 6C), suggesting that NF-κB activation by fl-coll requires p38α activity. Depending on the extracellular signals, p38-mediated NF-κB activation is manifested by nuclear translocation [12], phosphorylation of p65 itself [13] or association of NF-κB with basal transcription factors such as TFIIB and TATA-binding protein [11]. Because we have shown that fl-coll induces NF-κB nuclear translocation [1], the effects of p38α on DNA binding of NF-κB and the nuclear presence of p50 and p65, two subunits previously identified present in the NF-κB DNA-binding complex in fl-coll-induced fibroblasts [1], were examined.…”

“…Several studies have reported that p38 mitogenactivated protein kinase (p38 MAPK) regulates NF-κB activation [11][12][13]. The p38 group of MAPKs is activated through phosphorylation of specific tyrosine and threonine residues in response to physical and chemical stress signals, such as hyperosmolarity and H # O # [14,15].…”

Loss of E-cadherin leads to upregulation of NFκB activity in malignant melanoma

“…A possible interaction between p38 MAPK and NFkB was first suggested by Maulik et al (1998). They presented evidence that the p38 inhibitor SB203580 prevents NFkB nuclear translocation during ischemic adaptation.…”