• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • The canonical tumor suppressor p has also been implicated


    The canonical tumor suppressor p53 has also been implicated as a transcriptional mediator of ferroptotic death (Jiang et al., 2015, Tarangelo et al., 2018, Wang et al., 2016, Xie et al., 2017). Specifically, p53 negatively regulates transcription of SLC7A11, the cystine-glutamate antiporter (Xc-) (Jiang et al., 2015, Tarangelo et al., 2018). The ability of p53 to repress SCL7A11 and induce ferroptosis is consistent with prior observations that pharmacological inhibition of SCL7A11 also resulted in ferroptosis (e.g., via exposure to erastin, glutamate, HCA; Dixon et al., 2012). Indeed, in vivo, the tumor suppressive effects of an acetylation defective mutant of p53, which does not induce cell-cycle arrest, senescence, or apoptosis, can be overcome by forced expression of SLC7A11 (Jiang et al., 2015). Altogether, these findings suggest that p53 has multiple modes of tumor suppression including the activation of ferroptosis via suppression of SLC7A11 transcription. By contrast, p53-dependent transcription of p21(waf1/cip1) (Tarangelo et al., 2018) or p53-dependent nuclear accumulation of DPP4 (Xie et al., 2017) appears to suppress ferroptosis via preservation of the redox balance, raising the possibility that p53 has multiple arms that lead to ferroptotic death or cell-cycle inhibition depending on levels of stress or damage. In addition to p53, the electrophile responsive transcription factor Nrf-2 can also suppress ferroptosis in tumor CCG 50014 receptor (Fan et al., 2017) or in neuronal cultures when activated selectively in glial cells (Haskew-Layton et al., 2010). While SCL7A11 has been a logical focus of the transcriptional regulation of ferroptosis outlined above, recent studies have highlighted the central role that selenium plays in modulating ferroptotic death via its co-translational incorporation into selenocysteine in proteins such as glutathione peroxidase-4 (GPX4; Ingold et al., 2018). However, little is known about whether GPX4 and other selenoproteins are induced at a transcriptional level by ferroptotic stimuli and whether such a putative homeostatic adaptive response can be harnessed to limit ferroptosis in disease (Stoytcheva and Berry, 2009). Here, we show that selenoproteins, including GPX4, are induced at a transcriptional level as a frustrated adaptive response to ferroptotic stimuli in vitro and in vivo in the nervous system. Unexpectedly, supraphysiological levels of selenium drive this transcriptional response, the selenome, via TFAP2c and Sp1 to prevent ferroptosis and ferroptosis-independent modes of cell death. Delivery of selenium directly into the cerebral ventricle or systemically via brain penetrant, selenocysteine peptides activates the adaptive transcriptional response to ferroptosis and improves functional recovery following stroke.
    Discussion While selenium was discovered over 200 years ago (Berzelius, 1818), only recent data have established its indispensability for the function of prosurvival proteins, specifically GPX4, associated with ferroptosis (Ingold et al., 2018). Our findings extend this essential physiological perspective on selenium biology to suggest that pharmacological selenium supplementation, even in the absence of nutritional deficiency (Figures 2D, 5C, and 6E), has an unexpected ability to drive adaptive transcription to counter ferroptosis (and other stresses) and protect neurons. Knowledge of how to drive GPX4 expression pharmacologically in the brain and other organs has clear therapeutic implications for hemorrhagic stroke, and possibly other CNS and non-CNS conditions associated with ferroptotic death (e.g., Parkinson’s disease and liver ischemia; Bellinger et al., 2011, Friedmann Angeli et al., 2014, Hauser et al., 2013). It may also have implications for diseases associated with ER stress (e.g., ALS; Saxena et al., 2009) and excitotoxicity (e.g., ischemia; Goldberg and Choi, 1993, Sattler et al., 1999, Dixon et al., 2012, Yigitkanli et al., 2013).