Triptolide-induced transcriptional arrest is associated with changes in nuclear substructure.
Triptolide, an active component of the medicinal herb lei gong teng, is a potent anticancer and anti-inflammatory therapeutic. It potently inhibits nuclear factor-kappaB transcriptional activation after DNA binding, although a precise mechanism is as yet unknown. Here, we report that triptolide also induces distinct nuclear substructural changes in HeLa cells. These changes in the nucleolus and nuclear speckles are reversible and dependent on both time and concentration. Furthermore, nuclear changes occurred within hours of triptolide treatment and were calcium and caspase independent. Rounding of nuclear speckles, an indication of transcriptional arrest, was evident and was associated with a decrease in RNA polymerase II (RNA Pol II) COOH-terminal domain Ser(2) phosphorylation. Additionally, the nucleolus disassembled and RNA Pol I activity declined after RNA Pol II inhibition. We therefore conclude that triptolide causes global transcriptional arrest as evidenced by inactivity of RNA Pol I and II and the subsequent alteration in nuclear substructure.
Leuenroth
Stephanie J
SJ
Department of Molecular, Yale University, New Haven, Connecticut 06520-8103, USA.
Crews
Craig M
CM
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism / Q000502:physiology; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure*; D002999:Clone Cells; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D004852:Epoxy Compounds / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D000090243:Nucleophosmin; D010616:Phenanthrenes / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D035463:Pol1 Transcription Initiation Complex Proteins / Q000378:metabolism; D012319:RNA Polymerase II / Q000187:drug effects / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D014158:Transcription, Genetic / Q000187:drug effects*; D000097796:Nucleolin
D018906:Antineoplastic Agents, Alkylating; D002118:Calcium; D020169:Caspases; D004224:Diterpenes; D004852:Epoxy Compounds; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D010616:Phenanthrenes; D010750:Phosphoproteins; D035463:Pol1 Transcription Initiation Complex Proteins; D012319:RNA Polymerase II; D016601:RNA-Binding Proteins; D000097796:Nucleolin; C063844:transcription factor UBF; C001899:triptolide