Transcriptome analysis of human OXR1 depleted cells reveals its role in regulating the p53 signaling pathway

Abstract

The oxidation resistance gene 1 (OXR1) is crucial for protecting against oxidative stress; however, its molecular function is unknown. We employed RNA sequencing to examine the role of human OXR1 for genome wide transcription regulation. In total, in non-treated and hydrogen peroxide exposed HeLa cells, OXR1 depletion resulted in down-regulation of 554 genes and up-regulation of 253 genes. These differentially expressed genes include transcription factors (i.e. HIF1A, SP6, E2F8 and TCF3), antioxidant genes (PRDX4, PTGS1 and CYGB) and numerous genes of the p53 signaling pathway involved in cell-cycle arrest (i.e. cyclin D, CDK6 and RPRM) and apoptosis (i.e. CytC and CASP9). We demonstrated that OXR1 depleted cells undergo cell cycle arrest in G2/M phase during oxidative stress and increase protein expression of the apoptosis initiator protease CASP9. In summary, OXR1 may act as a sensor of cellular oxidative stress to regulate the transcriptional networks required to detoxify reactive oxygen species and modulate cell cycle and apoptosis.

Oxidation resistance 1 is a novel senolytic target

“…OXR1 is crucial for protecting cells against oxidative stress by regulating the expression of several enzymes that detoxify ROS (Jaramillo‐Gutierrez, Molina‐Cruz, Kumar & Barillas‐Mury, 2010; Oliver et al., 2011; Yang et al., 2015), and it may be particularly important as a senolytic target of PL because SCs are known to produce high levels of ROS but remain resistant to oxidative stress (Supporting Information Figure S2) (Chandrasekaran, Idelchik & Melendez, 2017; Davalli, Mitic, Caporali, Lauriola & D'Arca, 2016; Lee et al., 1999; Lu & Finkel, 2008). In addition, LMD‐3, homolog of OXR1 in Caenorhabditis elegans , has been shown to protect against oxidative stress and accelerated aging in the worm (Sanada et al., 2014).…”

“…OXR1 is an important antioxidant protein that protects cells from oxidative stress by regulating the expression of enzymes that detoxify ROS, such as glutathione peroxidase 2 (GTX2), heme oxygenase 1 (HO‐1), and catalase (CAT) (Jaramillo‐Gutierrez et al., 2010; Oliver et al., 2011; Yang et al., 2015). SCs are known to produce high levels of ROS, but they are highly resistant to oxidative stress (Chandrasekaran et al., 2017; Davalli et al., 2016; Lee et al., 1999; Lu & Finkel, 2008).…”

“…Among these possible senolytic targets of PL, we pursued OXR1 because it helps protect cells from oxidative stress by regulating several ROS‐detoxifying enzymes (Jaramillo‐Gutierrez et al., 2010; Oliver et al., 2011; Yang et al., 2015). Our studies showed that OXR1 is upregulated in both prematurely SCs induced by IR and replicative SCs in conjunction with the increased production of ROS and elevated expression of OXR1‐regulated ROS‐detoxifying enzymes such as GPX2, HO‐1, and CAT.…”

“…OXR1 is a cellular oxidative stress sensor that regulates the expression of a variety of antioxidant enzymes and modulates the cell cycle and apoptosis (Oliver et al., 2011; Yang et al., 2015). We found that OXR1 was upregulated in SCs induced by ionizing radiation (IR) or extensive replication.…”

Molecular and Cellular Mechanisms of Apoptosis during Dissociated Spermatogenesis

“…These observations were consistent with previous studies in various mammalian cells. Indeed, the CytC-Caspase axis in the p53 signaling pathway has been suggested to play a pivotal role in the execution of apoptosis under various physiological and pathological conditions (Zhang et al, 2014; Yang et al, 2015). Taken together, it is reasonable to infer that the seasonal effects of germ cell apoptosis might be monitored by the CytC-Caspase model involved in the p53 signaling pathway during spermatogenesis in P. sinensis .…”