NF-κB Transcriptional Activity Is Modulated by FK506-binding Proteins FKBP51 and FKBP52

Erlejman, Alejandra G.; Leo, Sonia A. De; Mazaira, Gisela Ileana; Molinari, Alejandro M.; Camisay, María Fernanda; Fontana, Vanina Andrea; Cox, Marc B.; Piwien-Pilipuk, Graciela; Galigniana, Mario D.

doi:10.1074/jbc.m114.582882

Cited by 85 publications

(113 citation statements)

References 83 publications

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“…Thus, it has been shown that Hsp90 and p23 are both recruited to glucocorticoid-responsive elements upon steroid activation of the GR [132]. The need of FKBP51 is in agreement with the effect of this IMM on the nuclear retention of nuclear factors by competition with the anchoring effect of FKBP52 [36,110]. A similar effect is observed in FKBP52 KO cells and due to the overexpression of the TPR peptide, which abolishes the nuclear pool of steroid receptors in the nucleus due to a 'dominant-negative' effect on receptor anchorage to nuclear structures [36].…”

Section: Nuclear Eventssupporting

confidence: 62%

“…Very recent findings from our laboratory also demonstrated that the NF-B transport towards the nucleus is also regulated by the expression balance of the TPR-domain IMMs FKBP52 and FKBP51 [110]. Interestingly, NF-B is not chaperoned by Hsp90, which assigns a cardinal role to these TPR proteins per se.…”

Section: Nuclear Eventsmentioning

confidence: 78%

“…Also, FKBP52 shows high level of expression in hepatocellular carcinomas [141] and prostate cancer cells and has been proposed as a biomarker for the latter pathology [142]. Recently, we demonstrated that FKBP52 greatly enhances NF-B biological response [110], a transcription factor that is linked to chronic inflammation processes and progression of multiple diseases, including cancer, where NF-kB is related to tumor promotion and progression, as well as chemotherapy and radiotherapy resistance [143,144].…”

Section: Tpr-domain Immunophilins In Cancermentioning

confidence: 99%

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The Emerging Role of TPR-Domain Immunophilins in the Mechanism of Action of Steroid Receptors

Mazaira

Lagadari

Erlejman

et al. 2014

Nuclear Receptor Research

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Abstract. In the absence of ligand, some members of nuclear receptor family such as corticosteroid receptors are primarily located in the cytoplasm, and they rapidly accumulate in the nucleus upon ligand-binding. Other members of the family such as the estrogen receptor are mostly nuclear. Regardless of their primary location, these oligomeric proteins undergo a dynamic nuclearcytoplasmic shuttling, and their transport through the cytoplasmic compartment has always been assumed to occur in a stochastic manner by simple diffusion. Although heuristic, this oversimplified model has never been demonstrated. Moreover, it has always been assumed that the first step related to receptor activation is the dissociation of the Hsp90-based heterocomplex, a process referred to as 'transformation.' Nonetheless, recent experimental evidence indicates that the chaperone machinery is required for the retrotransport of the receptor throughout the cytoplasm and facilitates its active passage through the nuclear pore. Therefore, transformation is actually a nuclear event. A group of Hsp90-binding cochaperones belonging to the immunophilin family plays a cardinal role not only in the mechanism for receptor movement, but also in nuclear events leading to interactions with nuclear sites of action and the regulation of transcriptional activity. In this article we analyze the importance of molecular chaperones and TPR-domain immunophilins in the molecular mechanism of action of steroid receptors.

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Section: Nuclear Eventssupporting

confidence: 62%

Section: Nuclear Eventsmentioning

confidence: 78%

Section: Tpr-domain Immunophilins In Cancermentioning

confidence: 99%

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The Emerging Role of TPR-Domain Immunophilins in the Mechanism of Action of Steroid Receptors

Mazaira

Lagadari

Erlejman

et al. 2014

Nuclear Receptor Research

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“…24 As shown in Supplementary Figure 4, both wt and K422R FKBP51 inhibit NF-κB activity and interact with NF-κB, showing that mutation of K422 does not alter the general function of the protein.…”

Section: Resultsmentioning

confidence: 86%

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

et al. 2016

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FK506-binding protein 51 (FKBP51) regulates the activity of the glucocorticoid receptor (GR), and is therefore a key mediator of the biological actions of glucocorticoids. However, the understanding of the molecular mechanisms that govern its activity remains limited. Here, we uncover a novel regulatory switch for GR activity by the post-translational modification of FKBP51 with small ubiquitin-like modifier (SUMO). The major SUMO-attachment site, lysine 422, is required for FKBP51-mediated inhibition of GR activity in hippocampal neuronal cells. Importantly, impairment of SUMO conjugation to FKBP51 impacts on GR-dependent neuronal signaling and differentiation. We demonstrate that SUMO conjugation to FKBP51 is enhanced by the E3 ligase PIAS4 and by environmental stresses such as heat shock, which impact on GR-dependent transcription. SUMO conjugation to FKBP51 regulates GR hormone-binding affinity and nuclear translocation by promoting FKBP51 interaction within the GR complex. SUMOylation-deficient FKBP51 fails to interact with Hsp90 and GR thus facilitating the recruitment of the closely related protein, FKBP52, which enhances GR transcriptional activity. Moreover, we show that the modification of FKBP51 with SUMO modulates its binding to Hsp90. Our data establish SUMO conjugation as a novel regulatory mechanism in the Hsp90 cochaperone activity of FKBP51 with a functional impact on GR signaling in a neuronal context.

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“…ChIP experiments were performed in CNE-1/2 cells using the ChIP assay kit (Millipore, Billerica, MA, USA) (Erlejman et al 2014). Briefly, proteins and DNA were cross-linked after CNE-1/2 cells were treated with 1 % formaldehyde for 10 min at 37°C and neutralized with glycine added at a final concentration of 0.125 M. Cells were rinsed twice with cold PBS containing 2.5 ml Protease Inhibitor cocktail II (Abcam, Cambridge, MA, USA), scraped, and centrifuged at 72009g for 5 min at 4°C.…”

Section: Chromatin Immunoprecipitation (Chip) Assaysmentioning

confidence: 99%

Viral IL-10 down-regulates the “MHC-I antigen processing operon” through the NF-κB signaling pathway in nasopharyngeal carcinoma cells

et al. 2016

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NF-κB Transcriptional Activity Is Modulated by FK506-binding Proteins FKBP51 and FKBP52

Cited by 85 publications

References 83 publications

The Emerging Role of TPR-Domain Immunophilins in the Mechanism of Action of Steroid Receptors

The Emerging Role of TPR-Domain Immunophilins in the Mechanism of Action of Steroid Receptors

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

Viral IL-10 down-regulates the “MHC-I antigen processing operon” through the NF-κB signaling pathway in nasopharyngeal carcinoma cells

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