Depletion of the cisplatin targeted HMGB-box factor UBF selectively induces p53-independent apoptotic death in transformed cells

Oncotarget
Nourdine HamdaneTom Moss

Abstract

Cisplatin-DNA adducts act as strong decoys for the Upstream Binding Factor UBF (UBTF) and have been shown to inhibit transcription of the ribosomal RNA genes by RNA polymerase I. However, it is unclear if this plays a significant role in the chemotherapeutic activity of cis- or carboplatin. We find that cisplatin in fact induces a very rapid displacement of UBF from the ribosomal RNA genes and strong inhibition of ribosomal RNA synthesis, consistent with this being an important factor in its cytotoxicity. Using conditional gene deletion, we recently showed that UBF is an essential factor for transcription of the ribosomal RNA genes and for ribosome biogenesis. We now show that loss of UBF arrests cell proliferation and induces fully penetrant, rapid and synchronous apoptosis, as well as nuclear disruption and cell death, specifically in cells subjected to oncogenic stress. Apoptosis is not affected by homozygous deletion of the p53 gene and occurs equally in cells transformed by SV40 T antigens, by Myc or by a combination of Ras & Myc oncogenes. The data strongly argue that inhibition of UBF function is a major factor in the cytotoxicity of cisplatin. Hence, drug targeting of UBF may be a preferable approach to the use of the h...Continue Reading

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Citations

Jan 5, 2018·Human Molecular Genetics·Camilo ToroMark S LeDoux
May 5, 2016·Histochemistry and Cell Biology·Dariusz Stępiński
Apr 4, 2021·Genes·Cecelia M HaroldSusan J Baserga
Apr 4, 2021·International Journal of Molecular Sciences·Małgorzata Grzanka, Agnieszka Piekiełko-Witkowska
Apr 6, 2021·The Journal of Biological Chemistry·Emily C Sutton, Victoria J DeRose
Sep 1, 2021·Signal Transduction and Targeted Therapy·Jian KangElaine Sanij

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Methods Mentioned

BETA
FACS
transfection
PCR
electrophoresis
immunoprecipitations
Assay

Software Mentioned

FACSDiva
Volocity

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