Dept. Gene Expression Regulation
|Professor||Hozumi Motohashi, MD. PhD.|
|Assistant Professor||Hiroki Sekine, MD. PhD|
|Assistant Professor||Hiroshi KITAMURAI, PhD|
We are very interested in the transcriptional regulation of gene expression that is important for the maintenance of homeostasis. CNC-sMaf is a family of heterodimeric transcription factors possessing a well-conserved basic region-leucine zipper (bZip) motif. There are four members of CNC proteins, p45, Nrf1, Nrf2 and Nrf3, which heterdimerize with sMaf proteins and bind to Maf Recognition Element (MARE) (Figure 1). MARE and its related sequences comprise the CNC-sMaf cistrome, which directs a unique transcriptional regulation network regulating the maturation and maintenance of cells, such as megakaryocytic maturation, maintenance of neuronal cells, detoxification of intrinsic and extrinsic toxicants, and protection from pre-senile cataract.
One of the family members, Nrf2-sMaf, coordinately activates many cytoprotective genes in response to oxidative and xenobiotic stresses (Figure 2). Keap1 is a negative regulator of Nrf2, promoting the degradation of Nrf2 through proteasome under unstressed conditions. On the exposure to electrophiles or reactive oxygen species, Nrf2 is stabilized by the inactivation of Keap1 and activates transcription by heterodimerizing with sMaf. It has been shown that Nrf2-activating chemicals, either naturally occurring or artificially synthesized, are beneficial for our health. On the other hand, aberrant activation of Nrf2 has been found in many human cancers in lung, esophagus, colon, prostate, and mammary gland. Clinical studies have demonstrated that Nrf2 accumulation strongly correlates with poor clinical outcome. Recently we have found that Nrf2 contributes to the malignant evolution of cancer cells by modulating cellular metabolic activity.
Dysregulation of Nrf2 activity is closely related to the pathogenesis of various diseases. We are currently investigating the role of Nrf2-sMaf in cancers and inflammation. We are also interested in the maintenance of redox homeostasis within the nucleus and the contribution of Nrf2-sMaf to the protection from the intrinsic genotoxicity. Our goal is to understand the molecular basis of various pathological conditions relating to the aging process from the viewpoint of transcriptional regulation by Nrf2-sMaf and its related factors.
- Ida T, Sawa T, Ihara H, Tsuchiya Y, Watanabe Y, Kumagai Y, Suematsu M, Motohashi H, Fujii S, Matsunaga T, Yamamoto M, Ono K, Devarie-Baez NO, XianM, Fukuto JM and Akaike T. Reactive cysteine persulfides and S-polythiolation regulate oxidative stress and redox signaling. Proc Natl Acad Sci USA in press.
- Shirasaki K, Taguchi K, Unno M, Motohashi H*, and Yamamoto M*. Nrf2 promotes compensatory liver hypertrophy after portal vein branch ligation in mice. Hepatology in press. (* corresponding authors)
- Taguchi K, Hirano I, Itoh T, Tanaka M, Miyajima A, Suzuki A, Motohashi H*, and Yamamoto M*. Nrf2 enhances cholangiocyte expansion in Pten-deficient livers. Mol Cell Biol 34, 900-913, 2014.(* corresponding authors)
- Onodera Y, Motohashi H, Takagi K, Miki Y, Shibahara Y, Watanabe M, Ishida T, Hirakawa H, Sasano H, Yamamoto M, and Suzuki T. NRF2 immunolocalization in human breat cancer patients as a prognostic factor. Endocri Relat Cancer 21, 241-252, 2014.
- Murakami S, Shimizu R, Romeo P-H, Yamamoto M*, and Motohashi H*. Keap1-Nrf2 system regulates cell fate determination of hematopoietic stem cells. Genes Cells 19, 239-253, 2014. (* corresponding authors)
- Murakami S, Yamamoto M*, and Motohashi H*. Hematopoietic stem and progenitor cell activation during chronic dermatitis provoked by constitutively active aryl-hydrocarbon receptor driven by Keratin14 promoter. Toxicol Sci 138, 47-58, 2014. (* corresponding authors)
- Hirano K, Kinoshita T, Uemura T, Motohashi H, Watanabe Y, Ebihara T, Nishiyama H, Sato M, Suga M, Maruyama Y, Tsuji NM, Yamamoto M, Nishida S, and Sato C. Electron microscopy of primary cell cultures in solution and correlative optical microscopy using ASEM. Ultramicroscopy. 2013 Oct 22. pii: S0304-3991(13)00285-4.
- Ichimura Y, Waguri S, Sou YS, Kageyama S, Hasegawa J, Ishimura R, Saito T, Yang Y, Kouno T, Fukutomi T, Hoshii T, Hirao A, Takagi K, Mizushima T, Motohashi H, Lee MS, Yoshimori T, Tanaka K, Yamamoto M, Komatsu M. Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol Cell 51, 618-631, 2013.
- Okita Y, Kamoshida A, Suzuki H, Itoh K, Motohashi H, Igarashi K, Ogami T, Koinuma D, Kato M. Transforming growth factor-βinduces transcription factors MafK and Bach1 to suppress expression of the heme oxygenase-1 gene. J Biol Chem 288, 20658-20667, 2013.
- Fujita R, Takayama-Tsujimoto M, Satoh H, Gutiérrez L, Aburatani H, Fujii S, Sarai A, Bresnick EH, Yamamoto M*, and Motohashi H*. NF-E2 p45 is important for establishing normal function of platelets. Mol Cell Biol 33, 2659-2670, 2013. (* corresponding authors)
- Suzuki T, Shibata T, Takaya K, Shiraishi K, Kohno T, Kunitoh H, Tsuta K, Furuta K, Goto K, Hosoda F, Sakamoto H, Motohashi H and Yamamoto M*. Regulatory nexus of synthesis and degradation deciphers cellular Nrf2 expression levels. Mol Cell Biol 33, 2402-2412, 2013.
- Suzuki M, Yamazaki H, Mukai HY, Motohashi H, Shi L, Tanabe O, Engel JD and Yamamoto M. Disruption of the Hbsl1-Myb locus causes hereditary persistence of fetal hemoglobin in mouse. Mol Cell Biol 33, 1687-1695, 2013.
- Taguchi K, Fujikawa N, Komatsu M, Ishii T, Unno M, Akaike T, Motohashi H and Yamamoto M. Keap1 degradation by autophagy for the maintenance of redox homeostasis. Proc Natl Acad Sci USA 109, 13561-13566, 2012.
- Takaya K, Suzuki T, Motohashi H, Onodera K, Satomi S, Kensler TW and Yamamoto M. Validation of the multiple sensor mechanism of the Keap1-Nrf2 system. Free Rad Biol Med 53, 817-827, 2012.
- Nishida M, Sawa T, Kitajima N, Ono K, Inoue H, Ihara H, Motohashi H, Yamamoto M, Suematsu M, Kurose H, van der Vliet A, Freeman B, Shibata T, Ucnida K, Kumagai Y and Akaike T. Hydrogen sulfide anion regulates redox signaling via electrophile sulfation. Nat Chem Biol 8, 714-724, 2012.
- Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H, Yamamoto M*, and Motohashi H*. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22, 66-79, 2012. (* corresponding authors)
- Inoue D, Suzuki T, Mitsuishi Y, Miki Y, Suzuki S, Sugawara S, Watanabe M, Sakudara A, Endo C, Uruno A, Sasano H, Nakagawa T, Satoh K, Tanaka N, Kubo H, Motohashi H*, and Yamamoto M*. Accumulation of p62/SQSTM1 is associated with poor prognosis in patients with lung adenocarcinoma. Cancer Sci 103,760-766, 2012. (* corresponding authors)
- Yamazaki H, Katsuoka F, Motohashi H, Engel JD and Yamamoto M. Embryonic lethality and fetal liver apoptosis in mice lacking all three small maf proteins. Mol Cell Biol 32, 808-816, 2012.
- Inoue D, Kubo H, Taguchi K, Suzuki T, Komatsu M, Motohashi H*, and Yamamoto M*. Inducible disruption of autophagy in the lung causes airway hyper-responsiveness. Biochem Biophys Res Commun 405, 13-18, 2011. (* corresponding authors)
- Motohashi H*, Fujita R, Takayama M, Inoue A, Katsuoka F, Bresnick EH and Yamamoto M. Molecular determinants for small Maf protein control of platelet production. Mol Cell Biol 31, 151-162, 2011. Erratum in: Mol Cell Biol. 32, 2041, 2012. (* corresponding author)
- Fujii S, Sawa T, Ihara H, Tong KI, Ida T, Okamoto T, Ahtesham AK, Ishima Y, Motohashi H, Yamamoto M and Akaike T. The critical role of nitric oxide signalling, via protein S-guanylation and nitrated cyclic GMP, in the antioxidant adaptive response. J Biol Chem 285, 23970-23984, 2010.
- Taguchi K, Maher JM, Suzuki T, Kawatani Y, Motohashi H, and Yamamoto M. Genetic analysis of cytoprotective functions supported by graded expression of Keap1. Mol Cell Biol 30, 3016-3026, 2010.
- Takayama M, Fujita R, Suzuki M, Okuyama R, Aiba S, Motohashi H*, and Yamamoto M*. Genetic analysis of hierarchical regulation for Gata1 and NF-E2 p45 gene expression in megakaryopoiesis. Mol Cell Biol 30, 2668-2680, 2010. (*corresponding authors)
- Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, Sou Y.-S., Ueno I, Sakamoto A, Tong KI, Kim M, Nishito Y, Iemura S.-i., Natsume T, Ueno T, Kominami E, Motohashi H, Tanaka K and Yamamoto M. The selective autophagy substrate p62 activates the stress response transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol 12, 213-223, 2010.
- Motohashi H*, Kimura M, Fujita R, Inoue A, Pan X, Takayama M, Katsuoka F, Aburatani H, Bresnick EH and Yamamoto M. NF-E2 domination over Nrf2 promotes ROS accumulation and megakaryocytic maturation. Blood 115, 677-686, 2010. (* corresponding author)