Neutrophil lactoferrin upregulates the human p53 gene through induction of NF-κB activation cascade

Sang Muk Oh, Chul Woong Pyo, Youngho Kim, Sang-Yun Choi

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45 Citations (Scopus)

Abstract

Neutrophil lactoferrin (Lf) was previously shown to act as a transcriptional activator in various mammalian cells. Here, we describe that Lf specifically transactivates the p53 tumor suppressor gene through the activation of nuclear factor-κB (NF-κB) and consequently regulates p53-responsive oncogenes. In HeLa cervical carcinoma cells stably expressing Lf (HeLa-Lf), expression of mdm2 and p21waf1/cip1 as well as p53 was greatly enhanced. Transient expression of Lf also markedly transactivates transcription of a p53 promoter-driven reporter and NF-κB-driven reporters in various mammalian cells. However, mutation of the NF-κB site or treatment with an NF-κB inhibitor abrogated the transactivation, suggesting that NF-κB should play an essential role in the Lf-induced transactivation. Increased binding activity and nuclear translocation of p65 in response to Lf strongly support these findings. Furthermore, Lf-mediated NF-κB activation is diminished in IKKα- or IKKβ-deficient mouse embryonic fibroblast cells. The activation of both IKKs and NF-κB by Lf is over-ridden by the expression of dominant-negative mutants of NIK, MEKK1, IKKα and IKKβ. Collectively, we conclude that overexpressed Lf directly relays signals to upstream components responsible for NF-κB activation, thereby leading to the activation of NF-κB target genes.

Original languageEnglish
Pages (from-to)8282-8291
Number of pages10
JournalOncogene
Volume23
Issue number50
DOIs
Publication statusPublished - 2004 Oct 28

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Keywords

  • Lactoferrin
  • NF-κB
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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