Induction of nerve growth factor by phorbol 12-myristate 13-acetate is dependent upon the mitogen activated protein kinase pathway

Abstract

Several small molecules have been identified that induce glial cells to synthesize and secrete nerve growth factor (NGF), a critical neurotrophin that supports neuronal growth and survival, and as such show promise in the development of drugs for the chemoprevention of Alzheimer's disease. To map the signal transduction cascade leading to NGF synthesis and secretion, cultured human glial cells were stimulated by phorbol 12-myristate 13-acetate (PMA), an agonist of Protein Kinase C. Changes in intracellular protein phosphorylation states were evaluated by reverse phase protein microarrays (RPPA), selectively screening over 130 protein endpoints. Of these, 55 proteins showed statistically significant changes in phosphorylation state due to cellular exposure to PMA. A critical signal transduction pathway was identified, and subsequent validation by ELISA and qPCR revealed that the signaling proteins Raf, MEK, ERK, and the signal transduction factor CREB are all essential to the upregulation of NGF gene expression by PMA. Additionally, members of the RSK family of kinases appear to be involved in glial secretion (exocytosis) of the NGF protein. Furthermore, through RPPA, the effects of PMA on apoptosis signaling events and cell proliferation were differentiated from the pathway to NGF upregulation. Overall, this study reveals potential protein targets for the rational design of Alzheimer's therapeutics.

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“…However, it could be observed that both treatments resulted in a similar difference in proliferation rate in comparison to the control (Figure 5C). Reconciling with the previous finding that PMA induces nerve growth factor secretion and differentiation of PC12 cells, 44,45 we found that the PMA treatment alone can induce cellular transformation with neuritic outgrowth (Figure 5D). Regardless of this transformation, the cells did not express PSD-95 protein, as evidenced by the transient transfection of the PMA-treated cells with the plasmid pAAV ORANGE Dlg4 HaloTg KI (Figure 5E).…”

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“…It causes cellular survival increasing via NGF. Furthermore, in the absence of NGF, expression of preapoptotic protein increases, which is the result of cell‐activated transcription by the c‐Jun factor (Davis et al, ). However, several studies showed that NGF participates in other ways; not only to the cell cycle regulating pathways (Molloy, Read, & Gorman, ; Read, Molloy, & Gorman, ), but also it can increase the expression of genes such as Bcl‐2 by binding to the TrkA receptor, which increases the proliferation and survival of the target neuron (Figure ; path 3).…”

“…These considerable correlations were found between HUR1 and the genes of central triangle (CCW); CSTF2, CPSF7, and WDR33 (Table 4). (Davis et al, 2018). However, several studies showed that NGF participates in other ways; not only to the cell cycle regulating pathways ), but also it can increase the expression of genes such as Bcl-2 by binding to the TrkA receptor, which increases the proliferation and survival of the target neuron (Figure 3; path 3).…”