Interdependency of estradiol-mediated ERα activation and subsequent PR and GREB1 induction to control cell cycle progression.

Various groups of chemicals that we encounter in every-day life are known to disrupt the endocrine system, such as estrogen mimics that can disturb normal cellular development and homeostasis. To understand the effect of estrogen on intracellular protein dynamics and how this relates to cell proliferation, we aimed to develop a quantitative description of transcription factor complexes and their regulation of cell cycle progression in response to estrogenic stimulation. We designed a mathematical model that describes the dynamics of three proteins, GREB1, PR and TFF1, that are transcriptionally activated upon binding of 17β-estradiol (E2) to estrogen receptor alpha (ERα).

Development of tailored splice-switching oligonucleotides for progressive brain disorders in Europe: development, regulation, and implementation considerations.

Splice-modulating antisense oligonucleotides (ASOs) offer treatment options for rare neurological diseases, including those with very rare mutations, where patient-specific, individualized ASOs have to be developed. Inspired by the development of milasen, the 1 Mutation 1 Medicine (1M1M) and Dutch Center for RNA Therapeutics (DCRT) aim to develop patient-specific ASOs and treat eligible patients within Europe and the Netherlands, respectively. Treatment will be provided under a named patient setting.

Evaluation of an imaging-based in vitro screening platform for estrogenic activity with OECD reference chemicals.

Estrogen receptor alpha (ERα) is often a primary target of endocrine disrupting chemicals (EDCs) and therefore several biochemical and cell-based assays for the detection of chemicals with estrogenic properties have been developed in the past. However, the current approaches are not suitable for the monitoring of pathway activation dynamics, and they are mostly based on expression constructs that lack physiological promoter regulation. We recently developed MCF7 fluorescent reporter cell lines of 3 different green fluorescent protein (GFP)-tagged ERα target genes: GREB1, PGR and TFF1.

Physiologically Relevant Estrogen Receptor Alpha Pathway Reporters for Single-Cell Imaging-Based Carcinogenic Hazard Assessment of Estrogenic Compounds.

Estrogen receptor alpha (ERα) belongs to the nuclear hormone receptor family of ligand-inducible transcription factors and regulates gene networks in biological processes such as cell growth and proliferation. Disruption of these networks by chemical compounds with estrogenic activity can result in adverse outcomes such as unscheduled cell proliferation, ultimately culminating in tumor formation. To distinguish disruptive activation from normal physiological responses, it is essential to quantify relationships between different key events leading to a particular adverse outcome.

Human Cytochrome P450 2W1 Is Not Expressed in Adrenal Cortex and Is Only Rarely Expressed in Adrenocortical Carcinomas.

Human cytochome P450 2W1 (CYP2W1) enzyme is expressed in fetal colon and in colon tumors. The level of expression is higher in colon metastases than in the parent tumors and the enzyme is a possible drug target for treatment of colorectal cancer, as demonstrated in mouse xenograft studies. A previous study published in this journal reported that CYP2W1 is highly expressed in normal and transformed adrenal tissue.