Elucidating the mechanism of action of the immunosuppressant 15-deoxyspergualin.
15-Deoxyspergualin (DSG) is an immunosuppressive agent currently in Phase I/II clinical trials. We have previously shown that DSG specifically interacts with Hsc70, a member of the heat shock protein 70 family. In this article we show that DSG appears to bind either kinetically or to a different site on Hsc70 from that of peptides. In addition, we show that DSG inhibits the localization of Hsp70 into the nucleus in response to heat shock. Finally, data are presented showing that there is a correlation between decreases in the transcription factor nuclear factor kappa B and kappa light chain expression in response to varying doses of DSG.
Nadler
S G
SG
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121, USA.
Eversole
A C
AC
Tepper
M A
MA
Cleaveland
J S
JS
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002467:Cell Nucleus / Q000187:drug effects; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D007145:Immunoglobulin kappa-Chains / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology*; D007939:Leukemia L1210; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000187:drug effects; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding
D006146:Guanidines; D018840:HSP70 Heat-Shock Proteins; D007145:Immunoglobulin kappa-Chains; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D010455:Peptides; C037258:gusperimus