The extra-nuclear interactome of the estrogen receptors: implications for physiological functions.

Over the last decades, a great body of evidence has defined a novel view of the cellular mechanism of action of the steroid hormone 17ß-estradiol (E2) through its estrogen receptors (i.e., ERα and ERß). It is now clear that the E2-activated ERs work both as transcription factors and extra-nuclear plasma membrane-localized receptors. The activation of a plethora of signal transduction cascades follows the E2-dependent engagement of plasma membrane-localized ERs and is required for the coordination of gene expression, which ultimately controls the occurrence of the pleiotropic effects of E2. The definition of the molecular mechanisms by which the ERs locate at the cell surface (i.e., palmitoylation and protein association) determined the quest for understanding the specificity of the extra-nuclear E2 signaling. The use of mice models lacking the plasma membrane ERα localization unveiled that the extra-nuclear E2 signaling is operational in vivo but tissue-specific. However, the underlying molecular details for such ERs signaling diversity in the perspective of the E2 physiological functions in the different cellular contexts are still not understood. Therefore, to gain insights into the tissue specificity of the extra-nuclear E2 signaling to physiological functions, here we reviewed the known ERs extra-nuclear interactors and tried to extrapolate from available databases the ERα and ERß extra-nuclear interactomes. Based on literature data, it is possible to conclude that by specifically binding to extra-nuclear localized proteins in different sub-cellular compartments, the ERs fine-tune their molecular activities. Moreover, we report that the context-dependent diversity of the ERs-mediated extra-nuclear E2 actions can be ascribed to the great flexibility of the physical structures of ERs and the spatial-temporal organization of the logistics of the cells (i.e., the endocytic compartments). Finally, we provide lists of proteins belonging to the potential ERα and ERß extra-nuclear interactomes and propose that the systematic experimental definition of the ERs extra-nuclear interactomes in different tissues represents the next step for the research in the ERs field. Such characterization will be fundamental for the identification of novel druggable targets for the innovative treatment of ERs-related diseases.

Neuroglobin: A Novel Player in the Oxidative Stress Response of Cancer Cells.

Reactive oxygen species (ROS) result from intracellular aerobic metabolism and/or extracellular stimuli. Although endogenous antioxidant systems exquisitely balance ROS production, an excess of ROS production, commonly found in diverse human degenerative pathologies including cancer, gives rise to the oxidative stress. Increased oxidative stress in cancer is related to the sustained proliferation and metabolism of cancer cells. However, cancer cells show an intrinsic higher antioxidant capacity with respect to the normal counterpart as well as an ability to cope with oxidative stress-induced cell death by establishing mechanisms of adaptation, which define a selective advantage against the adverse oxidative stress environment. The identification of survival factors and adaptive pathways, set up by cancer cells against oxidative stress, provides multiple targets for the therapeutic intervention against cancer. Neuroglobin (NGB), a globin primarily described in neurons as an oxidative stress sensor and cytoprotective factor against redox imbalance, has been recently recognized as a novel tumor-associated protein. In this review, the involvement of NGB in the cancer cell adaptation and resistance to oxidative stress will be discussed highlighting the globin role in the regulation of both the stress-induced apoptotic pathway and antioxidant systems activated by cancer cells.