Effects on normal fibroblasts and neuroblastoma cells of the activation of the p53 response by the nuclear export inhibitor leptomycin B.
p53 tumour suppressor protein levels and p53-dependent transcriptional activity have been recently shown to increase in cells treated with leptomycin B (LMB), an inhibitor of nuclear export. Experiments presented here show that LMB treatment leads to growth arrest and a senescence-like phenotype in human normal fibroblast cultures. This effect is reversible after removal of the drug and further passage by trypsinization. Instead, LMB has a strong cytotoxic effect on human neuroblastoma cell lines even at nanomolar concentrations. In both these cell types the effects of LMB are attenuated when the activity of the endogenous wild type p53 protein is abrogated by overexpression of a dominant negative p53 mutant. We conclude that the induction of the p53 response by LMB plays an important role in the effects of this drug on cultured cells.
Smart
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P
CRC Cell Structure Research Group, Department of Anatomy and Physiology, MSI/WTB Complex, University of Dundee, Dundee DD1 5EH, UK.
Lane
E B
EB
Lane
D P
DP
Midgley
C
C
Vojtesek
B
B
Laín
S
S
D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000502:physiology; D005231:Fatty Acids, Unsaturated / Q000378:metabolism / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016158:Genes, p53; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*
D000903:Antibiotics, Antineoplastic; D005231:Fatty Acids, Unsaturated; C038753:leptomycin B