Blockage of JNK pathway enhances arsenic trioxide-induced apoptosis in human keratinocytes

Huei-Sheng Huang, Zi Miao Liu, Duang Yang Hong

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Arsenic is well known as a carcinogen predisposing humans to some severe diseases and also as an effective medicine for treating acute promyelocytic leukemia, syphilis, and psoriasis. Multiple active mechanisms, including cell cycle arrest and apoptosis, have been proposed in therapy; however, the opposing effects of arsenic remain controversial. Our previous study found that arsenic trioxide (ATO)-induced activation of p21WAF1/CIP1 (p21) led to A431 cell death through the antagonistic effects of the signaling of ERK1/2 and JNK1. In the current study, the inhibitory effects of JNK1 on ATO-induced p21 expression were explored. Over-expression of JNK1 in A431 cells could inhibit p21 expression, which was associated with HDAC1 and TGIF. Using the GST pull-down assay and fluorescence resonance energy transfer analysis, N-terminal domain (amino acids 1-108) of TGIF, critical to its binding with c-Jun, was found. Using reporter assays, requirement of the C-terminal domain (amino acids 138-272) of TGIF to suppress ATO-induced p21 expression was observed. Thus, the domains of TGIF that carried out its inhibitory effects on p21 were identified. Finally, treatment with JNK inhibitor SP600125 could enhance ATO-induced apoptosis of HaCaT keratinocytes by using flow cytometry.

Original languageEnglish
Pages (from-to)234-241
Number of pages8
JournalToxicology and Applied Pharmacology
Volume244
Issue number2
DOIs
Publication statusPublished - 2010 Apr 1

Fingerprint

MAP Kinase Signaling System
Keratinocytes
Apoptosis
Arsenic
Assays
Amino Acids
Fluorescence Resonance Energy Transfer
Acute Promyelocytic Leukemia
Flow cytometry
Cell death
Syphilis
Cell Cycle Checkpoints
Psoriasis
Carcinogens
Medicine
Flow Cytometry
Cell Death
Chemical activation
Cells
arsenic trioxide

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Toxicology

Cite this

@article{4e19da4e59cd4d3aa84aa224ca33eb3a,
title = "Blockage of JNK pathway enhances arsenic trioxide-induced apoptosis in human keratinocytes",
abstract = "Arsenic is well known as a carcinogen predisposing humans to some severe diseases and also as an effective medicine for treating acute promyelocytic leukemia, syphilis, and psoriasis. Multiple active mechanisms, including cell cycle arrest and apoptosis, have been proposed in therapy; however, the opposing effects of arsenic remain controversial. Our previous study found that arsenic trioxide (ATO)-induced activation of p21WAF1/CIP1 (p21) led to A431 cell death through the antagonistic effects of the signaling of ERK1/2 and JNK1. In the current study, the inhibitory effects of JNK1 on ATO-induced p21 expression were explored. Over-expression of JNK1 in A431 cells could inhibit p21 expression, which was associated with HDAC1 and TGIF. Using the GST pull-down assay and fluorescence resonance energy transfer analysis, N-terminal domain (amino acids 1-108) of TGIF, critical to its binding with c-Jun, was found. Using reporter assays, requirement of the C-terminal domain (amino acids 138-272) of TGIF to suppress ATO-induced p21 expression was observed. Thus, the domains of TGIF that carried out its inhibitory effects on p21 were identified. Finally, treatment with JNK inhibitor SP600125 could enhance ATO-induced apoptosis of HaCaT keratinocytes by using flow cytometry.",
author = "Huei-Sheng Huang and Liu, {Zi Miao} and Hong, {Duang Yang}",
year = "2010",
month = "4",
day = "1",
doi = "10.1016/j.taap.2009.12.037",
language = "English",
volume = "244",
pages = "234--241",
journal = "Toxicology and Applied Pharmacology",
issn = "0041-008X",
publisher = "Academic Press Inc.",
number = "2",

}

Blockage of JNK pathway enhances arsenic trioxide-induced apoptosis in human keratinocytes. / Huang, Huei-Sheng; Liu, Zi Miao; Hong, Duang Yang.

In: Toxicology and Applied Pharmacology, Vol. 244, No. 2, 01.04.2010, p. 234-241.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Blockage of JNK pathway enhances arsenic trioxide-induced apoptosis in human keratinocytes

AU - Huang, Huei-Sheng

AU - Liu, Zi Miao

AU - Hong, Duang Yang

PY - 2010/4/1

Y1 - 2010/4/1

N2 - Arsenic is well known as a carcinogen predisposing humans to some severe diseases and also as an effective medicine for treating acute promyelocytic leukemia, syphilis, and psoriasis. Multiple active mechanisms, including cell cycle arrest and apoptosis, have been proposed in therapy; however, the opposing effects of arsenic remain controversial. Our previous study found that arsenic trioxide (ATO)-induced activation of p21WAF1/CIP1 (p21) led to A431 cell death through the antagonistic effects of the signaling of ERK1/2 and JNK1. In the current study, the inhibitory effects of JNK1 on ATO-induced p21 expression were explored. Over-expression of JNK1 in A431 cells could inhibit p21 expression, which was associated with HDAC1 and TGIF. Using the GST pull-down assay and fluorescence resonance energy transfer analysis, N-terminal domain (amino acids 1-108) of TGIF, critical to its binding with c-Jun, was found. Using reporter assays, requirement of the C-terminal domain (amino acids 138-272) of TGIF to suppress ATO-induced p21 expression was observed. Thus, the domains of TGIF that carried out its inhibitory effects on p21 were identified. Finally, treatment with JNK inhibitor SP600125 could enhance ATO-induced apoptosis of HaCaT keratinocytes by using flow cytometry.

AB - Arsenic is well known as a carcinogen predisposing humans to some severe diseases and also as an effective medicine for treating acute promyelocytic leukemia, syphilis, and psoriasis. Multiple active mechanisms, including cell cycle arrest and apoptosis, have been proposed in therapy; however, the opposing effects of arsenic remain controversial. Our previous study found that arsenic trioxide (ATO)-induced activation of p21WAF1/CIP1 (p21) led to A431 cell death through the antagonistic effects of the signaling of ERK1/2 and JNK1. In the current study, the inhibitory effects of JNK1 on ATO-induced p21 expression were explored. Over-expression of JNK1 in A431 cells could inhibit p21 expression, which was associated with HDAC1 and TGIF. Using the GST pull-down assay and fluorescence resonance energy transfer analysis, N-terminal domain (amino acids 1-108) of TGIF, critical to its binding with c-Jun, was found. Using reporter assays, requirement of the C-terminal domain (amino acids 138-272) of TGIF to suppress ATO-induced p21 expression was observed. Thus, the domains of TGIF that carried out its inhibitory effects on p21 were identified. Finally, treatment with JNK inhibitor SP600125 could enhance ATO-induced apoptosis of HaCaT keratinocytes by using flow cytometry.

UR - http://www.scopus.com/inward/record.url?scp=77950058429&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77950058429&partnerID=8YFLogxK

U2 - 10.1016/j.taap.2009.12.037

DO - 10.1016/j.taap.2009.12.037

M3 - Article

VL - 244

SP - 234

EP - 241

JO - Toxicology and Applied Pharmacology

JF - Toxicology and Applied Pharmacology

SN - 0041-008X

IS - 2

ER -