Activating transcription factor 1 (ATF1), CREB, and the cyclic AMP (cAMP) response element modulatory protein (CREM), which constitute a subfamily of the basic leucine zipper transcription factors, activate gene expression by binding as homo-or heterodimers to the cAMP response element in regulatory regions of target genes. To investigate the function of ATF1 in vivo, we inactivated the corresponding gene by homologous recombination. In contrast to CREB-deficient mice, which suffer from perinatal lethality, mice lacking ATF1 do not exhibit any discernible phenotypic abnormalities. Since ATF1 and CREB but not CREM are strongly coexpressed during early mouse development, we generated mice deficient for both CREB and ATF1. ATF1 CREB؊/؊ embryos die before implantation due to developmental arrest. ATF1 ؉/؊ CREB ؊/؊ embryos display a phenotype of embryonic lethality around embryonic day 9.5 due to massive apoptosis. These results indicate that CREB and ATF1 act in concert to mediate signals essential for maintaining cell viability during early embryonic development.The activating transcription factor 1 (ATF1), CREB, and the cyclic AMP response element modulatory protein (CREM) share high sequence homology and mediate the transcriptional response to various extracellular signals, including peptide hormones (15, 27), growth factors (10, 11, 26), neurotransmitters, and Ca 2ϩ (17,23). Activation of the CREB/CREM/ATF1 proteins is mediated via different signaling pathways which converge to phosphorylate a distinct serine residue (22). Phosphorylation of CREB by mitogen-activated protein kinase and Akt/protein kinase B has been implicated as important for cellular survival in cultured cells (4, 9). CREB is also thought to act as an antiapoptotic factor in sympathetic neurons (19). In human clear cell sarcoma, the ATF1 gene is fused to the genes encoding Ewing's sarcoma protein and seems to be responsible for maintaining tumor viability (5). It was also suggested that ATF1 is upregulated in human metastatic melanoma cells. Disruption of ATF1 activity in these cells by using an inhibitory anti-ATF1 antibody fragment suppressed their tumorigenicity and metastatic potential in nude mice (14).As previously reported, the corresponding genes of CREB and CREM have been inactivated by gene targeting in mice. Mice lacking the CREM gene exhibit an arrest in spermatogenesis (3, 16), whereas CREB-deficient mice die perinatally due to atelectasis of the lung (21). We show here that loss of ATF1 function after inactivation of the ATF1 gene in mice does not cause any obvious phenotypic abnormalities. Our expression studies showed that ATF1 and CREB but not CREM are strongly coexpressed during early mouse development. To identify the role of both proteins during early development and to circumvent possible compensatory effects, we therefore generated mice deficient for both ATF1 and CREB. Interestingly, complete inactivation of both proteins, ATF1 and CREB, results in embryonic death before implantation. Embryos with only one functional ATF1...
The transcription factor cAMP-responsive element binding protein (CREB) has been shown to regulate different physiological responses including drug addiction and emotional behavior. Molecular changes including adaptive modifications of the transcription factor CREB are produced during drug dependence in many regions of the brain, including the locus coeruleus (LC), but the molecular mechanisms involving CREB within these regions have remained controversial. To further investigate the involvement of CREB in emotional behavior, drug reward and opioid physical dependence, we used two independently generated CREB-deficient mice. We employed the Cre/loxP system to generate mice with a conditional CREB mutation restricted to the nervous system, where all CREB isoforms are lacking in the brain (Creb1 NesCre ). A genetically defined cohort of the previously described hypomorphic Creb1 aD mice, in which the two major transcriptionally active isoforms (a and D) are disrupted throughout the organism, were also used. First, we investigated the responses to stress of the CREB-deficient mice in several paradigms, and we found an increased anxiogenic-like response in the both Creb1 mutant mice in different behavioral models. We investigated the rewarding properties of drugs of abuse (cocaine and morphine) and natural reward (food) using the conditioned place-preference paradigm. No modification of motivational responses of morphine, cocaine, or food was observed in mutant mice. Finally, we evaluated opioid dependence by measuring the behavioral expression of morphine withdrawal and electrophysiological recordings of LC neurons. We showed an important attenuation of the behavioral expression of abstinence and a decrease in the hyperactivity of LC neurons in both Creb1 mutant mice. Our results emphasize the selective role played by neuronal CREB in emotional-like behavior and the somatic expression morphine withdrawal, without participating in the rewarding properties induced by morphine and cocaine.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.