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

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), NFkappaB, 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.
AuthorsMakoto Hiromura, Futoshi Suizu, Masumi Narita, Keiichi Kinowaki, Masayuki Noguchi
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 281 Issue 38 Pg. 27753-64 (Sep 22 2006) ISSN: 0021-9258 [Print] United States
PMID16835233 (Publication Type: Journal Article)
Chemical References
  • DNA-Binding Proteins
  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • MAS1 protein, human
  • NR4A1 protein, human
  • Nr4a1 protein, mouse
  • Nr4a1 protein, rat
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • TCL1A protein, human
  • Transcription Factors
  • Nerve Growth Factor
  • Proto-Oncogene Proteins c-akt
Topics
  • Animals
  • Base Sequence
  • DNA-Binding Proteins (metabolism)
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors (physiology)
  • Humans
  • Mice
  • Molecular Sequence Data
  • Nerve Growth Factor (pharmacology)
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Phosphorylation
  • Platelet-Derived Growth Factor (pharmacology)
  • Promoter Regions, Genetic
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins (genetics)
  • Proto-Oncogene Proteins c-akt (physiology)
  • Rats
  • Receptors, Cytoplasmic and Nuclear (metabolism)
  • Receptors, Steroid (metabolism)
  • Response Elements (physiology)
  • Transcription Factors (metabolism)

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