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

Research output: Contribution to journalArticle

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

Fingerprint

Lactoferrin
Complement Factor B
p53 Genes
Neutrophils
Up-Regulation
Transcriptional Activation
Tumor Suppressor Genes
Oncogenes
Fibroblasts
Carcinoma
Mutation

Keywords

  • Lactoferrin
  • NF-κB
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Neutrophil lactoferrin upregulates the human p53 gene through induction of NF-κB activation cascade. / Oh, Sang Muk; Pyo, Chul Woong; Kim, Youngho; Choi, Sang-Yun.

In: Oncogene, Vol. 23, No. 50, 28.10.2004, p. 8282-8291.

Research output: Contribution to journalArticle

Oh, Sang Muk ; Pyo, Chul Woong ; Kim, Youngho ; Choi, Sang-Yun. / Neutrophil lactoferrin upregulates the human p53 gene through induction of NF-κB activation cascade. In: Oncogene. 2004 ; Vol. 23, No. 50. pp. 8282-8291.
@article{cd893fcbf2074ba88647bcadafe4c1da,
title = "Neutrophil lactoferrin upregulates the human p53 gene through induction of NF-κB activation cascade",
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.",
keywords = "Lactoferrin, NF-κB, p53",
author = "Oh, {Sang Muk} and Pyo, {Chul Woong} and Youngho Kim and Sang-Yun Choi",
year = "2004",
month = "10",
day = "28",
doi = "10.1038/sj.onc.1208021",
language = "English",
volume = "23",
pages = "8282--8291",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "50",

}

TY - JOUR

T1 - Neutrophil lactoferrin upregulates the human p53 gene through induction of NF-κB activation cascade

AU - Oh, Sang Muk

AU - Pyo, Chul Woong

AU - Kim, Youngho

AU - Choi, Sang-Yun

PY - 2004/10/28

Y1 - 2004/10/28

N2 - 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.

AB - 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.

KW - Lactoferrin

KW - NF-κB

KW - p53

UR - http://www.scopus.com/inward/record.url?scp=8844263029&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=8844263029&partnerID=8YFLogxK

U2 - 10.1038/sj.onc.1208021

DO - 10.1038/sj.onc.1208021

M3 - Article

VL - 23

SP - 8282

EP - 8291

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 50

ER -