Late-onset increases in oxidative stress and other tumorigenic activities and tumors with a Ha-ras mutation in the liver of adult male C3H mice gestationally exposed to arsenic.

Tumorigenesis is a complex process involving genetic, epigenetic, and metabolic alterations. Gestational arsenic exposure has been shown to increase hepatic tumors in adult male offspring of C3H mice, which spontaneously develop hepatic tumors often harboring activating Ha-ras mutation. We explored tumor-promoting changes by gestational arsenic exposure with a focus on Ha-ras mutation and gene expression changes.

Global DNA methylation in the mouse liver is affected by methyl deficiency and arsenic in a sex-dependent manner.

Arsenic, a carcinogen, is assumed to induce global DNA hypomethylation by consuming the universal methyl donor S-adenosylmethionine (SAM) in the body. A previous study reported that a methyl-deficient diet (MDD) with arsenic intake greatly reduced global DNA methylation (the content of 5-methylcytosine) in the liver of male C57BL/6 mice. In the present study, we investigated the DNA methylation level, SAM content, and expression of DNA methyltransferases (DNMTs) in the liver of male and female C57BL/6 mice fed a methyl-sufficient diet (MSD), an MDD, or an MDD + arsenic.

Arsenite-induced thymus atrophy is mediated by cell cycle arrest: a characteristic downregulation of E2F-related genes revealed by a microarray approach.

Thymus atrophy is induced by a variety of chemicals, including environmental contaminants and is used as a sensitive index to detect their adverse effects on lymphocytes. In the present study we adopted a toxicogenomics approach to identify the pathways that mediate the atrophy induced by arsenite. We also analyzed gene expression changes observed in the course of thymus atrophy by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), dexamethasone (DEX), and estradiol (E2), to determine whether arsenite induces atrophy by activating an arsenite-specific pathway or the same pathways as other chemicals.

Turning off estrogen receptor beta-mediated transcription requires estrogen-dependent receptor proteolysis.

Recent studies have shed light on the ligand-dependent transactivation mechanisms of nuclear receptors (NRs). When the ligand dose is reduced, the transcriptional activity of NRs should be downregulated. Here we show that a ubiquitin-proteasome pathway plays a key role in turning off transcription mediated by estrogen receptor beta (ERbeta).

A specific CpG site demethylation in the human interleukin 2 gene promoter is an epigenetic memory.

DNA demethylation plays a critical role in transcriptional regulation in differentiated somatic cells. However, there is no experimental evidence that CpG methylation in a small region of a genome restricts gene expression. Here, we show that the anti-CD3repsilon/CD28 antibody stimulation of human CD4+ T cells induces IL2 expression following epigenetic changes, including active demethylation of a specific CpG site, recruitment of Oct-1, and changes in histone modifications.

Ligand-dependent switching of ubiquitin-proteasome pathways for estrogen receptor.

Recent evidence indicates that the transactivation of estrogen receptor alpha (ERalpha) requires estrogen-dependent receptor ubiquitination and degradation. Here we show that estrogen-unbound (unliganded) ERalpha is also ubiquitinated and degraded through a ubiquitin-proteasome pathway. To investigate this ubiquitin-proteasome pathway, we purified the ubiquitin ligase complex for unliganded ERalpha and identified a protein complex containing the carboxyl terminus of Hsc70-interacting protein (CHIP).

Full activation of estrogen receptor alpha activation function-1 induces proliferation of breast cancer cells.

The effects of estrogen and anti-estrogen are mediated through the estrogen receptors (ER) alpha and beta, which function as ligand-induced transcriptional factors. Recently, one of the phthalate esters, n-butylbenzyl phthalate (BBP), has been shown to induce estrogen receptor-mediated responses. By using the truncated types of ER mutants, we revealed that activation function-1 (AF-1) activity was necessary for the BBP-dependent transactivation function of ERalpha.