TY - JOUR
T1 - 4-Hydroxynonenal induces p53-mediated apoptosis in retinal pigment epithelial cells
AU - Sharma, Abha
AU - Sharma, Rajendra
AU - Chaudhary, Pankaj
AU - Vatsyayan, Rit
AU - Pearce, Virginia
AU - Jeyabal, Prince V.S.
AU - Zimniak, Piotr
AU - Awasthi, Sanjay
AU - Awasthi, Yogesh C.
N1 - Funding Information:
Supported in part by NIH Grants ES012171, EY 04396 (Y.C.A.), CA77495 (S.A.).
PY - 2008/12/15
Y1 - 2008/12/15
N2 - 4-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.
AB - 4-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.
KW - 4-Hydroxynonenal
KW - Apoptosis
KW - Glutathione S-transferase
KW - Lipid peroxidation
KW - Oxidative stress
KW - Retinal pigment epithelial (RPE) cells
KW - p53
UR - http://www.scopus.com/inward/record.url?scp=55849108107&partnerID=8YFLogxK
U2 - 10.1016/j.abb.2008.09.016
DO - 10.1016/j.abb.2008.09.016
M3 - Article
C2 - 18930016
AN - SCOPUS:55849108107
SN - 0003-9861
VL - 480
SP - 85
EP - 94
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
IS - 2
ER -