Characterizing the role of Hsp90 in production of heat shock proteins in motor neurons reveals a suppressive effect of wild-type Hsf1.
Induction of heat shock proteins (Hsps) is under investigation as treatment for neurodegenerative disorders, yet many types of neurons, including motor neurons that degenerate in amyotrophic lateral sclerosis (ALS), have a high threshold for activation of the major transcription factor mediating stress-induced Hsp upregulation, heat shock transcription factor 1 (Hsf1). Hsf1 is tightly regulated by a series of inhibitory checkpoints that include sequestration in multichaperone complexes governed by Hsp90. This study examined the role of multichaperone complexes in governing the heat shock response in motor neurons. Hsp90 inhibitors induced expression of Hsp70 and Hsp40 and transactivation of a human inducible hsp70 promoter-green fluorescent protein (GFP) reporter construct in motor neurons of dissociated spinal cord-dorsal root ganglion (DRG) cultures. On the other hand, overexpression of activator of Hsp90 adenosine triphosphatase ([ATPase 1], Aha1), which should mobilize Hsf1 by accelerating turnover of mature, adenosine triphosphate-(ATP) bound Hsp90 complexes, and death domain-associated protein (Daxx), which in cell lines has been shown to promote transcription of heat shock genes by relieving inhibition exerted by interactions between nuclear Hsp90/multichaperone complexes and trimeric Hsf1, failed to induce Hsps in the absence or presence of heat shock. These results indicate that disruption of multichaperone complexes alone is not sufficient to activate the neuronal heat shock response. Furthermore, in motor neurons, induction of Hsp70 by Hsp90-inhibiting drugs was prevented by overexpression of wild-type Hsfl, contrary to what would be expected for a classical Hsf1-mediated pathway. These results point to additional differences in regulation of hsp genes in neuronal and nonneuronal cells.
Taylor
David M
DM
Montreal Neurological Institute, McGill University, 3801 University St., Montreal, Quebec H3A 2B4, Canada.
Tradewell
Miranda L
ML
Minotti
Sandra
S
Durham
Heather D
HD
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D006979:Hyperthermia, Induced; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D018832:Molecular Chaperones; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
D002352:Carrier Proteins; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; C491473:Daxx protein, mouse; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D014157:Transcription Factors
J Cell Biochem. 2005 Apr 15;94(6):1199-209
15696546
Gene Expr. 1999;7(4-6):311-9
10440232
Cell Stress Chaperones. 2005 Autumn;10(3):185-96
16184763
Biochem Cell Biol. 2005 Dec;83(6):703-10
16333321
J Biol Chem. 2006 Jan 13;281(2):782-91
16278218
Curr Opin Genet Dev. 2006 Feb;16(1):71-7
16377176
Trends Cell Biol. 2006 Feb;16(2):97-104
16406523
J Biol Chem. 2006 May 19;281(20):14457-64
16565516
J Cell Biochem. 2006 Aug 15;98(6):1528-42
16552721
Neurobiol Dis. 2006 Nov;24(2):213-25
16950627
Mol Cell Neurosci. 2007 Jan;34(1):20-33
17113785
Biophys J. 2005 Mar;88(3):1646-58
15626701
Mol Cell Biol. 2000 Mar;20(5):1784-96
10669754
EMBO J. 2001 Jul 16;20(14):3800-10
11447121
J Biol Chem. 2001 Nov 30;276(48):45160-7
11574536
J Biol Chem. 2001 Dec 7;276(49):45791-9
11583998
Mol Cell. 2002 Dec;10(6):1255-6
12503997
Mol Cell. 2002 Dec;10(6):1307-18
12504007
J Cell Sci. 2003 Feb 1;116(Pt 3):513-24
12508112
Exp Biol Med (Maywood). 2003 Feb;228(2):111-33
12563018
J Biol Chem. 2003 May 9;278(19):17228-35
12604615
Science. 2003 May 16;300(5622):1142-5
12750521
J Neurosci. 2003 Jul 2;23(13):5789-98
12843283
Curr Cancer Drug Targets. 2003 Oct;3(5):301-23
14529383
Curr Cancer Drug Targets. 2003 Oct;3(5):377-83
14529389
Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4100-5
15016915
Cell Stress Chaperones. 2004 Summer;9(2):122-33
15497499
Science. 1992 Mar 6;255(5049):1243-5
1546322
J Neurosci Res. 1992 Apr;31(4):606-15
1578512
Nature. 1993 Mar 4;362(6415):59-62
8446170
Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8324-8
8078881
J Biol Chem. 1995 Jun 16;270(24):14412-9
7782303
Mol Cell Biol. 1995 Aug;15(8):4319-30
7623826
J Neurosci. 1996 Jan 15;16(2):478-85
8551332
Annu Rev Cell Dev Biol. 1995;11:441-69
8689565
J Cell Biochem. 1995 Dec;59(4):498-513
8749719
Mol Endocrinol. 1996 Jun;10(6):705-12
8776730
Exp Cell Res. 1996 Nov 25;229(1):35-47
8940247
J Biol Chem. 1996 Nov 29;271(48):30847-57
8940068
Biochemistry. 1996 Nov 26;35(47):14889-98
8942653
Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14536-41
8962087
J Biol Chem. 1997 Feb 14;272(7):4094-102
9020119
J Neuropathol Exp Neurol. 1997 May;56(5):523-30
9143265
Cell. 1997 Jun 27;89(7):1067-76
9215629
J Biol Chem. 1998 Mar 27;273(13):7523-8
9516453
Cell Stress Chaperones. 1998 Jun;3(2):100-8
9672245
Cell. 1998 Aug 21;94(4):471-80
9727490
Genes Dev. 1998 Dec 15;12(24):3788-96
9869631
J Med Chem. 1999 Jan 28;42(2):260-6
9925731
Brain Res. 1999 Mar 13;821(2):333-40
10064819
Biochem J. 2005 May 1;387(Pt 3):789-96
15584899