Thromboxane A₂ Receptor‐Mediated Cell Proliferation, Survival and Gene Expression in Oligodendrocytes

Abstract

Thromboxane A 2 receptors (TP) were previously localized to discrete regions in the rat brain on myelinated fiber tracts and oligodendrocytes (OLGs). The present studies extended these findings and investigated the effects of TP signaling on cell proliferation, survival, and gene expression in OLG progenitor cells (OPCs) and OLGs. It was found that the TP agonist, U46619 stimulated the proliferation of OPCs and promoted the survival of mature OLGs. Examination of the early gene expression events involved in OPC proliferation, revealed that c-fos expression was substantially increased by U46619 stimulation. Treatment of OPCs or OLGs with U46619 caused activation of the mitogen-activated protein kinases (MAPK) ERK 1/2. In OPCs this activation was blocked by inhibition of src. However, in OLGs this phosphorylation was not only blocked by inhibition of src but also by inhibition of protein kinase C (PKC). Furthermore, U46619 was found to increase CREB phosphorylation in both OPCs and OLGs. Similar to ERK 1/2 activation, there was a divergence in the mechanism of the TP-mediated CREB response for each cell type. Specifically, U46619 activation was attenuated by src and protein kinase A (PKA) inhibition in OPCs, whereas in OLGs this effect was blocked by inhibition of src, PKA as well as by inhibition of PKC. Collectively, these results provide the first demonstration that TP-activated nuclear signaling events are involved in the proliferation of OPCs, the survival of mature OLGs, and the stimulation of gene expression.

Thromboxane A2 Receptor Inhibition Suppresses Multiple Myeloma Cell Proliferation by Inducing p38/c-Jun N-terminal Kinase (JNK) Mitogen-activated Protein Kinase (MAPK)-mediated G2/M Progression Delay and Cell Apoptosis

“…Here, we showed that NS398, SQ29548, and TP silencing induced apoptosis in two MM cell lines, and U46619 protected MM cells from apoptosis. These findings were consistent with previous data from other cell types (7,49,50). Meanwhile, we found that NS398, SQ29548, and TP silencing elevated caspase 3 activity, and, as expected, U46619 decreased caspase 3 activity, in accordance with flow cytometry results.…”

“…TP belongs to the G-protein-coupled receptor superfamily and is expressed as two isoforms in humans, named TP ␣ and TP ␤ (6). Notably, TxA 2 stimulates proliferation of several types of cells, including oligodendrocytes (7), smooth muscle cells (8), and lung cancer cells (9). For example, dual TxA 2 inhibitors repress NCI-H23 lung adenocarcinoma cell growth by inducing G 2 /M phase arrest and cell apoptosis although the detailed mechanisms are not shown (10).…”

A Novel Nuclear Signaling Pathway for Thromboxane A2 Receptors in Oligodendrocytes: Evidence for Signaling Compartmentalization during Differentiation

“…The present study investigated the changes in G protein signaling interactions for a particular GPCR, i.e., TPR known to be involved in the development and function of oligodendrocytes (OLGs) (25,41). To this end, we determined the expression and localization of TPR-associated heterotrimeric G␣ subunits and purified TPR-G␣ complexes formed during OLG differentiation.…”

Glycogen Synthase Kinase-3 Phosphorylation, T-Cell Factor Signaling Activation, and Cell Morphology Change following Stimulation of Thromboxane Receptor α

“…Stimulation of cell proliferation by TP agonists was observed beyond vascular smooth cells. Lin et al (2005) reported that U-46619 stimulated the proliferation of oligodendrocyte progenitor cells and promoted the survival of mature oligodendrocyte in central nervous system. It seems that TP-mediated cell proliferation and survival are mainly dependent on two interactive pathways: one pathway is through transactivation of EGFR leading to phosphorylation of ERK; another pathway is activation of PKA-dependent pathway.…”