Acrylamide-regulated neurofilament expression in rat pheochromocytoma cells.
Using the rat pheochromocytoma cell line (PC12), we present molecular evidence that the neurotoxicant acrylamide directly induces neurofilament gene expression, and the signaling pathways are initially distinctive from, but eventually merged into, that for nerve growth factor (NGF)-induced neurofilament expression. In PC12 cells, acrylamide increased neurofilament protein levels and synthesis. Acrylamide had no effect on the stability of neurofilament mRNAs suggesting that it directly increased neurofilament mRNA synthesis. K252a, a selective inhibitor for NGF receptor gp140trk, had no effect on acrylamide induction, but completely inhibited NGF-induced neurofilament protein synthesis. Therefore, the initial step for acrylamide signaling was distinctive from NGF. Dexamethasone reversed the effects of both NGF and acrylamide on neurofilament protein levels and synthesis indicated that there is a dexamethasone-sensitive signaling step upon which NGF and acrylamide merge, suggesting involvement of transcription-activating proteins like AP-1. These results, taken together with previous studies of transgenic mice that overexpress neurofilament genes, may partially explain the mechanisms of neurofilament accumulation in distal parts of large axons, a pathognomonic feature of acrylamide neurotoxicity in animals.
Lin
W W
WW
Department of Pharmacology, Duke University Medical Center, Durham, NC 27710, USA.
Friedman
M A
MA
Wang
X F
XF
Abou-Donia
M B
MB
D020106:Acrylamide / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D003907:Dexamethasone / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000494:pharmacology; D016900:Neurofilament Proteins / Q000032:analysis / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology; D016716:PC12 Cells; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020917:Receptor, trkA / Q000032:analysis / Q000235:genetics; D012260:Ribonucleases; D015398:Signal Transduction / Q000187:drug effects
D005938:Glucocorticoids; D009414:Nerve Growth Factors; D016900:Neurofilament Proteins; D009498:Neurotoxins; D012333:RNA, Messenger; C044882:neurofilament protein L; C061195:neurofilament protein M; D020106:Acrylamide; D003907:Dexamethasone; D020917:Receptor, trkA; D012260:Ribonucleases