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Title: Cadmium induces phosphorylation and stabilization of c-Fos in HK-2 renal proximal tubular cells

Abstract

We examined the effects of cadmium chloride (CdCl{sub 2}) exposure on the expression and phosphorylation status of members of the Fos family, components of the activator protein-1 transcription factor, in HK-2 human renal proximal tubular cells. Following the exposure to CdCl{sub 2}, the expression of c-fos, fosB, fra-1, and fra-2 increased markedly, with different magnitudes and time courses. The levels of Fos family proteins (c-Fos, FosB, Fra-1, and Fra-2) also increased in response to CdCl{sub 2} exposure. Although the elevation of c-fos transcripts was transient, c-Fos protein levels increased progressively with lower electrophoretic mobility, suggesting stabilization of c-Fos through post-translational modifications. Consistently, we observed phosphorylation of c-Fos at Ser362 and Ser374 in HK-2 cells treated with CdCl{sub 2}. Phosphorylated forms of mitogen-activated protein kinases (MAPKs)-including extracellular signal-regulated protein kinase (ERK), c-Jun NH{sub 2}-terminal kinase, and p38-increased after CdCl{sub 2} exposure, whereas treatment with the MAPK/ERK kinase inhibitor U0126 and the p38 inhibitor SB203580 suppressed the accumulation and phosphorylation of c-Fos. We mutated Ser362 to alanine (S362A), Ser374 to alanine (S374A), and both residues to alanines (S362A/S374A) to inhibit potential phosphorylation of c-Fos at these sites. S374A or double S362A/S374A mutations reduced c-Fos level markedly, but S362A mutation did not. Onmore » the other hand, S362A/S374A mutations induced a more pronounced reduction in c-Fos DNA-binding activity than S374A mutation. These results suggest that while Ser374 phosphorylation seems to play a role in c-Fos stabilization, phosphorylation at two C-terminal serine residues is required for the transcriptional activation of c-Fos in HK-2 cells treated with CdCl{sub 2}.« less

Authors:
; ;
Publication Date:
OSTI Identifier:
21535256
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 251; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2010.12.015; PII: S0041-008X(11)00002-0; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ALANINES; CADMIUM; CADMIUM CHLORIDES; DMSO; ELECTROPHORESIS; KIDNEYS; MUTATIONS; PHOSPHORYLATION; PHOSPHOTRANSFERASES; POLYMERASE CHAIN REACTION; RESIDUES; SERINE; TRANSCRIPTION FACTORS; AMINO ACIDS; BODY; CADMIUM COMPOUNDS; CADMIUM HALIDES; CARBOXYLIC ACIDS; CHEMICAL REACTIONS; CHLORIDES; CHLORINE COMPOUNDS; ELEMENTS; ENZYMES; GENE AMPLIFICATION; HALIDES; HALOGEN COMPOUNDS; HYDROXY ACIDS; METALS; ORGANIC ACIDS; ORGANIC COMPOUNDS; ORGANIC SULFUR COMPOUNDS; ORGANS; PHOSPHORUS-GROUP TRANSFERASES; PROTEINS; SULFOXIDES; TRANSFERASES

Citation Formats

Iwatsuki, Mamiko, Inageda, Kiyoshi, and Matsuoka, Masato. Cadmium induces phosphorylation and stabilization of c-Fos in HK-2 renal proximal tubular cells. United States: N. p., 2011. Web. doi:10.1016/j.taap.2010.12.015.
Iwatsuki, Mamiko, Inageda, Kiyoshi, & Matsuoka, Masato. Cadmium induces phosphorylation and stabilization of c-Fos in HK-2 renal proximal tubular cells. United States. https://doi.org/10.1016/j.taap.2010.12.015
Iwatsuki, Mamiko, Inageda, Kiyoshi, and Matsuoka, Masato. 2011. "Cadmium induces phosphorylation and stabilization of c-Fos in HK-2 renal proximal tubular cells". United States. https://doi.org/10.1016/j.taap.2010.12.015.
@article{osti_21535256,
title = {Cadmium induces phosphorylation and stabilization of c-Fos in HK-2 renal proximal tubular cells},
author = {Iwatsuki, Mamiko and Inageda, Kiyoshi and Matsuoka, Masato},
abstractNote = {We examined the effects of cadmium chloride (CdCl{sub 2}) exposure on the expression and phosphorylation status of members of the Fos family, components of the activator protein-1 transcription factor, in HK-2 human renal proximal tubular cells. Following the exposure to CdCl{sub 2}, the expression of c-fos, fosB, fra-1, and fra-2 increased markedly, with different magnitudes and time courses. The levels of Fos family proteins (c-Fos, FosB, Fra-1, and Fra-2) also increased in response to CdCl{sub 2} exposure. Although the elevation of c-fos transcripts was transient, c-Fos protein levels increased progressively with lower electrophoretic mobility, suggesting stabilization of c-Fos through post-translational modifications. Consistently, we observed phosphorylation of c-Fos at Ser362 and Ser374 in HK-2 cells treated with CdCl{sub 2}. Phosphorylated forms of mitogen-activated protein kinases (MAPKs)-including extracellular signal-regulated protein kinase (ERK), c-Jun NH{sub 2}-terminal kinase, and p38-increased after CdCl{sub 2} exposure, whereas treatment with the MAPK/ERK kinase inhibitor U0126 and the p38 inhibitor SB203580 suppressed the accumulation and phosphorylation of c-Fos. We mutated Ser362 to alanine (S362A), Ser374 to alanine (S374A), and both residues to alanines (S362A/S374A) to inhibit potential phosphorylation of c-Fos at these sites. S374A or double S362A/S374A mutations reduced c-Fos level markedly, but S362A mutation did not. On the other hand, S362A/S374A mutations induced a more pronounced reduction in c-Fos DNA-binding activity than S374A mutation. These results suggest that while Ser374 phosphorylation seems to play a role in c-Fos stabilization, phosphorylation at two C-terminal serine residues is required for the transcriptional activation of c-Fos in HK-2 cells treated with CdCl{sub 2}.},
doi = {10.1016/j.taap.2010.12.015},
url = {https://www.osti.gov/biblio/21535256}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 251,
place = {United States},
year = {Tue Mar 15 00:00:00 EDT 2011},
month = {Tue Mar 15 00:00:00 EDT 2011}
}