Ubiquitin-binding protein p62 expression is induced during apoptosis and proteasomal inhibition in neuronal cells

Neuronal apoptosis is involved in several pathological conditions of the brain. Using cDNA arrays, we observed upregulation of ubiquitin-binding protein p62 expression during serum withdrawal-induced apoptosis in Neuro-2a cells. We demonstrate here that the expression levels of p62 mRNA and protein were increased in Neuro-2a cells and cultured rat hippocampal neurons by different types of proapoptotic treatments, including serum deprivation, okadaic acid, etoposide, and trichostatin A. Ubiquitin-binding protein p62 is a widely expressed cytoplasmic protein of unclear function. The ability of p62 to bind noncovalently to ubiquitin and to several signalling proteins suggests that p62 may play a regulatory role connected to the ubiquitin system. Accordingly, we show that proteasomal inhibitors MG-132, lactacystin, and PSI caused a prominent upregulation of p62 mRNA and protein expression, with a concomitant increase in ubiquitinated proteins. To conclude, p62 upregulation appears to be a common event in neuronal apoptosis. Results also suggest that the induction of p62 expression by proteasomal inhibitors may be a response to elevated levels of ubiquitinated proteins, possibly constituting a protective mechanism.