QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Kim, C.-H. Articles by Kim, K.-S. Search for Related Content PubMed PubMed Citation Articles by Kim, C.-H. Articles by Kim, K.-S.

 Previous Article  |  Next Article 

The Journal of Neuroscience, April 1, 2002, 22(7):2579-2589

A Proximal Promoter Domain Containing a Homeodomain-Binding Core Motif Interacts with Multiple Transcription Factors, Including HoxA5 and Phox2 Proteins, and Critically Regulates Cell Type-Specific Transcription of the Human Norepinephrine Transporter Gene

Chun-Hyung Kim, Dong-Youn Hwang, Jae-Joon Park, and Kwang-Soo Kim

Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478

Expression of the norepinephrine transporter (NET), which mediates the reuptake of norepinephrine into presynaptic nerve terminals, is restricted to noradrenergic (NA) neurons. We have demonstrated previously that the 9.0 kb upstream sequences and the first intron residing in the 5' untranslated area are critical for high-level and NA cell-specific transcription. Here, using transient transfection assays, we show that 4.0 kb of the 5' upstream sequences contains sufficient genetic information to drive reporter gene expression in an NA cell type-specific manner. Three functional domains appear to be potentially important for the regulation of human NET (hNET) gene transcription: an upstream enhancer region at 4.0 to 3.1 kb, a proximal domain at 133 to 75 bp, and a middle silencer region between these two domains. DNase I footprinting analysis of the proximal promoter region shows that a subdomain at 128 to 80 bp is protected in a cell-specific manner. We provide evidence that multiple protein factors interact with the proximal promoter domain to critically regulate the transcriptional activity of the hNET gene. In the middle of this proximal subdomain resides a homeodomain (HD)-binding core motif, which interacts with HD factors, including Phox2a and HoxA5, in an NA-specific manner. Cotransfection analyses suggest that HoxA5 and Phox2a may transactivate the hNET gene promoter. Together with previous studies indicating direct activation of dopamine -hydroxylase transcription by Phox2a/2b, the present results support a model whereby Phox2 proteins may coordinately regulate the phenotypic specification of NA neurons by activating both NA biosynthetic and reuptake genes.

Key words: norepinephrine transporter; promoter; noradrenergic neuron; cell type-specific transcription; cis-acting element; homeodomain; Phox2a; HoxA5

---

Copyright © 2002 Society for Neuroscience  0270-6474/02/2272579-11$05.00/0

This article has been cited by other articles:

				R. Kvetnansky, E. L. Sabban, and M. Palkovits Catecholaminergic Systems in Stress: Structural and Molecular Genetic Approaches Physiol Rev, April 1, 2009; 89(2): 535 - 606. [Abstract] [Full Text] [PDF]

				C.-H. Kim, M. K. Hahn, Y. Joung, S. L. Anderson, A. H. Steele, M. S. Mazei-Robinson, I. Gizer, M. H. Teicher, B. M. Cohen, D. Robertson, et al. A polymorphism in the norepinephrine transporter gene alters promoter activity and is associated with attention-deficit hyperactivity disorder PNAS, December 12, 2006; 103(50): 19164 - 19169. [Abstract] [Full Text] [PDF]

				J. Lee, C.-H. Kim, D. K. Simon, L. R. Aminova, A. Y. Andreyev, Y. E. Kushnareva, A. N. Murphy, B. E. Lonze, K.-S. Kim, D. D. Ginty, et al. Mitochondrial Cyclic AMP Response Element-binding Protein (CREB) Mediates Mitochondrial Gene Expression and Neuronal Survival J. Biol. Chem., December 9, 2005; 280(49): 40398 - 40401. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help