Regulation of transcription factor C/ATF by the cAMP signal activation in hippocampal neurons, and molecular interaction of C/ATF with signal integrator CBP/p300

• Published in: Brain research. Molecular brain research. 1999-05, Vol.69 (1), p.124-134
• Main Authors: Yukawa, Kazunori, Tanaka, Takashi, Tsuji, Shigekatsu, Akira, Shizuo
• Format: Article
• Language: English
• Subjects: Activating Transcription Factor 4; Activating transcription factor 4, ATF4; Animals; Aplysia; C/ATF protein; cAMP; CCAAT-Enhancer-Binding Proteins; CCAAT/enhancer binding proteins related activating transcription factor, C/ATF; Cells, Cultured; CREB binding protein/p300, CBP/p300; CREB-binding protein; Cyclic AMP - physiology; Cyclic AMP Response Element-Binding Protein - genetics; Cyclic AMP Response Element-Binding Protein - metabolism; DNA Probes; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Drosophila; E1A-Associated p300 Protein; Gene Expression - physiology; Hippocampal neurons; Hippocampus - cytology; Leucine Zippers - genetics; Mice; Neurons - chemistry; Neurons - cytology; Neurons - physiology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; p160 protein; p300 protein; Protein Binding - genetics; Rats; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Signal Transduction - physiology; SRC-1 protein; STAT2 Transcription Factor; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0169-328X; 1872-6941
• DOI: 10.1016/S0169-328X(99)00086-8

The CCAAT/enhancer binding proteins related activating transcription factor, C/ATF, is a mouse leucine-zipper transcription factor which is structurally homologous to ApCREB2, a suppressor integral to long-term synaptic plasticity in Aplysia. To gain a clue to whether C/ATF is involved in long-term plasticities of brain, we examined if the expression levels of C/ATF are modulated by cAMP, an inducer crucial for memory formation in Aplysia, Drosophila and mice. Our in situ hybridization analysis revealed the expression of C/ATF mRNA in hippocampal neurons. C/ATF protein levels increased after the cAMP signal stimulation in hippocampal neurons, while C/ATF mRNA levels remained constant. The human activating transcription factor 4 (hATF4), another homolog of ApCREB2, interacts with multiple domains of the coactivator CREB-binding protein (CBP), resulting in the potentiation of its ability to activate transcription. As expected, C/ATF was found to interact with three domains of CBP including CREB binding domain or kinase-inducible interaction (KIX) domain, the third cysteine–histidine-rich region (CH3 domain) and the nuclear receptor coactivator p160/SRC-1-interacting domain. Interestingly, C/ATF was further found to interact strongly with CREB binding protein/p300 (CBP/p300) CH1 domain. Mammalian two hybrid assays indicated that the interaction between C/ATF and CBP/p300 can occur in mammalian cells, and that the p300 CH1 domain is critical for the interaction. Thus, C/ATF may be implicated in transcription-dependent phase of hippocampal long-term plasticities through the modulation of its protein level under cAMP signal and the interaction with signal integrator, CBP/p300.