Opposite functions of Jun‐B and c‐jun in growth regulation and neuronal differentiation

Abstract

Induction of the jun-B and/or c-jun transcription factors is part of the immediate early response to diverse stimuli that induce alterations in cellular programs. While c-jun is a protooncogene whose expression is required for induction of cell proliferation, jun-B has recently been found to be induced by stimuli inducing differentiation in various cell lines. Furthermore, its expression is largely restricted to differentiating cells during embryogenesis. To determine the functional significance of these findings, we used antisense phosphorothioate oligodeoxynucleotides to inhibit expression of the two genes in proliferating and neuronally differentiating cells. While selective inhibition of c-jun expression reduced proliferation rates, inhibition of jun-B protein synthesis markedly increased proliferation in 3T3 fibroblasts, human mammary carcinoma cells and PC-12 pheochromocytoma cells, suggesting jun-B involvement in negative growth control. Neuronal differentiation of PC-12 cells induced by nerve growth factor (NGF) was prevented by inhibition of jun-B protein synthesis. PC-12 cells not only failed to grow neurites but also remained in the proliferative state. Furthermore, in cultured primary neurons from rat hippocampus, inhibition of jun-B expression, again, markedly reduced morphological differentiation. Conversely, inhibition of c-jun protein synthesis enhanced morphological differentiation of both primary neurons and PC-12 tumor cells. Thus, jun-B expression is required for neuronal differentiation and its balance with c-jun activity is involved in regulating key steps in proliferation and differentiation processes.

Alteration ofJun proto-oncogene status by plasmid transfection affects growth of human ovarian cancer cells

“…Our findings for jun-B do not support an important role for this gene in the growth or survival of ovarian cancer cells in vitro. This observation is compatible with the variable functions previously attributed to this gene (Schütte et al, 1989;Castellazzi et al, 1991;Schlingensiepen et al, 1993).…”

Inhibition of Jun N-Terminal Kinase (JNK) Enhances Glucocorticoid Receptor-Mediated Function in Mouse Hippocampal HT22 Cells

“…Indeed, the mouse hippocampal HT22 cell line has been widely used as an in vitro model system to study signal transduction pathways involving Jun (Rossler et al, 2002), g-proteins (Ignatov et al, 2003), and glucocorticoids (Schmidt et al, 2001) as well as oxidative stress (Behl, 2000), the effects of antidepressants (Herr et al, 2003), and the pathogenesis of Alzheimer disease (Behl, 1998). Moreover, inhibition of c-Jun activity has been found to increase sprouting and cell number in primary rat hippocampal neurons and reduce toxin-mediated cell death in nigrostriatal neurons (Schlingensiepen et al, 1993;Yue et al, 1998). Finally, given the role of hippocampal GR in feedback regulation of neuroendocrine responses, JNKrelated influences on the GR may play a role in the pathophysiology of altered hypothalamic-pituitary-adrenal axis function found in neuropsychiatric disorders including depression.…”

Dopamine Induces Apoptosis through an Oxidation-involved SAPK/JNK Activation Pathway

“…Overexpression of activated cJun produces apoptosis, and suppression of c-Jun protects against neuronal death induced by deprivation of NGF in sympathetic neurons (32,41) and neonatal hippocampal neurons (42). Based on the above non-neuronal data and increase of c-Jun expression by activation of the JNK pathway in neonatal striatal cells (Fig.…”