4.6 Article

The GTPase KRAS suppresses the p53 tumor suppressor by activating the NRF2-regulated antioxidant defense system in cancer cells

期刊

JOURNAL OF BIOLOGICAL CHEMISTRY
卷 295, 期 10, 页码 3055-3063

出版社

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA119.011930

关键词

p53; GTPase Kras (KRAS); reactive oxygen species (ROS); redox signaling; RalB; TBK1

资金

  1. Molecular Genomics Facility at Moffitt Cancer Center, an National Cancer Institute Comprehensive Cancer Center [P30-CA076292]

向作者/读者索取更多资源

In human cancer cells that harbor mutant KRAS and WT p53 (p53), KRAS contributes to the maintenance of low p53 levels. Moreover, KRAS depletion stabilizes and reactivates p53 and thereby inhibits malignant transformation. However, the mechanism by which KRAS regulates p53 is largely unknown. Recently, we showed that KRAS depletion leads to p53 Ser-15 phosphorylation (P-p53) and increases the levels of p53 and its target p21/WT p53-activated fragment 1 (WAF1)/CIP1. Here, using several human lung cancer cell lines, siRNA-mediated gene silencing, immunoblotting, quantitative RT-PCR, promoter?reporter assays, and reactive oxygen species (ROS) assays, we demonstrate that KRAS maintains low p53 levels by activating the NRF2 (NFE2-related factor 2)?regulated antioxidant defense system. We found that KRAS depletion led to down-regulation of NRF2 and its targets NQO1 (NAD(P)H quinone dehydrogenase 1) and SLC7A11 (solute carrier family 7 member 11), decreased the GSH/GSSG ratio, and increased ROS levels. We noted that the increase in ROS is required for increased P-p53, p53, and p21(Waf1/cip1) levels following KRAS depletion. Downstream of KRAS, depletion of RalB (RAS-like proto-oncogene B) and I?B kinase?related TANK-binding kinase 1 (TBK1) activated p53 in a ROS- and NRF2-dependent manner. Consistent with this, the I?B kinase inhibitor BAY11-7085 and dominant-negative mutant I?B?M inhibited NF-?B activity and increased P-p53, p53, and p21(Waf1/cip1) levels in a ROS-dependent manner. In conclusion, our findings uncover an important role for the NRF2-regulated antioxidant system in KRAS-mediated p53 suppression.

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