Arsenic attenuates gli signaling, increasing or decreasing its transcriptional program in a context-dependent manner

Bin Li, Camilla Giambelli, Bo Tang, Emily Winterbottom, Jun Long, Ke Jin, Zhiqiang Wang, Dennis Liang Fei, Dao M. Nguyen, Mohammad Athar, Baolin Wang, Subbayan Pochi, Lily Wang, Priyamvada Rai, Bach Ardalan, Anthony J. Capobianco, David J. Robbins

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The metalloid arsenic is a worldwide environmental toxicant, exposure to which is associated with many adverse outcomes. Arsenic is also an effective therapeutic agent in certain disease settings. Arsenic was recently shown to regulate the activity of the Hedgehog (HH) signal transduction pathway, and this regulation of HH signaling was proposed to be responsible for a subset of arsenic's biologic effects. Surprisingly, these separate reports proposed contradictory activities for arsenic, as either an agonist or antagonist of HH signaling. Here we provide in vitro and in vivo evidence that arsenic acts as a modulator of the activity of the HH effector protein glioma-Associated oncogene family zinc finger (GLI), activating or inhibiting GLI activity in a context-dependent manner. This arsenic-induced modulation of HH signaling is observed in cultured cells, patients with colorectal cancer who have received arsenic-based therapy, and a mouse colorectal cancer xenograft model. Our results show that arsenic activates GLI signaling when the intrinsic GLI activity is low but inhibits signaling in the presence of high-level GLI activity. Furthermore, we show that this modulation occurs downstream of primary cilia, evidenced by experiments in suppressor of fused homolog (SUFU) deficient cells. Combining our findings with previous reports, we present an inclusive model in which arsenic plays dual roles in GLI signaling modulation: when GLIs are primarily in their repressor form, arsenic antagonizes their repression capacity, leading to low-level GLI activation, but when GLIs are primarily in their activator form, arsenic attenuates their activity.

Original languageEnglish (US)
Pages (from-to)226-232
Number of pages7
JournalMolecular Pharmacology
Volume89
Issue number2
DOIs
StatePublished - Feb 1 2016

Fingerprint

Arsenic
Hedgehogs
Colorectal Neoplasms
Hedgehog Proteins
Metalloids
Cilia
Zinc Fingers
Environmental Exposure
Oncogenes
Heterografts
Glioma
Cultured Cells
Signal Transduction

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Arsenic attenuates gli signaling, increasing or decreasing its transcriptional program in a context-dependent manner. / Li, Bin; Giambelli, Camilla; Tang, Bo; Winterbottom, Emily; Long, Jun; Jin, Ke; Wang, Zhiqiang; Fei, Dennis Liang; Nguyen, Dao M.; Athar, Mohammad; Wang, Baolin; Pochi, Subbayan; Wang, Lily; Rai, Priyamvada; Ardalan, Bach; Capobianco, Anthony J.; Robbins, David J.

In: Molecular Pharmacology, Vol. 89, No. 2, 01.02.2016, p. 226-232.

Research output: Contribution to journalArticle

Li, Bin ; Giambelli, Camilla ; Tang, Bo ; Winterbottom, Emily ; Long, Jun ; Jin, Ke ; Wang, Zhiqiang ; Fei, Dennis Liang ; Nguyen, Dao M. ; Athar, Mohammad ; Wang, Baolin ; Pochi, Subbayan ; Wang, Lily ; Rai, Priyamvada ; Ardalan, Bach ; Capobianco, Anthony J. ; Robbins, David J. / Arsenic attenuates gli signaling, increasing or decreasing its transcriptional program in a context-dependent manner. In: Molecular Pharmacology. 2016 ; Vol. 89, No. 2. pp. 226-232.
@article{30051b5b5dc941358bd3fc56d976f0cd,
title = "Arsenic attenuates gli signaling, increasing or decreasing its transcriptional program in a context-dependent manner",
abstract = "The metalloid arsenic is a worldwide environmental toxicant, exposure to which is associated with many adverse outcomes. Arsenic is also an effective therapeutic agent in certain disease settings. Arsenic was recently shown to regulate the activity of the Hedgehog (HH) signal transduction pathway, and this regulation of HH signaling was proposed to be responsible for a subset of arsenic's biologic effects. Surprisingly, these separate reports proposed contradictory activities for arsenic, as either an agonist or antagonist of HH signaling. Here we provide in vitro and in vivo evidence that arsenic acts as a modulator of the activity of the HH effector protein glioma-Associated oncogene family zinc finger (GLI), activating or inhibiting GLI activity in a context-dependent manner. This arsenic-induced modulation of HH signaling is observed in cultured cells, patients with colorectal cancer who have received arsenic-based therapy, and a mouse colorectal cancer xenograft model. Our results show that arsenic activates GLI signaling when the intrinsic GLI activity is low but inhibits signaling in the presence of high-level GLI activity. Furthermore, we show that this modulation occurs downstream of primary cilia, evidenced by experiments in suppressor of fused homolog (SUFU) deficient cells. Combining our findings with previous reports, we present an inclusive model in which arsenic plays dual roles in GLI signaling modulation: when GLIs are primarily in their repressor form, arsenic antagonizes their repression capacity, leading to low-level GLI activation, but when GLIs are primarily in their activator form, arsenic attenuates their activity.",
author = "Bin Li and Camilla Giambelli and Bo Tang and Emily Winterbottom and Jun Long and Ke Jin and Zhiqiang Wang and Fei, {Dennis Liang} and Nguyen, {Dao M.} and Mohammad Athar and Baolin Wang and Subbayan Pochi and Lily Wang and Priyamvada Rai and Bach Ardalan and Capobianco, {Anthony J.} and Robbins, {David J.}",
year = "2016",
month = "2",
day = "1",
doi = "10.1124/mol.115.100867",
language = "English (US)",
volume = "89",
pages = "226--232",
journal = "Molecular Pharmacology",
issn = "0026-895X",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - Arsenic attenuates gli signaling, increasing or decreasing its transcriptional program in a context-dependent manner

AU - Li, Bin

AU - Giambelli, Camilla

AU - Tang, Bo

AU - Winterbottom, Emily

AU - Long, Jun

AU - Jin, Ke

AU - Wang, Zhiqiang

AU - Fei, Dennis Liang

AU - Nguyen, Dao M.

AU - Athar, Mohammad

AU - Wang, Baolin

AU - Pochi, Subbayan

AU - Wang, Lily

AU - Rai, Priyamvada

AU - Ardalan, Bach

AU - Capobianco, Anthony J.

AU - Robbins, David J.

PY - 2016/2/1

Y1 - 2016/2/1

N2 - The metalloid arsenic is a worldwide environmental toxicant, exposure to which is associated with many adverse outcomes. Arsenic is also an effective therapeutic agent in certain disease settings. Arsenic was recently shown to regulate the activity of the Hedgehog (HH) signal transduction pathway, and this regulation of HH signaling was proposed to be responsible for a subset of arsenic's biologic effects. Surprisingly, these separate reports proposed contradictory activities for arsenic, as either an agonist or antagonist of HH signaling. Here we provide in vitro and in vivo evidence that arsenic acts as a modulator of the activity of the HH effector protein glioma-Associated oncogene family zinc finger (GLI), activating or inhibiting GLI activity in a context-dependent manner. This arsenic-induced modulation of HH signaling is observed in cultured cells, patients with colorectal cancer who have received arsenic-based therapy, and a mouse colorectal cancer xenograft model. Our results show that arsenic activates GLI signaling when the intrinsic GLI activity is low but inhibits signaling in the presence of high-level GLI activity. Furthermore, we show that this modulation occurs downstream of primary cilia, evidenced by experiments in suppressor of fused homolog (SUFU) deficient cells. Combining our findings with previous reports, we present an inclusive model in which arsenic plays dual roles in GLI signaling modulation: when GLIs are primarily in their repressor form, arsenic antagonizes their repression capacity, leading to low-level GLI activation, but when GLIs are primarily in their activator form, arsenic attenuates their activity.

AB - The metalloid arsenic is a worldwide environmental toxicant, exposure to which is associated with many adverse outcomes. Arsenic is also an effective therapeutic agent in certain disease settings. Arsenic was recently shown to regulate the activity of the Hedgehog (HH) signal transduction pathway, and this regulation of HH signaling was proposed to be responsible for a subset of arsenic's biologic effects. Surprisingly, these separate reports proposed contradictory activities for arsenic, as either an agonist or antagonist of HH signaling. Here we provide in vitro and in vivo evidence that arsenic acts as a modulator of the activity of the HH effector protein glioma-Associated oncogene family zinc finger (GLI), activating or inhibiting GLI activity in a context-dependent manner. This arsenic-induced modulation of HH signaling is observed in cultured cells, patients with colorectal cancer who have received arsenic-based therapy, and a mouse colorectal cancer xenograft model. Our results show that arsenic activates GLI signaling when the intrinsic GLI activity is low but inhibits signaling in the presence of high-level GLI activity. Furthermore, we show that this modulation occurs downstream of primary cilia, evidenced by experiments in suppressor of fused homolog (SUFU) deficient cells. Combining our findings with previous reports, we present an inclusive model in which arsenic plays dual roles in GLI signaling modulation: when GLIs are primarily in their repressor form, arsenic antagonizes their repression capacity, leading to low-level GLI activation, but when GLIs are primarily in their activator form, arsenic attenuates their activity.

UR - http://www.scopus.com/inward/record.url?scp=84958162723&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84958162723&partnerID=8YFLogxK

U2 - 10.1124/mol.115.100867

DO - 10.1124/mol.115.100867

M3 - Article

C2 - 26573582

AN - SCOPUS:84958162723

VL - 89

SP - 226

EP - 232

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 2

ER -