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

Journal Article · Tue Mar 15 04:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.12.015· OSTI ID:21535256

Iwatsuki, Mamiko; Inageda, Kiyoshi; Matsuoka, Masato

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}.

• OSTI ID: 21535256
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 251; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ALANINES
AMINO ACIDS
BODY
CADMIUM
CADMIUM CHLORIDES
CADMIUM COMPOUNDS
CADMIUM HALIDES
CARBOXYLIC ACIDS
CHEMICAL REACTIONS
CHLORIDES
CHLORINE COMPOUNDS
DMSO
ELECTROPHORESIS
ELEMENTS
ENZYMES
GENE AMPLIFICATION
HALIDES
HALOGEN COMPOUNDS
HYDROXY ACIDS
KIDNEYS
METALS
MUTATIONS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC SULFUR COMPOUNDS
ORGANS
PHOSPHORUS-GROUP TRANSFERASES
PHOSPHORYLATION
PHOSPHOTRANSFERASES
POLYMERASE CHAIN REACTION
PROTEINS
RESIDUES
SERINE
SULFOXIDES
TRANSCRIPTION FACTORS
TRANSFERASES