Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response.
In response to oxidative stress, Nrf2 and p21(Cip1/WAF1) are both upregulated to protect cells from oxidative damage. Nrf2 is constantly ubiquitinated by a Keap1 dimer that interacts with a weak-binding (29)DLG motif and a strong-binding (79)ETGE motif in Nrf2, resulting in degradation of Nrf2. Modification of the redox-sensitive cysteine residues on Keap1 disrupts the Keap1-(29)DLG binding, leading to diminished Nrf2 ubiquitination and activation of the antioxidant response. However, the underlying mechanism by which p21 protects cells from oxidative damage remains unclear. Here we present molecular and genetic evidence suggesting that the antioxidant function of p21 is mediated through activation of Nrf2 by stabilizing the Nrf2 protein. The (154)KRR motif in p21 directly interacts with the (29)DLG and (79)ETGE motifs in Nrf2 and thus competes with Keap1 for Nrf2 binding, compromising ubiquitination of Nrf2. Furthermore, the physiological significance of our findings was demonstrated in vivo using p21-deficient mice.
Chen
Weimin
W
Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, USA.
Sun
Zheng
Z
Wang
Xiao-Jun
XJ
Jiang
Tao
T
Huang
Zheping
Z
Fang
Deyu
D
Zhang
Donna D
DD
D020816:Amino Acid Motifs; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001665:Binding Sites; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D018384:Oxidative Stress; D054875:Ubiquitination; D015854:Up-Regulation
D000975:Antioxidants; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse