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FKBP5  -  FK506 binding protein 5

Homo sapiens

Synonyms: 51 kDa FK506-binding protein, 51 kDa FKBP, 54 kDa progesterone receptor-associated immunophilin, AIG6, Androgen-regulated protein 6, ...
 
 
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Disease relevance of FKBP5

  • Androgen mediated regulation and functional implications of fkbp51 expression in prostate cancer [1].
  • Overexpression of FKBP51 in idiopathic myelofibrosis regulates the growth factor independence of megakaryocyte progenitors [2].
  • Coexpression of folding accessory proteins, molecular chaperones, and human peptidyl-prolyl cis-trans isomerase (PPIase) increased production of active cyclodextrin glycosyltransferase (CGTase) of Bacillus macerans, which is otherwise mainly expressed as inclusion body in recombinant Escherichia coli [3].
  • If this hypothesis is confirmed, therapeutic attempts using rotamase activity-inhibiting immunophilin ligand administration in neurodegenerative disease patients need to be carefully designed [4].
  • Ng-MIP, a surface-exposed lipoprotein of Neisseria gonorrhoeae, has a peptidyl-prolyl cis/trans isomerase (PPIase) activity and is involved in persistence in macrophages [5].
 

Psychiatry related information on FKBP5

  • Shortfalls in the peptidyl-prolyl cis-trans isomerase protein Pin1 in neurons are associated with frontotemporal dementias [6].
 

High impact information on FKBP5

 

Biological context of FKBP5

  • These interactions, in turn, result in chromatin remodeling that affects the enhancer proper but not the FKBP5 locus as a whole [11].
  • Furthermore, in contrast to prostate-specific antigen-regulatory mechanisms, we show that transactivation of the FKBP5 gene does not rely on a single looping complex to mediate communication between the distal enhancer and proximal promoter [11].
  • GZMA and FKBP5 have a cluster of putative glucocorticoid response elements (GREs) in introns 1 and 2, respectively, that was identified to be responsible for the response to GC [12].
  • Intronic hormone response elements mediate regulation of FKBP5 by progestins and glucocorticoids [13].
  • One region of intron E of FKBP5 (pIE2) conferred both glucocorticoid and progestin responsiveness to 2 heterologous reporter genes, whereas the other, less-conserved region of intron E (pIE1) was responsive only to progestins [13].
 

Anatomical context of FKBP5

  • Unlike FKBP12, FKBP51 transiently expressed in COS-7 cells was precipitated by calcineurin bound to calmodulin-Sepharose beads in the absence of either FK506 or rapamycin [14].
  • FKBP51 had androgen induced RNA and protein expression in LNCaP cells and decreased expression in normal prostate epithelial cells following castration [1].
  • In conclusion, FKBP51 is overexpressed in IMF megakaryocytes and this overexpression could be, in part, responsible for the megakaryocytic accumulation observed in this disorder by regulating their apoptotic program [2].
  • Overexpression of FKBP51 in a UT-7/Mpl cell line and in normal CD34(+) cells induced a resistance to apoptosis mediated by cytokine deprivation with no effect on proliferation [2].
  • Approximately one-half of the GR.hsp90 heterocomplexes in L cell cytosol contains an immunophilin with high affinity FK506 binding activity, such as FKBP51 or FKBP52, and approximately 35% contains PP5 [15].
 

Associations of FKBP5 with chemical compounds

  • FKBP5 encodes an immunophilin that has been previously implicated in glucocorticoid and progestin signaling pathways and that likely influences prostate physiology in the presence of androgens [11].
  • Several androgen up-regulated genes, including immunophilin FKBP51 and prostate specific antigen (PSA), were reduced by GA treatment [16].
  • Induction of FKBP51 mRNA was unaffected by 1 micro g/ml cycloheximide but was blocked by the progestin receptor (PR) antagonist RU486 (1 micro M) [17].
  • Furthermore, overexpression of FKBP51 in the squirrel monkey may be a contributing cause of progesterone resistance in this species [17].
  • Pharmacologic inhibition of calcineurin by cyclosporin A mimicked the effect of FKBP51 [2].
 

Physical interactions of FKBP5

  • Regulation of GR binding by FKBP51 represents a previously unrecognized mechanism for regulating glucocorticoid sensitivity [18].
 

Enzymatic interactions of FKBP5

 

Regulatory relationships of FKBP5

  • Mutations in the TPR of squirrel monkey FKBP51 that inhibit association with heat shock protein 90 blocked GR inhibitory activity [19].
 

Other interactions of FKBP5

  • We discovered that nuclear translocation of the glucocorticoid receptor was delayed by FKBP51 [20].
  • We concluded from our results that the mechanisms of the regulatory system FKBP51/FKBP52 discovered in yeast also operate in mammals to modulate hormone binding of the receptor [20].
  • FKBP54, a novel FK506-binding protein in avian progesterone receptor complexes and HeLa extracts [21].
  • Interestingly, Cyp40 and FKBP51 are the more potent chaperones [22].
  • Pharmacogenetic studies show a relationship between antidepressant response and HTR2A or FKBP5 [23].
 

Analytical, diagnostic and therapeutic context of FKBP5

References

  1. Androgen mediated regulation and functional implications of fkbp51 expression in prostate cancer. Febbo, P.G., Lowenberg, M., Thorner, A.R., Brown, M., Loda, M., Golub, T.R. J. Urol. (2005) [Pubmed]
  2. Overexpression of FKBP51 in idiopathic myelofibrosis regulates the growth factor independence of megakaryocyte progenitors. Giraudier, S., Chagraoui, H., Komura, E., Barnache, S., Blanchet, B., LeCouedic, J.P., Smith, D.F., Larbret, F., Taksin, A.L., Moreau-Gachelin, F., Casadevall, N., Tulliez, M., Hulin, A., Debili, N., Vainchenker, W. Blood (2002) [Pubmed]
  3. Coexpression of folding accessory proteins for production of active cyclodextrin glycosyltransferase of Bacillus macerans in recombinant Escherichia coli. Kim, S.G., Kweon, D.H., Lee, D.H., Park, Y.C., Seo, J.H. Protein Expr. Purif. (2005) [Pubmed]
  4. Immunophilins and their ligands: insights into survival and growth of human neurons. Avramut, M., Achim, C.L. Physiol. Behav. (2002) [Pubmed]
  5. Ng-MIP, a surface-exposed lipoprotein of Neisseria gonorrhoeae, has a peptidyl-prolyl cis/trans isomerase (PPIase) activity and is involved in persistence in macrophages. Leuzzi, R., Serino, L., Scarselli, M., Savino, S., Fontana, M.R., Monaci, E., Taddei, A., Fischer, G., Rappuoli, R., Pizza, M. Mol. Microbiol. (2005) [Pubmed]
  6. Shortfalls in the peptidyl-prolyl cis-trans isomerase protein Pin1 in neurons are associated with frontotemporal dementias. Thorpe, J.R., Mosaheb, S., Hashemzadeh-Bonehi, L., Cairns, N.J., Kay, J.E., Morley, S.J., Rulten, S.L. Neurobiol. Dis. (2004) [Pubmed]
  7. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Binder, E.B., Salyakina, D., Lichtner, P., Wochnik, G.M., Ising, M., Pütz, B., Papiol, S., Seaman, S., Lucae, S., Kohli, M.A., Nickel, T., Künzel, H.E., Fuchs, B., Majer, M., Pfennig, A., Kern, N., Brunner, J., Modell, S., Baghai, T., Deiml, T., Zill, P., Bondy, B., Rupprecht, R., Messer, T., Köhnlein, O., Dabitz, H., Brückl, T., Müller, N., Pfister, H., Lieb, R., Mueller, J.C., Lõhmussaar, E., Strom, T.M., Bettecken, T., Meitinger, T., Uhr, M., Rein, T., Holsboer, F., Muller-Myhsok, B. Nat. Genet. (2004) [Pubmed]
  8. The Hsp90-binding peptidylprolyl isomerase FKBP52 potentiates glucocorticoid signaling in vivo. Riggs, D.L., Roberts, P.J., Chirillo, S.C., Cheung-Flynn, J., Prapapanich, V., Ratajczak, T., Gaber, R., Picard, D., Smith, D.F. EMBO J. (2003) [Pubmed]
  9. A novel multi-functional chloroplast protein: identification of a 40 kDa immunophilin-like protein located in the thylakoid lumen. Fulgosi, H., Vener, A.V., Altschmied, L., Herrmann, R.G., Andersson, B. EMBO J. (1998) [Pubmed]
  10. Structure of the large FK506-binding protein FKBP51, an Hsp90-binding protein and a component of steroid receptor complexes. Sinars, C.R., Cheung-Flynn, J., Rimerman, R.A., Scammell, J.G., Smith, D.F., Clardy, J. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  11. Direct, androgen receptor-mediated regulation of the FKBP5 gene via a distal enhancer element. Magee, J.A., Chang, L.W., Stormo, G.D., Milbrandt, J. Endocrinology (2006) [Pubmed]
  12. Identification of novel direct transcriptional targets of glucocorticoid receptor. U, M., Shen, L., Oshida, T., Miyauchi, J., Yamada, M., Miyashita, T. Leukemia (2004) [Pubmed]
  13. Intronic hormone response elements mediate regulation of FKBP5 by progestins and glucocorticoids. Hubler, T.R., Scammell, J.G. Cell Stress Chaperones (2004) [Pubmed]
  14. Calcium- and FK506-independent interaction between the immunophilin FKBP51 and calcineurin. Li, T.K., Baksh, S., Cristillo, A.D., Bierer, B.E. J. Cell. Biochem. (2002) [Pubmed]
  15. Protein phosphatase 5 is a major component of glucocorticoid receptor.hsp90 complexes with properties of an FK506-binding immunophilin. Silverstein, A.M., Galigniana, M.D., Chen, M.S., Owens-Grillo, J.K., Chinkers, M., Pratt, W.B. J. Biol. Chem. (1997) [Pubmed]
  16. Effect of geldanamycin on androgen receptor function and stability. Vanaja, D.K., Mitchell, S.H., Toft, D.O., Young, C.Y. Cell Stress Chaperones (2002) [Pubmed]
  17. The FK506-binding immunophilin FKBP51 is transcriptionally regulated by progestin and attenuates progestin responsiveness. Hubler, T.R., Denny, W.B., Valentine, D.L., Cheung-Flynn, J., Smith, D.F., Scammell, J.G. Endocrinology (2003) [Pubmed]
  18. Glucocorticoid resistance in the squirrel monkey is associated with overexpression of the immunophilin FKBP51. Reynolds, P.D., Ruan, Y., Smith, D.F., Scammell, J.G. J. Clin. Endocrinol. Metab. (1999) [Pubmed]
  19. Structure-function analysis of squirrel monkey FK506-binding protein 51, a potent inhibitor of glucocorticoid receptor activity. Denny, W.B., Prapapanich, V., Smith, D.F., Scammell, J.G. Endocrinology (2005) [Pubmed]
  20. FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells. Wochnik, G.M., Rüegg, J., Abel, G.A., Schmidt, U., Holsboer, F., Rein, T. J. Biol. Chem. (2005) [Pubmed]
  21. FKBP54, a novel FK506-binding protein in avian progesterone receptor complexes and HeLa extracts. Smith, D.F., Albers, M.W., Schreiber, S.L., Leach, K.L., Deibel, M.R. J. Biol. Chem. (1993) [Pubmed]
  22. Functional analysis of the Hsp90-associated human peptidyl prolyl cis/trans isomerases FKBP51, FKBP52 and Cyp40. Pirkl, F., Buchner, J. J. Mol. Biol. (2001) [Pubmed]
  23. Molecular genetics of bipolar disorder and depression. Kato, T. Psychiatry Clin. Neurosci. (2007) [Pubmed]
  24. Is FKBP5 a genetic marker of affective psychosis? A case control study and analysis of disease related traits. Gawlik, M., Moller-Ehrlich, K., Mende, M., Jovnerovski, M., Jung, S., Jabs, B., Knapp, M., Stoeber, G. BMC psychiatry (2006) [Pubmed]
  25. Constitutive expression of the FK506 binding protein 51 (FKBP51) in bone marrow cells and megakaryocytes derived from idiopathic myelofibrosis and non-neoplastic haematopoiesis. Bock, O., Neusch, M., Büsche, G., Mengel, M., Kreipe, H. Eur. J. Haematol. (2004) [Pubmed]
  26. Identification and validation of novel androgen-regulated genes in prostate cancer. Velasco, A.M., Gillis, K.A., Li, Y., Brown, E.L., Sadler, T.M., Achilleos, M., Greenberger, L.M., Frost, P., Bai, W., Zhang, Y. Endocrinology (2004) [Pubmed]
 
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