Nrf2 in stress response and cancer development
B6.129P2-Nfe2l2tm1Mym/MymRbrc RBRC01390 (C57BL/6JJcl background)
C.129P2-Nfe2l2tm1Mym/MymRbrc RBRC02190 (BALB/cAJcl background)
ICR;129P2-Nfe2l2tm1Mym/MymRbrc RBRC00984 (Jcl:ICR background)
Lewis lung carcinoma cells were intravenously injected into wild-type and Nrf2-null mice. Lung metastasis was examined 20 days after the inoculation. Metastatic nodules were more apparent in Nrf2-null mice. Scale bar, 5 mm.
Nuclear factor, erythroid derived 2, like 2 (Nfe2l2, or Nrf2) is a transcription factor, that serves as a key regulator of the cellular defense against oxidative and electrophilic stresses . Under normal conditions, Nrf2 is rapidly degraded through its association with kelch-like ECH-associated protein 1 (Keap1). Upon exposure to oxidative and electrophilic stress, the reactive cysteine residues of Keap1 become modified, liberating Nrf2 from its Keap1-mediated degradation. Polyubiquitin-binding protein p62 also interacts with the Nrf2-binding site on Keap1, resulting in the stabilization of Nrf2 .
Nrf2-regulated cytoprotective genes include heme oxygenase-1 (HO-1) and glutathione S-transferase (GST). The target genes are involved in elimination of reactive oxygen species (ROS), glutathione synthesis, foreign material metabolism, and drug transport. Nrf2 deficiency in mice increases their sensitivity to cigarette smoke, lipopolysaccharides, high-fat diet, and UV irradiation. Missense mutations in NRF2 and KEAP1 have recently been identified in many types of human cancer. Nrf2-deficient mice exhibit increased susceptibility to lung metastasis, which is associated with greater inflammation . Different strains of Nrf2-deficient mice will provide the opportunity to understanding the role of Nrf2 in various common diseases.
|Related strain||:||STOCK Ahrtm1Yfk Nfe2l2tm1Mym/MymRbrc RBRC01236|
|Depositor||:||Dr. Masayuki Yamamoto, Tohoku University School of Medicine|
|References||:||||Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima Y. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun; 236(2):313-22, 1997.|
|||Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, Sou YS, Ueno I, Sakamoto A, Tong KI, Kim M, Nishito Y, Iemura S, Natsume T, Ueno T, Kominami E, Motohashi H, Tanaka K, Yamamoto M. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol; 12(3):213-23, 2010./td>|
|||Satoh H, Moriguchi T, Taguchi K, Takai J, Maher JM, Suzuki T, Winnard PT Jr, Raman V, Ebina M, Nukiwa T, Yamamoto M. Nrf2-deficiency creates a responsive microenvironment for metastasis to the lung. Carcinogenesis; 31(10):1833-43, 2010.|