The effect of sulforaphane on gene expression in FHL124 - a human lens epithelial cell line
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Ian Michael Wormstone
PROVIDER: E-MEXP-3923 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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2009-06-08 | E-GEOD-13979 | biostudies-arrayexpress
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Project description:Deregulated cell migration and invasion, which are hallmarks of metastatic cancer cells, are correlated to structural and functional alterations of the actin cytoskeleton associated to a large panel of actin-binding proteins. Among these, the actin-bundling protein L-plastin, initially detected in leukocytes, is ectopically expressed in several solid tumours and is often considered as a metastatic marker. Phosphorylation of L-plastin on residue serine 5 (Ser5) has been shown to activate L-plastin and to be crucial for invasion and metastasis formation. Here, we investigate the signalling pathway leading to L-plastin Ser5 phosphorylation in four breast cancer cell lines. Whole genome microarray analysis comparing cell lines with different invasive capacities and corresponding L-plastin Ser5 phosphorylation levels revealed that genes of the MAPK/ERK pathway are differentially expressed. In line, in vitro kinase assays showed that MAPK/ERK pathway downstream kinases RSK1 and RSK2 are able to directly phosphorylate L-plastin on Ser5. In parallel to a knockdown approach, activation and inhibition studies of signalling molecules of the MAPK/ERK pathway, followed by computational modelling analysis, confirmed that RSK is an important activator of L-plastin in all four studied cell lines. Finally and rounding up our study, RSK knockdown significantly impaired migratory and invasive capacities of a selected invasive cell line, thus consolidating RSK as a promising therapeutic target in certain invasive carcinomas. Altogether, our data provide substantial evidence that the MAPK/ERK pathway is involved in L-plastin Ser5 phosphorylation in breast cancer cells with its downstream kinases RSK1 and RSK2 being able to directly phosphorylate L-plastin on Ser5.
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Project description:SH-SY5Y, neuroblastoma cells, were exposed to nicotine for 10, 60, and 90 minutes or cocaine for 5, 20, 40, and 60 minutes. Drugs of abuse modify behavior by altering gene expression in the brain. Gene expression can be regulated by changes in DNA methylation as well as by histone modifications, which alter chromatin structure, DNA compaction and DNA accessibility. In order to better understand the molecular mechanisms directing drug-induced changes in chromatin structure, we examined DNA-nucleosome interactions within promoter regions of 858 genes in human neuroblastoma cells (SH-SY5Y) exposed to nicotine or cocaine. Widespread, drug- and time-resolved repositioning of nucleosomes was identified at the transcription start site and promoter region of multiple genes. Nicotine and cocaine produced unique and shared changes in terms of the numbers and types of genes affected, as well as repositioning of nucleosomes at sites which could increase or decrease the probability of gene expression based on DNA accessibility. Half of the drug-induced nucleosome positions approximated a theoretical model of nucleosome occupancy based on physical and chemical characteristics of the DNA sequence, whereas the basal or drug-naive positions were generally DNA sequence independent. Thus we suggest that nucleosome repositioning represents an initial dynamic genome-wide alteration of the transcriptional landscape preceding more selective downstream transcriptional reprogramming, which ultimately characterizes the cell- and tissue-specific responses to drugs of abuse. SH-SY5Y, neuroblastoma cells, were exposed to nicotine for 10, 60, and 90 minutes or cocaine for 5, 20, 40, and 60 minutes. Two independently grown biological replicates for each time point and condition, and two controls were processed.
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