Differential inhibition of the DNA binding of transcription factors NFκB and OTF-1 by nitrogen mustard and quinacrine mustard: Transcriptional implications

Sandra Fabbri, Cesaria Prontera, Massimo Broggini, Maurizio D'Incalci

Research output: Contribution to journalArticle

Abstract

Nitrogen mustard (HN2) and quinacrine mustard (QM) both inhibited the binding of NFκB to the GC-rich consensus sequence in the HIV long terminal repeat (LTR), as assessed by gel-shift assays. QM also inhibited the binding of OTF-1 to the AT-rich octamer present in the H2B promoter whereas HN2 was inactive. Inhibition of the binding of transcription factors was due to the drug interaction with DNA, since it also occurred when transcription factors were added to DNA after removal of free drug. In Jurkat cells transfected with pI3CAT, where the chloramphenicol acetyltransferase (CAT) gene is under the control of the HIV LTR, both HN2 and QM inhibited CAT gene expression. However, in Jurkat cells transfected with plasmid -147, where the CAT gene is under the control of the H2B promoter, QM inhibited CAT expression but HN2 did not. These results were obtained at concentrations of HN2 or QM that inhibited total DNA and RNA synthesis to a similar extent. The present results suggest that the more selective pharmacological activity of HN2 (HN2 is an active antineoplastic agent whereas QM is inactive and very toxic) might be related to its preferential functional inhibition of GC-rich consensus sequence, possibly important in the regulation of genes involved in the malignant proliferation and behavior of some tumors.

Original languageEnglish
Pages (from-to)1963-1967
Number of pages5
JournalCarcinogenesis
Volume14
Issue number9
Publication statusPublished - Sep 1993

Fingerprint

Quinacrine Mustard
Octamer Transcription Factor-1
Mechlorethamine
Transcription factors
Transcription Factor
Nitrogen
Chloramphenicol O-Acetyltransferase
DNA
Genes
Gene
Promoter
Drugs
HIV Long Terminal Repeat
GC Rich Sequence
Drug interactions
RNA Synthesis
Jurkat Cells
Cell
Consensus Sequence
Proliferation

ASJC Scopus subject areas

  • Cancer Research
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Physiology (medical)
  • Physiology
  • Behavioral Neuroscience

Cite this

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abstract = "Nitrogen mustard (HN2) and quinacrine mustard (QM) both inhibited the binding of NFκB to the GC-rich consensus sequence in the HIV long terminal repeat (LTR), as assessed by gel-shift assays. QM also inhibited the binding of OTF-1 to the AT-rich octamer present in the H2B promoter whereas HN2 was inactive. Inhibition of the binding of transcription factors was due to the drug interaction with DNA, since it also occurred when transcription factors were added to DNA after removal of free drug. In Jurkat cells transfected with pI3CAT, where the chloramphenicol acetyltransferase (CAT) gene is under the control of the HIV LTR, both HN2 and QM inhibited CAT gene expression. However, in Jurkat cells transfected with plasmid -147, where the CAT gene is under the control of the H2B promoter, QM inhibited CAT expression but HN2 did not. These results were obtained at concentrations of HN2 or QM that inhibited total DNA and RNA synthesis to a similar extent. The present results suggest that the more selective pharmacological activity of HN2 (HN2 is an active antineoplastic agent whereas QM is inactive and very toxic) might be related to its preferential functional inhibition of GC-rich consensus sequence, possibly important in the regulation of genes involved in the malignant proliferation and behavior of some tumors.",
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AU - Prontera, Cesaria

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AU - D'Incalci, Maurizio

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AB - Nitrogen mustard (HN2) and quinacrine mustard (QM) both inhibited the binding of NFκB to the GC-rich consensus sequence in the HIV long terminal repeat (LTR), as assessed by gel-shift assays. QM also inhibited the binding of OTF-1 to the AT-rich octamer present in the H2B promoter whereas HN2 was inactive. Inhibition of the binding of transcription factors was due to the drug interaction with DNA, since it also occurred when transcription factors were added to DNA after removal of free drug. In Jurkat cells transfected with pI3CAT, where the chloramphenicol acetyltransferase (CAT) gene is under the control of the HIV LTR, both HN2 and QM inhibited CAT gene expression. However, in Jurkat cells transfected with plasmid -147, where the CAT gene is under the control of the H2B promoter, QM inhibited CAT expression but HN2 did not. These results were obtained at concentrations of HN2 or QM that inhibited total DNA and RNA synthesis to a similar extent. The present results suggest that the more selective pharmacological activity of HN2 (HN2 is an active antineoplastic agent whereas QM is inactive and very toxic) might be related to its preferential functional inhibition of GC-rich consensus sequence, possibly important in the regulation of genes involved in the malignant proliferation and behavior of some tumors.

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