Crosstalk between transcriptional control and energy pathways, mediated by hub metabolites

Scientific Research on Innovative Areas, a MEXT Grant-in-Aid Project FY2011-2015

Motohashi Group: Crosstalk between the oxidative stress response and metabolic regulation modulated by the chromatin environment

Research Structure

Principal Investigator hozumi-motohashi-236x300 Hozumi Motohashi
Department of Gene Expression Regulation, IDAC, Tohoku University


Metabolic activities in proliferating cells are fundamentally different from those in quiescent cells. Quiescent cells invest large amounts of energy in the maintenance of functional and morphological integrity against extrinsic and intrinsic insults, including oxidative stress. In contrast, proliferating cells take up abundant nutrients, including glucose and glutamine, and shunt their metabolites into anabolic pathways. The signals that promote cell proliferation direct the reprogramming of metabolic activities, which pushes quiescent cells into proliferative states. Recently, we have shown that the transcription factor Nrf2, which is a key regulator for the maintenance of redox homeostasis, reinforces the metabolic reprogramming triggered by proliferative signals and promotes cell proliferation.

In this project, in order to further clarify the molecular mechanisms underlying metabolic reprogramming, we will analyze how Nrf2 regulates anabolic reactions, and how metabolites control Nrf2 functions in turn. We will perform comprehensive examinations of the gene expression profile driven by Nrf2, the protein complex containing Nrf2, the epigenetic environment surrounding the Nrf2 target genes and the metabolomic profile achieved by Nrf2 in the presence proliferative signals and compare the results with those in the absence of proliferative signals. We also examine how tumor-specific metabolic profiles affect the nuclear function of Nrf2. This project aims at deciphering the functional interaction between cellular metabolic activities and epigenetic regulation regulating the Nrf2 function particularly in cancer cells. The outcome will provide beneficial information for developing the anti-cancer therapies preventing the malignant evolution of cancers.

Recent Publications new

  1. Honkura, Y., Matsuo, H., Murakami, S., Sakiyama, M., Mizutari, K., Shiotani, A., Yamamoto, M., Morita, I., Shinomiya, N., Kawase, T., Katori, Y.,and *Motohashi, H.
    NRF2 is a key target for prevention of noise-induced hearing loss by reducing oxidative damage of cochlea
    Sci Rep. 6,19329(2016) pubmed
  2. 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)    pubmed 
  3. 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)    pubmed 
  4. Uruno, A., and *Motohashi, H.
    The Keap1-Nrf2 system as an in vivo sensor for electrophiles.
    Nitric Oxide 25, 153-160 (2011)    pubmed

Major Publications

  1. *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)
  2. 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)
  3. Uruno, A. and *Motohashi, H. 
    The Keap1-Nrf2 system as an in vivo sensor for electrophiles.
    Nitric Oxide 25, 153-160 (2011)
  4. *Motohashi, H. and *Igarashi, K.
    MafB as a type I interferon rheostat.
    Nat. Immunol. 11, 695-696 (2010)
  5. 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)
  6. 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)
  7. *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)
  8. *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)
  9. Kimura, M., Yamamoto, T., Zhang, J., Itoh, K., Kyo, M., Kamiya, T., Aburatani, H., Katsuoka, F., Kurokawa, H., Tanaka, T., *Motohashi, H., and Yamamoto, M.
    Molecular basis distinguishing the DNA binding profile of NRF2-MAF heterodimer from that of MAF homodimer.
    J. Biol. Chem. 
    282, 33681-33690 (2007)
  10. *Motohashi, H., Katsuoka, F., Miyoshi, C., Uchimura, Y., Saitoh, H., Francastel, C., Engel, JD., and Yamamoto, M.
    MafG Sumoylation Is Required for Active Transcriptional Repression.
    Mol. Cell. Biol. 26, 4652-4663 (2006)

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