Molecules and Cells

  • 제45권8호
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  • Pages.537-549
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  • 2022
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  • 1016-8478(pISSN)
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  • 0219-1032(eISSN)
한국분자세포생물학회 (Korean Society for Molecular and Cellular Biology)
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Transcriptional Regulatory Role of NELL2 in Preproenkephalin Gene Expression

  • Ha, Chang Man (Brain Research Core Facilities and Global Relation Center of Research Strategy Office, Korea Brain Research Institute) ;
  • Kim, Dong Hee (Department of Biological Sciences, University of Ulsan) ;
  • Lee, Tae Hwan (Department of Biological Sciences, University of Ulsan) ;
  • Kim, Han Rae (Department of Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences) ;
  • Choi, Jungil (Bioenvironmental Science & Technology Division, Korea Institute of Toxicology) ;
  • Kim, Yoonju (Brain Research Core Facilities and Global Relation Center of Research Strategy Office, Korea Brain Research Institute) ;
  • Kang, Dasol (Department of Biological Sciences, University of Ulsan) ;
  • Park, Jeong Woo (Department of Biological Sciences, University of Ulsan) ;
  • Ojeda, Sergio R. (Division of Neuroscience, Oregon National Primate Research Center/Oregon Health & Science University) ;
  • Jeong, Jin Kwon (Department of Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences) ;
  • Lee, Byung Ju (Department of Biological Sciences, University of Ulsan)
  • 투고 : 2021.12.27
  • 심사 : 2022.04.03
  • 발행 : 2022.08.31
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초록

Preproenkephalin (PPE) is a precursor molecule for multiple endogenous opioid peptides Leu-enkephalin (ENK) and Met-ENK, which are involved in a wide variety of modulatory functions in the nervous system. Despite the functional importance of ENK in the brain, the effect of brain-derived factor(s) on PPE expression is unknown. We report the dual effect of neural epidermal growth factor (EGF)-like-like 2 (NELL2) on PPE gene expression. In cultured NIH3T3 cells, transfection of NELL2 expression vectors induced an inhibition of PPE transcription intracellularly, in parallel with downregulation of protein kinase C signaling pathways and extracellular signal-regulated kinase. Interestingly, these phenomena were reversed when synthetic NELL2 was administered extracellularly. The in vivo disruption of NELL2 synthesis resulted in an increase in PPE mRNA level in the rat brain, suggesting that the inhibitory action of intracellular NELL2 predominates the activation effect of extracellular NELL2 on PPE gene expression in the brain. Biochemical and molecular studies with mutant NELL2 structures further demonstrated the critical role of EGF-like repeat domains in NELL2 for regulation of PPE transcription. These are the first results to reveal the spatio-specific role of NELL2 in the homeostatic regulation of PPE gene expression.

키워드

과제정보

This research was supported by the Priority Research Centers Program (2014R1A6A1030318), the National Research Foundation of Korea (NRF-2020R1A2C1008080), KBRI research program through Korea Brain Research Institute funded by the Ministry of Science, ICT & Future Planning (No. 21-BR-03-02), and the Korean Government (MSIP) through the National Research Foundation of Korea (NRF-2020R1F1A1058459).

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