Hsf1-mediated stress response can transiently enhance cellular radioresistance.
To elucidate how the heat-shock transcription factor 1 (Hsf1)-mediated stress response affects cellular radioresistance, mouse embryo fibroblasts with Hsf1-gene knockout (Hsf1(-/-) cells) or with normal wild-type Hsf1 expression (Hsf1 wild-type cells) were preconditioned by heating (43 degrees C, 30 min) without or with quercetin (an inhibitor of Hsf1) and then exposed to gamma radiation (4 or 6 Gy). Some cell samples were infected with virus-based vectors to overexpress the constitutively active (mutant) form of Hsf1 or individual heat-shock proteins (Hsps). The heat preconditioning transiently up-regulated the Hsp levels in Hsf1 wild-type cells and significantly improved their postirradiation survival; these effects could be abolished by quercetin or simulated (without preheating) by the Hsf1 overexpression. In contrast, no enhanced radioresistance was found in heat-preconditioned Hsf1(-/-) cells that were unable to trigger Hsf1-mediated Hsp induction after heating. However, when the constitutively active Hsf1 was overexpressed in Hsf1(-/-) cells, the latter accumulated stress-inducible Hsps and became more radioresistant like heat-preconditioned Hsf1 wild-type cells. The overexpression of Hsp70 or/ and Hsp27 also enhanced radioresistance of both cell cultures. Thus the preirradiation stress response resulting in the intracellular Hsp accumulation can improve survival of severely irradiated mammalian cells.
Kabakov
Alexander E
AE
Medical Radiology Research Center, Obninsk 249036, Russia. aekabakov@hotmail.com
Malyutina
Yana V
YV
Latchman
David S
DS
D000818:Animals; D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology* / Q000528:radiation effects*; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000502:physiology* / Q000528:radiation effects*; D051379:Mice; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D014157:Transcription Factors