Characterization of the 5′-sequence of the mouse fatty acid amide hydrolase

Puffenbarger, Robyn A.; Kapulina, Oksana; Howell, Judy M.; Deutsch, Dale G.

doi:10.1016/s0304-3940(01)02274-1

Cited by 23 publications

(11 citation statements)

References 19 publications

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“…Two other interesting reports have characterized the promoter (38) and the transcriptional regulation (34) of mouse FAAH in neuronal cell lines. In particular, they have shown either putative (38) or imperfect (34) estrogen response elements in the FAAH promoter region, giving some ground to our previous report that estrogen down-regulates FAAH activity in mouse (39). Here, we show that in the human FAAH promoter estrogen response elements are replaced by an Ikaros binding site ( Fig.…”

Section: Discussionsupporting

confidence: 77%

“…These observations suggest a relevant species specificity of FAAH regulation, although the human and mouse FAAH (localized on chromosomes 1 and 4, respectively) share 84% sequence identity (21) and have a conserved genomic structure (33). In addition, also a tissue specificity of FAAH promoter activity has been observed (38), which might further contribute to divergent regulation in different species or in different tissues of the same species. The interaction between different transcription factors, some of which have been identified here for the first time, on FAAH regulation awaits for further clarification.…”

Section: Discussionmentioning

confidence: 93%

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Progesterone Activates Fatty Acid Amide Hydrolase (FAAH) Promoter in Human T Lymphocytes through the Transcription Factor Ikaros

Maccarrone

Bari

Rienzo

et al. 2003

Journal of Biological Chemistry

110

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Physiological concentrations of progesterone stimulate the activity of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) in human T lymphocytes, up to a ϳ270% over the untreated controls. Stimulation of FAAH occurred through up-regulation of gene expression at transcriptional and translational level and was specific. Indeed, neither the activity of the anandamide-synthesizing N-acyltransferase and phospholipase D, nor the activity of the anandamide transporter, nor the binding to cannabinoid receptors were affected by progesterone under the same experimental conditions. The activation of FAAH by progesterone was paralleled by a decrease (down to 60%) of the cellular levels of anandamide and involved increased nuclear levels of the transcription factor Ikaros. Analysis of the FAAH promoter showed an Ikaros binding site, and mutation of this site prevented FAAH activation by progesterone in transient expression assays. Electrophoretic mobility shift and supershift assays further corroborated the promoter activity data. Furthermore, the effect of progesterone on FAAH promoter was additive to that of physiological amounts of leptin, which binds to a cAMP response element-like site in the promoter region. Taken together, these results suggest that progesterone and leptin, by up-regulating the FAAH promoter at different sites, enhance FAAH expression, thus tuning the immunomodulatory effects of anandamide. These findings might also have critical implications for human fertility.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 93%

Progesterone Activates Fatty Acid Amide Hydrolase (FAAH) Promoter in Human T Lymphocytes through the Transcription Factor Ikaros

Maccarrone

Bari

Rienzo

et al. 2003

Journal of Biological Chemistry

110

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“…These observations suggest a relevant species specificity of FAAH regulation, though the human and mouse FAAH (localized on chromosome 1 and 4, respectively) share 84% sequence identity (25) and have a conserved genomic structure (34). In addition, also a tissue specificity of FAAH promoter activity has been observed (38), which might further contribute to divergent regulation in different species or in different tissues of the same species. The interaction between different transcription factors, some of which have been identified here for the first time, on FAAH regulation awaits for further clarification.…”

Section: Discussionmentioning

confidence: 90%

“…As yet, two interesting reports have characterized the promoter (38) and the transcriptional regulation (35) of mouse FAAH in neuronal cell lines. In particular, they have shown either putative (38) or imperfect (34) estrogen response elements in the FAAH promoter region, giving some ground to our previous report that estrogen downregulates FAAH activity in mouse (39). Remarkably, here we show that the human FAAH promoter does not contain an estrogen response element at the same position (Fig.…”

Section: Discussionmentioning

confidence: 99%

Leptin Activates the Anandamide Hydrolase Promoter in Human T Lymphocytes through STAT3

Maccarrone

Rienzo

Finazzi‐Agrò

et al. 2003

Journal of Biological Chemistry

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Physiological concentrations of leptin stimulate the activity of the endocannabinoid-degrading enzyme anandamide hydrolase (fatty acid amide hydrolase, FAAH) in human T lymphocytes up to ϳ300% over the untreated controls. Stimulation of FAAH occurred through up-regulation of gene expression at transcriptional and translational levels and involved binding of leptin to its receptor with an apparent dissociation constant (K d ) of 1.95 ؎ 0.14 nM and maximum binding (B max ) of 392 ؎ 8 fmol⅐mg protein ؊1 . Leptin binding to the receptor triggered activation of STAT3 but not STAT1 or STAT5 or the mitogen-activated protein kinases p38, p42, and p44. Peripheral lymphocytes of leptin knockout (ob/ob) mice showed decreased FAAH activity and expression (ϳ25% of the wild-type littermates), which were reversed to control levels by exogenous leptin. Analysis of the FAAH promoter showed a cAMPresponse element-like site, which is a transcriptional target of STAT3. Consistently, mutation of this site prevented FAAH activation by leptin in transient expression assays. Electrophoretic mobility shift and supershift assays further corroborated the promoter activity data. Taken together, these results suggest that leptin, by up-regulating the FAAH promoter through STAT3, enhances FAAH expression, thus tuning the immunomodulatory effects of anandamide. These findings might also have critical implications for human fertility. Leptin (L)1 is the 16-kDa non-glycosylated product of the obese gene, which is secreted by adipose cells, is released into the circulation, and transported across the blood-brain barrier into the central nervous system where it regulates energy homeostasis (1). Leptin also serves systemic functions apart from those related to food intake and energy expenditure in mammals, including regulation of fertility (2) and modulation of immune response (3). These two actions might be interconnected in humans because leptin alters the production from T lymphocytes of T helper 1 and 2 cytokines (4), which are critical in regulating embryo implantation and materno-fetal exchanges (5, 6). In this line, mice genetically defective in leptin (ob/ob knock-out) are obese, infertile, and immunodeficient, and administration of exogenous leptin can reverse these defects (1-4). Leptin signaling is mediated by the leptin receptor (LR), which exists in at least six different isoforms (1). Yet, only the long LR isoform has all intracellular motifs necessary for signaling via the signal transducer, activator of transcription (STAT), and/or the mitogen-activated protein kinase (MAPK) pathways (7-11). The relative importance of these divergent signaling events in leptin action is still unknown. Recently, leptin has been shown to reduce the levels of anandamide (arachidonoylethanolamide, AEA) in the hypothalamus of ob/ob mice, suggesting that this compound partakes of the neural circuitry regulated by leptin (12).AEA belongs to a group of endogenous lipids, which include amides, esters, and ethers of long chain polyunsaturated fatty acids, co...

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“…Recently, the X-ray structure of FAAH crystals in complex with its substrate was elucidated (Bracey et al, 2002) and suggested that the enzyme might be able to associate with the plasma membrane. The promoter region on the FAAH gene has been identified (Puffenbarger et al, 2001;Waleh et al, 2002), and seems to be upregulated by progesterone and leptin (Maccarrone et al, 2003a, b), and downregulated by estrogens and glucocorticoids (Waleh et al, 2002). FAAH 'knockout' mice have been developed that are more responsive to exogenously administered AEA (Cravatt et al, 2001), and whose brains contain 15-fold higher levels of brain AEA than wild-type mice.…”

Section: Endocannabinoid Metabolism -Hydrolysismentioning

confidence: 99%

The endocannabinoid system: a general view and latest additions

Petrocellis

Cascio

Marzo

2004

British J Pharmacology

430

356

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After the discovery, in the early 1990s, of specific G-protein-coupled receptors for marijuana's psychoactive principle D 9 -tetrahydrocannabinol, the cannabinoid receptors, and of their endogenous agonists, the endocannabinoids, a decade of investigations has greatly enlarged our understanding of this altogether new signalling system. Yet, while the finding of the endocannabinoids resulted in a new effort to reveal the mechanisms regulating their levels in the brain and peripheral organs under physiological and pathological conditions, more endogenous substances with a similar action, and more molecular targets for the previously discovered endogenous ligands, anandamide and 2-arachidonoylglycerol, or for some of their metabolites, were being proposed. As the scenario becomes subsequently more complicated, and the experimental tasks to be accomplished correspondingly more numerous, we briefly review in this article the latest 'additions' to the endocannabinoid system together with earlier breakthroughs that have contributed to our present knowledge of the biochemistry and pharmacology of the endocannabinoids.

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Characterization of the 5′-sequence of the mouse fatty acid amide hydrolase

Cited by 23 publications

References 19 publications

Progesterone Activates Fatty Acid Amide Hydrolase (FAAH) Promoter in Human T Lymphocytes through the Transcription Factor Ikaros

Progesterone Activates Fatty Acid Amide Hydrolase (FAAH) Promoter in Human T Lymphocytes through the Transcription Factor Ikaros

Leptin Activates the Anandamide Hydrolase Promoter in Human T Lymphocytes through STAT3

The endocannabinoid system: a general view and latest additions

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