Association of a 59-kilodalton immunophilin with the glucocorticoid receptor complex

Tai, Ping-Kaung Ku; Albers, Mark W.; Chang, Hong; Faber, Lee E.; Schreiber, Stuart L.

doi:10.1126/science.1376003

Cited by 303 publications

(145 citation statements)

References 34 publications

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“…There are some larger, multidomain FKBPs and also cyclophilins found as constituents in high molecular mass steroid receptor complexes [31,32]. The FKBP52 (also known as HSP56, p59, FKBP59 or HBI) (reviewed in [33]) contains three domains which are homologous to the FKBP12 [34].…”

Section: Discussionmentioning

confidence: 99%

An 11.8 kDa proteolytic fragment of the E. coli trigger factor represents the domain carrying the peptidyl‐prolyl cis/trans isomerase activity

Stoller¹,

Tradler²,

Rücknagel³

et al. 1996

FEBS Letters

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The 48 kDa trigger factor (TF) of E. coli was shown to be a peptidyl-prolyl cisltrans isomerase (PPIase). Its location on a ribosomal particle is unique among the PPIases described so far, and suggests a role in de novo protein folding. The trigger factor was investigated with regard to a domain carrying the catalytic activity. An enzymatieally active fragment could be isolated after proteolysis by subtifisin. The resulting polypeptide was analysed by N-terminal sequencing and MALDI-TOF mass spectrometry revealing an 11.8 kDa fragment of TF encompassing the amino acid residues Arg-145 to Glu-251. The nucleotide sequence encoding the amino acid residues Met-140 to Ala-250 of the TF was cloned into vector pQE32. After expression in E. coli the resulting His-tagged polypeptide was isolated on an Ni 2+-NTA column. Subsequent digestion with subtifisin and anionexchange chromatography yielded a TF fragment encompassing amino acids Gin-148 to Thr-249. This fragment may represent the catalytic core of TF since PPIase activity with a specificity constant kcat/Km of 1.3 ~1-1 s -l could be demonstrated when using Suc-Ala-Phe-Pro-Phe-NH-Np as a substrate. Moreover, as was observed for the complete, authentic TF the PPIase activity of the fragment was not inhibited by the peptidomacrofide FK506.

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Section: Discussionmentioning

confidence: 99%

An 11.8 kDa proteolytic fragment of the E. coli trigger factor represents the domain carrying the peptidyl‐prolyl cis/trans isomerase activity

Stoller¹,

Tradler²,

Rücknagel³

et al. 1996

FEBS Letters

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“…Therefore, substances that dissociate these proteins may facilitate nuclear translocation of GR and augment GC action. Recently, a GRassociated heat shock protein, hsp 56, has been shown to be identical to an immunophilin, FK506-binding protein (Tai et al, 1992;Yem et al, 1992). The association between immunophilin and GR suggests that FK506 may influence steroid receptor function.…”

Section: Discussionmentioning

confidence: 99%

“…In the cytoplasm, GR associates with several heat shock proteins (Pratt, 1993;Smith and Toft, 1993). Recent studies showed that the GR complex also contains members of the immunophilin class of proteins (Tai et al, 1992). Furthermore, Yem et al (Yem et al, 1992) reported that FK506-binding protein (FK-BP) is associated with the GR complex.…”

mentioning

confidence: 99%

FK506 Augments Glucocorticoid-Mediated Cyclooxygenase–2 Down-Regulation in Human Rheumatoid Synovial Fibroblasts

Migita

Tanaka

Okamoto

et al. 2000

Laboratory Investigation

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SUMMARY: Prostaglandins (PG) formed by cyclooxygenase (COX) enzymes are important mediators of inflammation in rheumatoid arthritis. The contribution of the inducible COX-2 to inflammation in the rheumatoid synovium is well documented. We examined the regulation of COX-2 mRNA and protein expression in response to both glucocorticoids (GC) and FK506 using rheumatoid synovial fibroblasts. Combined treatment of FK506 and a low concentration of dexamethasone (DEX) (10 Ϫ9 M) down-regulated synovial COX-2 mRNA and protein expression. In contrast, neither FK506 nor DEX (10 Ϫ9 M) alone influenced COX-2 expression. Immunocytochemical studies showed that pretreatment with FK506 enhanced the nuclear translocation of the glucocorticoid receptor (GR) in synovial fibroblasts in the presence of low concentrations of DEX (10 Ϫ9 M). Transient transfection experiments showed that treatment of cells with FK506 enhanced the expression of glucocorticoid-responsive gene reporter in the presence of DEX (10 Ϫ9 M). NF-B is known to mediate the transcriptional activation of the COX-2 gene. Electrophoretic mobility shift assay demonstrated that DNA-binding activity of NF-B was suppressed more profoundly by FK506 plus DEX (10 Ϫ9 M) treatment with those of DEX (10 Ϫ9 M) alone in IL-1␤-stimulated synovial cells. Our results indicated that FK506-induced potentiation of GR-mediated repression of synovial COX-2 gene transcription is the result of increased translocation of GR to the nucleus and subsequent repression of NF-B transactivation. Our results also suggest that FK506 may exert anti-inflammatory effects in the rheumatoid synovium by potentiating GR-mediated signal transduction. (Lab Invest 2000, 80:135-141).R heumatoid arthritis (RA) is an inflammatory joint disease in which perpetuation of synovitis leads to articular destruction (Zvaifler and Firestein, 1994). Rheumatoid synovial fibroblasts release various inflammatory mediators (Dayer et al, 1986). Prostaglandin (PG), one of the important mediators in rheumatoid synovitis, is synthesized by cyclooxygenases (COX) (Salmon et al, 1983;Wittenberg et al, 1993). It has been demonstrated that COX-2, an inducible COX isoform, is expressed in rheumatoid synovial fibroblasts and that treatment with IL-1␤ induces the synthesis of COX-2 mRNA and protein, while glucocorticoids (GC) suppress this induction (Crofford et al, 1994).GC has been used for decades as a clinical tool to suppress inflammatory and immune responses. GC action is known to be mediated by cellular glucocorticoid receptors (GR) (Bamberger et al, 1996). The binding of GC is followed by a conformational change in GR; the hormone-receptor complex translocates to the nucleus and binds to its acceptor site in DNA (Truss and Beato, 1993). In the cytoplasm, GR associates with several heat shock proteins (Pratt, 1993;Smith and Toft, 1993). Recent studies showed that the GR complex also contains members of the immunophilin class of proteins (Tai et al, 1992). Furthermore, Yem et al (Yem et al, 1992) reported that FK506-binding protein ...

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“…Readings in the shaded area constitute background+noise levels. Note that the Jurkat cell clones do not express the human GR measured by the chip, but instead high levels of stably-transfected rat GR not detected by the chip Oncogene Effects of dex treatment in lymphocytic leukemia P Obexer et al Interestingly, while the GR itself is induced by dex, three genes of the`repressed' list ( Table 2) encode proteins that have been found associated with the GR: hsp70 (Tai et al, 1992), the`immunophilin-like' protein phosphatase 5 (Silverstein et al, 1999) and a predominantly nuclear protein known under the names of glucocorticoid receptor-interacting protein (Zeiner and Gehring, 1995), receptor-associating protein of 46 kDa (RAP46; Zeiner et al, 1997) and hsp70-associated protein 46 (Hap46; Zeiner et al, 1999). RAP46 has been shown to inhibit GC-induced apoptosis (Kullmann et al, 1998).…”

Section: Effects On the Gr And Associated Proteinsmentioning

confidence: 99%

“…GC act by binding to the glucocorticoid receptor (GR), a protein that, in the absence of ligand, remains cytoplasmic by binding to a large, dynamic multiprotein complex containing heat shock protein molecules ± hsp90 or hsp90 plus hsp70 ± and an immunophilin component (Tai et al, 1992). The immunophilin moiety binds to hsp90 via its tetratricopeptide repeat domain and may be represented by any one of several proteins, such as FKBP51, FKBP52, CyP-40 or even protein phosphatase 5 (PP5) (Owens-Grillo et al, 1995;Silverstein et al, 1997Silverstein et al, , 1999.…”

Section: Introductionmentioning

confidence: 99%

Expression profiling of glucocorticoid-treated T-ALL cell lines: rapid repression of multiple genes involved in RNA-, protein- and nucleotide synthesis

et al. 2001

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To arrive at a better understanding of the e ects of the glucocorticoid component of chemotherap#y protocols on lymphocytic leukemia cells, we analysed early responses of T-lymphocytic leukemia cell lines Jurkat and CEM-C7, both of which undergo apoptosis in response to dexamethasone, via gene chips. Among genes identi®ed as repressed, a notable cluster seemed to be of importance for the processes of transcription, mRNA splicing and protein synthesis. Consequently, we assessed time-resolved uptake of uridine and methionine to monitor RNA and protein synthesis, along with parameters quantifying apoptosis. Repression of uptake to about 65% of that in untreated cells preceded the ®rst sign of apoptosis by several hours in both cell lines. In addition to this general repression of RNA and protein synthesis, several genes were found to be regulated that may contribute to synergistic action of glucocorticoids with other components of frequently used chemotherapy protocols such as antimetabolites, methotrexate and alkylating agents. Oncogene (2001) 20, 4324 ± 4336.

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Association of a 59-kilodalton immunophilin with the glucocorticoid receptor complex

Cited by 303 publications

References 34 publications

An 11.8 kDa proteolytic fragment of the E. coli trigger factor represents the domain carrying the peptidyl‐prolyl cis/trans isomerase activity

An 11.8 kDa proteolytic fragment of the E. coli trigger factor represents the domain carrying the peptidyl‐prolyl cis/trans isomerase activity

FK506 Augments Glucocorticoid-Mediated Cyclooxygenase–2 Down-Regulation in Human Rheumatoid Synovial Fibroblasts

Expression profiling of glucocorticoid-treated T-ALL cell lines: rapid repression of multiple genes involved in RNA-, protein- and nucleotide synthesis

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