PT  - JOURNAL ARTICLE
AU  - Grace Woodruff
AU  - Christian G Bouwkamp
AU  - Femke M de Vrij
AU  - Timothy Lovenberg
AU  - Pascal Bonaventure
AU  - Steven A Kushner
AU  - Anthony W Harrington
TI  - The zinc transporter SLC39A7 (ZIP7) is essential for regulation of cytosolic zinc levels
AID  - 10.1124/mol.118.112557
DP  - 2018 Jan 01
TA  - Molecular Pharmacology
PG  - mol.118.112557
4099  - http://molpharm.aspetjournals.org/content/early/2018/07/06/mol.118.112557.short
4100  - http://molpharm.aspetjournals.org/content/early/2018/07/06/mol.118.112557.full
AB  - Zinc homeostasis is a highly regulated process in mammalian cells that is critical for normal growth and development. Movement of zinc across cell compartments is controlled by two classes of transporters: Slc39a family members transport zinc into the cytosol from either the extracellular space or from intracellular stores such as the endoplasmic reticulum (ER), while the SSLC30A family mediates zinc efflux from the cytosol. Here we report that genetic ablation of SLC39A7 (ZIP7) results in decreased cytosolic zinc levels, increased ER zinc levels, impaired cell proliferation, and induction of ER stress. Confirmatory of impaired zinc transport as the causal mechanism, both the increased ER stress and impaired cell proliferation were rescued by increasing cytosolic zinc. Furthermore, using these robust cellular phenotypes we implemented a small molecule library screen with 2,800 compounds and identified one small molecule capable of rescuing ER stress and cell proliferation in ZIP7 deficient cells in the low micromolar range.