|
|
|
|
WDR23 regulates NRF2 independently of KEAP1
|
|
|
|
|
|
|
|
نویسنده
|
lo j.y. ,spatola b.n. ,curran s.p.
|
|
منبع
|
plos genetics - 2017 - دوره : 13 - شماره : 4
|
|
چکیده
|
Cellular adaptation to stress is essential to ensure organismal survival. nrf2/nfe2l2 is a key determinant of xenobiotic stress responses,and loss of negative regulation by the keap1-cul3 proteasome system is implicated in several chemo- and radiation-resistant cancers. advantageously using c. elegans alongside human cell culture models,we establish a new wdr23-ddb1-cul4 regulatory axis for nrf2 activity that operates independently of the canonical keap1-cul3 system. wdr23 binds the didlid sequence within the neh2 domain of nrf2 to regulate its stability; this regulation is not dependent on the keap1-binding dlg or etge motifs. the c-terminal domain of wdr23 is highly conserved and involved in regulation of nrf2 by the ddb1-cul4 complex. the addition of wdr23 increases cellular sensitivity to cytotoxic chemotherapeutic drugs and suppresses nrf2 in keap1-negative cancer cell lines. together,our results identify wdr23 as an alternative regulator of nrf2 proteostasis and uncover a cellular pathway that regulates nrf2 activity and capacity for cytoprotection independently of keap1. © 2017 lo et al.
|
|
|
|
|
آدرس
|
university of southern california,leonard davis school of gerontology,los angeles,ca,united states,university of southern california,dornsife college of letters,arts,and sciences,department of molecular and computational biology,los angeles,ca, United States, university of southern california,leonard davis school of gerontology,los angeles,ca,united states,university of southern california,dornsife college of letters,arts,and sciences,department of molecular and computational biology,los angeles,ca, United States, university of southern california,leonard davis school of gerontology,los angeles,ca,united states,university of southern california,dornsife college of letters,arts,and sciences,department of molecular and computational biology,los angeles,ca, United States
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Authors
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|