Редактирование: FKBP5

Peptidyl-prolyl cis-trans isomerase FKBP5 (EC 5.2.1.8) (PPIase FKBP5) (51 kDa FK506-binding protein) (51 kDa FKBP) (FKBP-51) (54 kDa progesterone receptor-associated immunophilin) (Androgen-regulated protein 6) (FF1 antigen) (FK506-binding protein 5) (FKBP-5) (FKBP54) (p54) (HSP90-binding immunophilin) (Rotamase) [AIG6] [FKBP51]

==Publications==

{{medline-entry
|title=Epigenetic upregulation of [[FKBP5]] by aging and stress contributes to NF-κB-driven inflammation and cardiovascular risk.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31113877
|abstract=Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that [[FKBP5]], a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total [i]n[/i] > 3,000), aging synergized with stress-related phenotypes, measured with childhood trauma and major depression questionnaires, to epigenetically up-regulate [i][[FKBP5]][/i] expression. These age/stress-related epigenetic effects were recapitulated in a cellular model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher [i][[FKBP5]][/i] mRNA with a proinflammatory profile and altered NF-κB-related gene networks. Accordingly, experiments in immune cells showed that higher [i][[FKBP5]][/i] promotes inflammation by strengthening the interactions of NF-κB regulatory kinases, whereas opposing [[FKBP5]] either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-κB. Further, the age/stress-related epigenetic signature enhanced [i][[FKBP5]][/i] response to NF-κB through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that aging/stress-driven [[FKBP5]]-NF-κB signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.
|mesh-terms=* Aging
* Cardiovascular Diseases
* Cellular Senescence
* Child, Preschool
* Depressive Disorder, Major
* Epigenesis, Genetic
* Female
* Genome-Wide Association Study
* Humans
* Inflammation
* Male
* NF-kappa B
* Risk Factors
* Signal Transduction
* Stress, Psychological
* Tacrolimus Binding Proteins
* Up-Regulation
|keywords=* FKBP5
* aging
* epigenetics
* inflammation
* psychosocial stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561294
}}
{{medline-entry
|title=The common functional [[FKBP5]] variant rs1360780 is associated with altered cognitive function in aged individuals.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25331639
|abstract=The common single nucleotide polymorphism (SNP) rs1360780 (C/T) of the FK506 Binding Protein 5 ([[FKBP5]]) gene has been reported to be associated with an altered response of the hypothalamic-pituitary-adrenal (HPA) axis and the development of stress-related psychiatric disorders such as posttraumatic stress disorder (PTSD). In the present study, we examined whether this SNP is associated with cognitive function in a non-clinical population. The full versions of the Wechsler Memory Scale-Revised and Wechsler Adult Intelligence Scale-Revised were administered to 742 and 627 Japanese individuals, respectively, followed by genotyping of rs1360780 by the TaqMan 5'-exonuclease allelic discrimination assay. For both cognitive tests, we found significantly poorer attention/concentration (working memory) in aged (>50 years old) individuals carrying the T allele compared with their counterparts. This finding accords with an altered HPA axis and vulnerability to stress-related psychiatric disorders. 
|mesh-terms=* Aged
* Aging
* Cognition
* Female
* Gene Frequency
* Genetic Association Studies
* Genotype
* Humans
* Hypothalamo-Hypophyseal System
* Male
* Memory, Short-Term
* Middle Aged
* Polymorphism, Single Nucleotide
* Stress Disorders, Post-Traumatic
* Tacrolimus Binding Proteins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4204028
}}
{{medline-entry
|title=Age-associated epigenetic upregulation of the [[FKBP5]] gene selectively impairs stress resiliency.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25191701
|abstract=Single nucleotide polymorphisms (SNPs) in the FK506 binding protein 5 ([[FKBP5]]) gene combine with traumatic events to increase risk for post-traumatic stress and major depressive disorders (PTSD and MDD). These SNPs increase [[FKBP5]]1 protein expression through a mechanism involving demethylation of the gene and altered glucocorticoid signaling. Aged animals also display elevated [[FKBP5]]1 levels, which contribute to impaired resiliency to depressive-like behaviors through impaired glucocorticoid signaling, a phenotype that is abrogated in [[FKBP5]]-/- mice. But the age of onset and progressive stability of these phenotypes remain unknown. Moreover, it is unclear how [[FKBP5]] deletion affects other glucocorticoid-dependent processes or if age-associated increases in [[FKBP5]]1 expression are mediated through a similar epigenetic process caused by SNPs in the [[FKBP5]] gene. Here, we show that [[FKBP5]]1-mediated impairment in stress resiliency and glucocorticoid signaling occurs by 10 months of age and this increased over their lifespan. Surprisingly, despite these progressive changes in glucocorticoid responsiveness, [[FKBP5]]-/- mice displayed normal longevity, glucose tolerance, blood composition and cytokine profiles across lifespan, phenotypes normally associated with glucocorticoid signaling. We also found that methylation of Fkbp5 decreased with age in mice, a process that likely explains the age-associated increases in [[FKBP5]]1 levels. Thus, epigenetic upregulation of [[FKBP5]]1 with age can selectively impair psychological stress-resiliency, but does not affect other glucocorticoid-mediated physiological processes. This makes [[FKBP5]]1 a unique and attractive therapeutic target to treat PTSD and MDD. In addition, aged wild-type mice may be a useful model for investigating the mechanisms of [[FKBP5]] SNPs associated with these disorders. 
|mesh-terms=* Aging
* Animals
* DNA Methylation
* Depressive Disorder, Major
* Epigenesis, Genetic
* Hydrocortisone
* Longevity
* Mice
* Mice, Knockout
* Polymorphism, Single Nucleotide
* Resilience, Psychological
* Stress Disorders, Post-Traumatic
* Stress, Psychological
* Tacrolimus Binding Proteins
* Up-Regulation

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4156438
}}
{{medline-entry
|title=Role of [[FKBP5]] in emotion processing: results on amygdala activity, connectivity and volume.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24756342
|abstract=Accumulating evidence suggests a role of [[FKBP5]], a co-chaperone regulating the glucocorticoid receptor sensitivity, in the etiology of depression and anxiety disorders. Based on recent findings of altered amygdala activity following childhood adversity, the present study aimed at clarifying the impact of genetic variation in [[FKBP5]] on threat-related neural activity and coupling as well as morphometric alterations in stress-sensitive brain systems. Functional magnetic resonance imaging during an emotional face-matching task was performed in 153 healthy young adults (66 males) from a high-risk community sample followed since birth. Voxel-based morphometry was applied to study structural alterations and DNA was genotyped for [[FKBP5]] rs1360780. Childhood adversity was measured using retrospective self-report (Childhood Trauma Questionnaire) and by a standardized parent interview assessing childhood family adversity. Depression was assessed by the Beck Depression Inventory. There was a main effect of [[FKBP5]] on the left amygdala, with T homozygotes showing the highest activity, largest volume and increased coupling with the left hippocampus and the orbitofrontal cortex (OFC). Moreover, amygdala-OFC coupling proved to be associated with depression in this genotype. In addition, our results support previous evidence of a gene-environment interaction on right amygdala activity with respect to retrospective assessment of childhood adversity, but clarify that this does not generalize to the prospective assessment. These findings indicated that activity in T homozygotes increased with the level of adversity, whereas the opposite pattern emerged in C homozygotes, with CT individuals being intermediate. The present results point to a functional involvement of [[FKBP5]] in intermediate phenotypes associated with emotional processing, suggesting a possible mechanism for this gene in conferring susceptibility to stress-related disorders. 
|mesh-terms=* Adult
* Aging
* Amygdala
* Child
* Child, Preschool
* Depressive Disorder
* Emotions
* Environment
* Family
* Female
* Genotype
* Humans
* Infant
* Magnetic Resonance Imaging
* Male
* Polymorphism, Single Nucleotide
* Prefrontal Cortex
* Prospective Studies
* Psychiatric Status Rating Scales
* Retrospective Studies
* Surveys and Questionnaires
* Tacrolimus Binding Proteins
* Young Adult

|full-text-url=https://sci-hub.do/10.1007/s00429-014-0729-5
}}
{{medline-entry
|title=Cell intrinsic role of COX-2 in pancreatic cancer development.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/22784710
|abstract=COX-2 is upregulated in pancreatic ductal adenocarcinomas (PDAC). However, how COX-2 promotes PDAC development is unclear. While previous studies have evaluated the efficacy of COX-2 inhibition via the use of nonsteroidal anti-inflammatory drugs (NSAID) or the COX-2 inhibitor celecoxib in PDAC models, none have addressed the cell intrinsic versus microenvironment roles of COX-2 in modulating PDAC initiation and progression. We tested the cell intrinsic role of COX-2 in PDAC progression using both loss-of-function and gain-of-function approaches. Cox-2 deletion in Pdx1  pancreatic progenitor cells significantly delays the development of PDAC in mice with K-ras activation and Pten haploinsufficiency. Conversely, COX-2 overexpression promotes early onset and progression of PDAC in the K-ras mouse model. Loss of [[PTEN]] function is a critical factor in determining lethal PDAC onset and overall survival. Mechanistically, COX-2 overexpression increases p-AKT levels in the precursor lesions of Pdx1( ); K-ras(G12D)(/ ); Pten(lox)(/ ) mice in the absence of Pten LOH. In contrast, Cox-2 deletion in the same setting diminishes p-AKT levels and delays cancer progression. These data suggest an important cell intrinsic role for COX-2 in tumor initiation and progression through activation of the PI3K/AKT pathway. PDAC that is independent of intrinsic COX-2 expression eventually develops with decreased [[FKBP5]] and increased GRP78 expression, two alternate pathways leading to AKT activation. Together, these results support a cell intrinsic role for COX-2 in PDAC development and suggest that while anti-COX-2 therapy may delay the development and progression of PDAC, mechanisms known to increase chemoresistance through AKT activation must also be overcome.
|mesh-terms=* Animals
* Carcinoma, Pancreatic Ductal
* Celecoxib
* Cell Membrane
* Cyclooxygenase 2
* Disease Models, Animal
* Disease Progression
* Enzyme Activation
* Feedback, Physiological
* Gene Deletion
* Gene Targeting
* Heat-Shock Proteins
* Homeodomain Proteins
* Integrases
* Life Expectancy
* Mice
* PTEN Phosphohydrolase
* Pancreatic Neoplasms
* Precancerous Conditions
* Proto-Oncogene Proteins c-akt
* Proto-Oncogene Proteins p21(ras)
* Pyrazoles
* Sulfonamides
* Survival Analysis
* Tacrolimus Binding Proteins
* Trans-Activators
* Up-Regulation

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3469770
}}
{{medline-entry
|title=[[FKBP5]] polymorphisms and antidepressant response in geriatric depression.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/19676097
|abstract=Genetic variation at the [[FKBP5]] locus has been reported to affect clinical outcomes in patients treated with antidepressant medications in several studies. However, other reports have not confirmed this association. [[FKBP5]] may regulate the sensitivity of the hypothalamic-pituitary-adrenal axis. We tested two [[FKBP5]] single nucleotide polymorphisms (rs1360780 and rs3800373) in a sample of 246 geriatric patients treated for 8 weeks in a double-blind randomized comparison trial of paroxetine and mirtazapine. These two polymorphisms had previously been reported to predict efficacy in depressed patients treated with selective serotonin reuptake inhibitors such as paroxetine, and those treated with mirtazapine, an agent with both serotonergic and noradrenergic actions. However, we found no significant associations between these [[FKBP5]] genetic variants and clinical outcomes. Neither mean Hamilton Depression Rating Scale scores nor time to remission or response were predicted by [[FKBP5]] genetic variation. These results suggest that [[FKBP5]] is unlikely to play a major role in determining antidepressant treatment outcomes in geriatric patients.
|mesh-terms=* Aged
* Antidepressive Agents
* Depression
* Double-Blind Method
* Female
* Genetic Variation
* Geriatrics
* Humans
* Male
* Mianserin
* Mirtazapine
* Paroxetine
* Polymorphism, Genetic
* Sequence Analysis, DNA
* Tacrolimus Binding Proteins
* Treatment Outcome

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2897151
}}