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.
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Authors | Makoto Hiromura, Futoshi Suizu, Masumi Narita, Keiichi Kinowaki, Masayuki Noguchi |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 281
Issue 38
Pg. 27753-64
(Sep 22 2006)
ISSN: 0021-9258 [Print] United States |
PMID | 16835233
(Publication Type: Journal Article)
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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
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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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