Proteasome inhibition by lactacystin in primary neuronal cells induces both potentially neuroprotective and pro-apoptotic transcriptional responses: a microarray analysis.
Although inhibition of the ubiquitin proteasome system has been postulated to play a key role in the pathogenesis of neurodegenerative diseases, studies have also shown that proteasome inhibition can induce increased expression of neuroprotective heat-shock proteins (HSPs). The global gene expression of primary neurons in response to treatment with the proteasome inhibitor lactacystin was studied to identify the widest range of possible pathways affected. Our results showed changes in mRNA abundance, both at different time points after lactacystin treatment and at different lactacystin concentrations. Genes that were differentially up-regulated at the early time point but not when most cells were undergoing apoptosis might be involved in an attempt to reverse proteasome inhibitor-mediated apoptosis and include HSP70, HSP22 and cell cycle inhibitors. The up-regulation of HSP70 and HSP22 appeared specific towards proteasome inhibitor-mediated cell death. Overexpression of HSP22 was found to protect against proteasome inhibitor-mediated loss of viability by up to 25%. Genes involved in oxidative stress and the inflammatory response were also up-regulated. These data suggest an initial neuroprotective pathway involving HSPs, antioxidants and cell cycle inhibitors, followed by a pro-apoptotic response possibly mediated by inflammation, oxidative stress and aberrant activation of cell cycle proteins.
Department of Biochemistry, Faculty of Medicine, National University of Singapore, Singapore.
Elaine Hau Jin
EH
Yew
Nam Sang
NS
Cheung
Meng Shyan
MS
Choy
Robert Z
RZ
Qi
Alan Yiu-Wah
AY
Lee
Zhao Feng
ZF
Peng
Alirio J
AJ
Melendez
Jayapal
J
Manikandan
Evelyn Siew-Chuan
ES
Koay
Lily-Lily
LL
Chiu
Wooi Loon
WL
Ng
Matthew
M
Whiteman
Jeyaseelan
J
Kandiah
Barry
B
Halliwell
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D050886:HSP20 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D018832:Molecular Chaperones; D009124:Muscle Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D016716:PC12 Cells; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D015854:Up-Regulation
D015853:Cysteine Proteinase Inhibitors; D050886:HSP20 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C490206:Hspb8 protein, mouse; D007976:Leupeptins; D018832:Molecular Chaperones; D009124:Muscle Proteins; D018696:Neuroprotective Agents; C067713:lactacystin; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine