The spliceosome inhibitors isoginkgetin and pladienolide B induce ATF3-dependent cell death

Autor: Pasan Fernando, Hadil Sayed, Bruce C. McKay, Erin J. Vanzyl, Kayleigh R C Rick, Alex B. Blackmore
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Activating transcription factor
Cultured tumor cells
Gene Expression
Apoptosis
Biochemistry
Mice
0302 clinical medicine
Spectrum Analysis Techniques
Nucleic Acids
Null cell
Cytotoxic T cell
RNA
Small Interfering
Cell Analysis
Multidisciplinary
Cell Death
Chemistry
Messenger RNA
Transfection
Small interfering RNA
Flow Cytometry
Cell biology
Bioassays and Physiological Analysis
Cell Processes
Spectrophotometry
030220 oncology & carcinogenesis
Gene Knockdown Techniques
RNA splicing
Medicine
Cell lines
Cytophotometry
Macrolides
Biological cultures
Research Article
Spliceosome
Cell Viability Testing
Science
03 medical and health sciences
Genetics
Animals
Biflavonoids
Humans
HeLa cells
Non-coding RNA
Transcription factor
Activating Transcription Factor 3
Intron
RNA
Biology and Life Sciences
Cell Biology
Fibroblasts
Cell cultures
Gene regulation
Research and analysis methods
030104 developmental biology
Cell culture
Spliceosomes
Epoxy Compounds
Zdroj: PLoS ONE
PLoS ONE, Vol 15, Iss 12, p e0224953 (2020)
ISSN: 1932-6203
Popis: The spliceosome assembles on pre-mRNA in a stepwise manner through five successive pre-spliceosome complexes. The spliceosome functions to remove introns from pre-mRNAs to generate mature mRNAs that encode functional proteins. Many small molecule inhibitors of the spliceosome have been identified and they are cytotoxic. However, little is known about genetic determinants of cell sensitivity. Activating transcription factor 3 (ATF3) is a transcription factor that can stimulate apoptotic cell death in response to a variety of cellular stresses. Here, we used a genetic approach to determine if ATF3 was important in determining the sensitivity of mouse embryonic fibroblasts (MEFs) to two splicing inhibitors: pladienolide B (PB) and isoginkgetin (IGG), that target different pre-spliceosome complexes. Both compounds led to increased ATF3 expression and apoptosis in control MEFs while ATF3 null cells were significantly protected from the cytotoxic effects of these drugs. Similarly, ATF3 was induced in response to IGG and PB in the two human tumour cell lines tested while knockdown of ATF3 protected cells from both drugs. Taken together, ATF3 appears to contribute to the cytotoxicity elicited by these spliceosome inhibitors in both murine and human cells.
Databáze: OpenAIRE
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