4-Hydroxynonenal induces p53-mediated apoptosis in retinal pigment epithelial cells

Abstract

Abstract4-Hydroxynonenal (4-HNE) has been suggested to be involved in stress-induced signaling for apoptosis. In present studies, we have examined the effects of 4-HNE on the intrinsic apoptotic pathway associated with p53 in human retinal pigment epithelial (RPE and ARPE-19) cells. Our results show that 4-HNE causes induction, phosphorylation, and nuclear accumulation of p53 which is accompanied with down regulation of MDM2, activation of the pro-apoptotic p53 target genes viz. p21 and Bax, JNK, caspase3, and onset of apoptosis in treated RPE cells. Reduced expression of p53 by an efficient silencing of the p53 gene resulted in a significant resistance of these cells to 4-HNE-induced cell death. The effects of 4-HNE on the expression and functions of p53 are blocked in GSTA4-4 over expressing cells indicating that 4-HNE-induced, p53-mediated signaling for apoptosis is regulated by GSTs. Our results also show that the induction of p53 in tissues of mGsta4 (-/-) mice correlate with elevated levels of 4-HNE due to its impaired metabolism. Together, these studies suggest that 4-HNE is involved in p53-mediated signaling in in vitro cell cultures as well as in vivo that can be regulated by GSTs.

4-Hydroxynonenal Induces G2/M Phase Cell Cycle Arrest by Activation of the Ataxia Telangiectasia Mutated and Rad3-related Protein (ATR)/Checkpoint Kinase 1 (Chk1) Signaling Pathway

“…p53, HSF1, and DAXX) require much higher HNE concentrations for their activation (32,51). Interestingly, activation of JNK, p53, and Nrf2 has also been observed in tissues of mGsta4 knock-out mice (51,72,73). Taken together with the results of the present study showing the activation of H2A.X in mGsta4 null mice, these findings strongly suggest that the in vitro effects of HNE presented here are physiologically relevant.…”

“…A concentration-dependent activation and phosphorylation of p53 by HNE observed in WT p53 HepG2 cells (Fig. 6, A and B) was consistent with our previous studies with other cell types (51). However, HNE induced the activation of p21 independent of p53 because our results showed that in p53 wild type HepG2 as well as in p53 null Hep3B (Fig.…”

“…Consistent with this idea, in vitro HNE activates membrane tyrosine kinase receptors (like EGFR, VEGFR, and PDGFR) at low concentrations of Ͻ1 M (69 -71), but cytosolic components (e.g. p53, HSF1, and DAXX) require much higher HNE concentrations for their activation (32,51). Interestingly, activation of JNK, p53, and Nrf2 has also been observed in tissues of mGsta4 knock-out mice (51,72,73).…”

Increased Lipid Oxidation Causes Oxidative Stress, Increased Peroxisome Proliferator-activated Receptor-γ Expression, and Diminished Pro-osteogenic Wnt Signaling in the Skeleton

“…Thus, oxidized PUFAs stimulate apoptosis of osteoblastic OB-6 cells via a PPAR␥-dependent mechanism, consistent with previous evidence for a negative impact of RGL on osteoblast survival in vitro (55) and in vivo (51). We found that the proapoptotic effect of 4-HNE is mediated by increased oxidative stress; however, other mechanisms, for example activation of p53 (56), could also be involved. NAC (12), as well as Wnt signaling (15,16) promote osteoblast survival in vivo.…”

Cell death and diseases related to oxidative stress:4-hydroxynonenal (HNE) in the balance

“…Figure 3 Intrinsic apoptotic pathway is induced by oxidative stress, p53 and mitochondrial membrane disturbances. cyt.c: cytochrome c; HNE: hydroxynonenal; and MOMP: mitochondrial outer membrane permeabilization Sharma et al 98 showed that exogenous HNE results in the phosphorylation of p53 (on Ser 15) and its nuclear translocation in retinal epithelial cells. Such activation is involved in apoptosis induction.…”