Identification by DNA macroarray of nur77 as a gene induced by di-n-butyltin dichloride: its role in organotin-induced apoptosis.
The thymotoxic organotin compounds di-n-butyltin dichloride (DBTC) and tri-n-butyltin chloride (TBTC) are known to induce apoptosis in vitro in rat thymocytes. They also affect macromolecular synthesis, inhibiting DNA synthesis and increasing RNA synthesis. Since these RNA molecules, likely to be involved in the initiation of the apoptotic process, have not been identified yet, the purpose of this research was to characterize by a cDNA macroarray the expression of genes involved in DBTC-induced apoptosis. We found that nur77 was rapidly transcripted in vitro following exposure of freshly isolated rat thymocytes to 3 microM DBTC. nur77 induction has also been observed in vivo after treatment of rats with apoptotic doses (60 mg/kg body wt) of DBTC. The products of nur77 are known to be involved in the apoptotic process, as nur77 is a transcription factor expressed in response to T-cell receptor-mediated apoptosis in immature T cells. Antisense oligonucleotide inhibition of nur77 expression prevented apoptosis induced by DBTC, supporting a role for nur77 in organotin-induced apoptotic cell death.
Gennari
Alessandra
A
Laboratory of Toxicology, Department of Pharmacological Sciences, University of Milan, Italy.
Bleumink
Rob
R
Viviani
Barbara
B
Galli
Corrado Lodovico
CL
Marinovich
Marina
M
Pieters
Raymond
R
Corsini
Emanuela
E
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D017403:In Situ Hybridization; D008297:Male; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D009693:Nucleic Acid Hybridization / Q000379:methods; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D009947:Organotin Compounds / Q000633:toxicity*; D012313:RNA / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D016376:Oligonucleotides, Antisense; D009947:Organotin Compounds; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; C056189:di-n-butyltin; D012313:RNA