p53 inhibitor pifithrin alpha can suppress heat shock and glucocorticoid signaling pathways.
Pifithrin alpha (PFTalpha) is a chemical compound isolated for its ability to suppress p53-mediated transactivation. It can protect cells from p53-mediated apoptosis induced by various stimuli and reduce sensitivity of mice to gamma radiation. Identification of molecular targets of PFTalpha is likely to provide new insights into mechanisms of regulation of p53 pathway and is important for predicting potential risks associated with administration of PFTalpha-like p53 inhibitors in vivo. We found that PFTalpha, in addition to p53, can suppress heat shock and glucocorticoid receptor signaling but has no effect on nuclear factor-kappaB signaling. PFTalpha reduces activation of heat shock transcription factor (HSF1) and increases cell sensitivity to heat. Moreover, it reduces activation of glucocorticoid receptor and rescues mouse thymocytes in vitro and in vivo from apoptotic death after dexamethasone treatment. PFTalpha affected both signaling pathways in a p53-independent manner. These observations suggest that PFTalpha targets some unknown factor that is common for three major signal transduction pathways.
Komarova
Elena A
EA
Department of Molecular Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Neznanov
Nickolay
N
Komarov
Pavel G
PG
Chernov
Mikhail V
MV
Wang
Kaihua
K
Gudkov
Andrei V
AV
D000818:Animals; D052160:Benzothiazoles; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D005938:Glucocorticoids / Q000494:pharmacology*; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000187:drug effects*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology*; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
D052160:Benzothiazoles; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D000076249:Heat Shock Transcription Factors; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D013844:Thiazoles; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin