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Identification of nerve growth factor-responsive element of the TCL1 promoter as a novel negative regulatory element

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Please use this identifier to cite or link to this item:http://hdl.handle.net/2115/14759

Title: Identification of nerve growth factor-responsive element of the TCL1 promoter as a novel negative regulatory element
Authors: Hiromura, Makoto Browse this author
Suizu, Futoshi Browse this author
Narita, Masumi Browse this author
Kinowaki, Keiichi Browse this author
Noguchi, Masayuki Browse this author →KAKEN DB
Issue Date: 22-Sep-2006
Publisher: American Society for Biochemistry and Molecular Biology
Journal Title: Journal of Biological Chemistry
Volume: 281
Issue: 38
Start Page: 27753
End Page: 27764
Publisher DOI: 10.1074/jbc.M602420200
PMID: 16835233
Abstract: The serine/threonine kinase, Akt (protein kinase B) plays a central role in the regulation of intracellular cell survival. Recently, we demonstrated that the proto-oncogene TCL1, overexpressed in human T-cell prolymphocytic leukemia, is an Akt kinase co-activator. Tightly restricted TCL1 gene expression in early developmental cells suggested that the TCL1 gene is regulated at a transcriptional level. To characterize how TCL1 gene expression is regulated, we cloned the 5'-promoter of the TCL1 gene located at human chromosome 14q32. The 5'-TCL1 promoter region contains a TATA box with cis-regulatory elements for Nur77/NGFI-B (nerve growth factor-responsive element (NBRE), CCAAGGTCA), NFB, and fork head transcription factor. Nur77/NGFI-B, an orphan receptor superfamily transcription factor implicated in T-cell apoptosis, is a substrate for Akt. We hypothesized that TCL1 transactivity is regulated through Akt-induced phosphorylation of Nur77/NGFI-B in vivo. In an electrophoretic mobility shift assay with chromosomal immunoprecipitation assays, wild-type Nur77, but not S350A mutant Nur77, could specifically bind to TCL1-NBRE. A luciferase assay demonstrated that TCL1-NBRE is required for inhibition of TCL1 transactivity upon nerve growth factor/platelet-derived growth factor stimulation, which activates Akt and phosphorylates Nur77. Using a chromosomal immunoprecipitation assay with reverse transcription-PCR, nerve growth factor stimulation inhibited binding of endogenous Nur77 to TCL1-NBRE, in turn, suppressing TCL1 gene expression. The results together establish that TCL1-NBRE is a novel negative regulatory element of Nur77 (NGFI-B). To the best of our knowledge, TCL1-NBRE is the first direct target of Nur77 involving the regulation of intracellular cell death survival. This Akt-induced inhibitory mechanism of TCL1 should play an important role in immunological and/or neuronal development in vivo
Rights: Copyright © 2006 by the American Society for Biochemistry and Molecular Biology
Relation: http://www.jpc.org/
Type: article (author version)
URI: http://hdl.handle.net/2115/14759
Appears in Collections:遺伝子病制御研究所 (Institute for Genetic Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 野口 昌幸

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