RETRACTED: Hsp90‐binding immunophilin FKBP51 forms complexes with hTERT enhancing telomerase activity

Lagadari, Mariana; Zgajnar, Nadia R.; Gallo, Luciana I.; Galigniana, Mario D.

doi:10.1016/j.molonc.2016.05.002

Cited by 37 publications

(47 citation statements)

References 81 publications

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“…FKBP51 promotes melanoma growth by modulating TGF‐β expression and activating NF‐κB, which induces interleukin‐8 (IL‐8) . Moreover, FKBP51 acts as an anti‐apoptotic factor in cancer development and progression by enhancing the telomerase activity of hTERT . FKBP51 controls androgen‐dependent growth of prostate cancer by enhancing activity of androgen receptor transcription .…”

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confidence: 99%

“…T he FK506 binding protein FKBP51 (also referred as FKBP5) is highly expressed in prostate cancer, lymphoma, and melanoma; furthermore, FKBP51 expression correlates with metastatic potential in melanoma and prostate cancer, and its silencing restores resistance to apoptosis in these two cancers. (1)(2)(3)(4)(5)(6)(7) FKBP51 promotes melanoma growth by modulating TGF-b expression and activating NF-jB, which induces interleukin-8 (IL-8). (3)(4)(5) Moreover, FKBP51 acts as an anti-apoptotic factor in cancer development and progression by enhancing the telomerase activity of hTERT.…”

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FKBP51 regulates cell motility and invasion via RhoA signaling

et al. 2017

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FK506 binding protein 51 (FKBP51), a member of the immunophilin family, is involved in multiple signaling pathways, tumorigenesis, and chemoresistance. FKBP51 expression correlates with metastatic potential in melanoma and prostate cancer. However, the functions of FKBP51, particularly involving the regulation of cell motility and invasion, are not fully understood. We discovered two novel interacting partner proteins of FKBP51, i.e., deleted in liver cancer 1 (DLC1) and deleted in liver cancer 2 (DLC2), using immunoprecipitation and mass spectrometry. DLC1 and DLC2 are Rho GTPase‐activating proteins that are frequently downregulated in various cancers. Next, we demonstrated that overexpression of FKBP51 enhances cell motility and invasion of U2OS cells via upregulation of RhoA activity and enhanced Rho‐ROCK signaling. Moreover, FKBP51‐depleted cells displayed a cortical distribution of actin filaments and decreased cell motility and invasion. Consistent with this phenotype, FKBP51 depletion caused a downregulation of RhoA activity. Considered together, our results demonstrate that FKBP51 positively controls cell motility by promoting RhoA and ROCK activation; thus, we have revealed a novel role for FKBP51 in cytoskeletal rearrangement and cell migration and invasion.

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FKBP51 regulates cell motility and invasion via RhoA signaling

et al. 2017

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“…These can only strengthen the argument that FKBP52 could have an important role in DNA damage signalling and repair, possibly through the cochaperone mechanism that also appears in many different processes or possibly it could be through the activity of its PPIase domain, which stabilises and activates many proteins in the cell. hTERT (Lagadari, Zgajnar, Gallo, & Galigniana, 2016). The study found that both FKBP51 and FKBP52 co-immunoprecipitate with hTERT.…”

Section: Fkbp52 and Tauopathiesmentioning

confidence: 86%

“…The proposed mechanism infers that FKBP52 is required for the retro transport of hTERT through dynein/dynactin. Once inside the nucleus FKBP51 replaces FKBP52 and enhances hTERT activity (Lagadari et al, 2016). The hTERT transport mechanism was further elucidated by Jong et al, (2016) showing that FKBP52 is required for the interaction with the dynein-dynactin motor protein complex, and subsequent transport of hTERT into the nucleus.…”

Section: Fkbp52 and Tauopathiesmentioning

confidence: 99%

“…An example of this is with hTERT, where FKBP52 is required for the transport of hTERT to the nucleus and if the hTERT is not transported to the nucleus it is degraded in the cytoplasm (Jeong et al, 2016;Lagadari et al, 2016). hSSB1 transcript levels were also examined and appear to show a 6-fold increase in the C4-3 population of cells.…”

Section: Fkbp52 Depletion Causes An Increase In P53 and Hssb1 Mrnamentioning

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FKBP52 and Its Role of in the DNA Damage Repair

Wallace¹

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Damage to genetic material represents a constant threat to genomic stability, with tens of thousands of DNA lesions being produced per day per cell. If DNA damage is not repaired correctly, it can be detrimental to the cell, leading to alterations in the genetic material and disease states such as cancer and neurodegenerative disorders. To protect the integrity of the DNA, cells have evolved a global signalling network known as the DNA damage response. This network detects different types of genotoxic stress to raise a versatile and coordinated response, which includes control of the cell cycle transitions, transcriptional processes and stimulation of DNA repair and apoptosis.Recently, the Richard Lab discovered the human single strand DNA binding protein 1 (hSSB1) to be a crucial component of the DNA damage signalling pathway.To increase our understanding of the function of hSSB1 in the DNA damage pathway, a connectivity screen was performed on hSSB1. The connectivity screen is a bioinformatic tool used to identify mRNA transcripts that are regulated in a similar manner as the bait (hSSB1). In this study, I sought to identify proteins that may also be involved in the DNA damage response (DDR) pathway, utilising hSSB1 as the bait.One of the transcripts identified from this screen was FKBP52. Based on the previously published literature, this protein has been linked to numerous cancers and in the regulation of other proteins involved in genome maintenance, such as p53, hTERT and NF-κB, making it a highly interesting candidate for further study. This study aims to determine if FKBP52 plays a role in the DDR and if it interacts or regulates hSSB1. To determine if FKBP52 and hSSB1 interact co-immunoprecipitation studies were performed as well as in vitro direct interaction assays. These showed that FKBP52 and hSSB1 might co-localise in a complex in vivo but that is was unlikely to be a direct interaction, leading to the theory that FKBP52 was potentially acting as a cochaperone. Supporting this proposition, was the in vivo observation that when FKBP52 levels were depleted by siRNA the corresponding levels of hSSB1 in the nucleus were reduced and showed little response to IR.FKBP52 expression was observed to responded to IR induced DNA damage.FKBP52 levels were also found to increase in the nucleus in response to IR and was observed to become chromatin associated. found to be bound to the nucleus, this suggesting it was involved in the DNA damage response. FKBP52 depletion also led to altered DNA damage signalling in particular with the phosphorylation of key regulatory proteins of the DNA damage pathway. It was also found that reduced levels via siRNA led to reduced survival after IR via clonogenic assays and reduced the efficiency of HR via the HR assay. FKBP52 levels in the nucleus were shown to be regulated by ATM and ATR consistent with this FKBP52 was found to be phosphorylated following IR on a putative ATM/ATR phosphorylation site. It was FKBP52 and its role in DNA Damage Repair iv found that phosphor...

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Mitochondrial–nuclear communication by FKBP51 shuttling

Zgajnar

Lagadari

Gallo

et al. 2023

J of Cellular Biochemistry

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The HSP90‐binding immunophilin FKBP51 is a soluble protein that shows high homology and structural similarity with FKBP52. Both immunophilins are functionally divergent and often show antagonistic actions. They were first described in steroid receptor complexes, their exchange in the complex being the earliest known event in steroid receptor activation upon ligand binding. In addition to steroid‐related events, several pleiotropic actions of FKBP51 have emerged during the last years, ranging from cell differentiation and apoptosis to metabolic and psychiatric disorders. On the other hand, mitochondria play vital cellular roles in maintaining energy homeostasis, responding to stress conditions, and affecting cell cycle regulation, calcium signaling, redox homeostasis, and so forth. This is achieved by proteins that are encoded in both the nuclear genome and mitochondrial genes. This implies active nuclear‐mitochondrial communication to maintain cell homeostasis. Such communication involves factors that regulate nuclear and mitochondrial gene expression affecting the synthesis and recruitment of mitochondrial and nonmitochondrial proteins, and/or changes in the functional state of the mitochondria itself, which enable mitochondria to recover from stress. FKBP51 has emerged as a serious candidate to participate in these regulatory roles since it has been unexpectedly found in mitochondria showing antiapoptotic effects. Such localization involves the tetratricopeptide repeats domains of the immunophilin and not its intrinsic enzymatic activity of peptidylprolyl‐isomerase. Importantly, FKBP51 abandons the mitochondria and accumulates in the nucleus upon cell differentiation or during the onset of stress. Nuclear FKBP51 enhances the enzymatic activity of telomerase. The mitochondrial‐nuclear trafficking is reversible, and certain situations such as viral infections promote the opposite trafficking, that is, FKBP51 abandons the nucleus and accumulates in mitochondria. In this article, we review the latest findings related to the mitochondrial‐nuclear communication mediated by FKBP51 and speculate about the possible implications of this phenomenon.

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RETRACTED: Hsp90‐binding immunophilin FKBP51 forms complexes with hTERT enhancing telomerase activity

Cited by 37 publications

References 81 publications

FKBP51 regulates cell motility and invasion via RhoA signaling

FKBP51 regulates cell motility and invasion via RhoA signaling

FKBP52 and Its Role of in the DNA Damage Repair

Mitochondrial–nuclear communication by FKBP51 shuttling

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