Characterization of high molecular weight FK-506 binding activities reveals a novel FK-506-binding protein as well as a protein complex.

Wiederrecht, Gregory; Hung, Shirley H.Y.; Chan, Hedy; Marcy, Alice I.; Martin, Mary M.; Calaycay, Jimmy; Boulton, D. A.; Sigal, Nolan H.; Kincaid, Randall L.; Siekierka, John

doi:10.1016/s0021-9258(19)36676-1

Cited by 108 publications

(18 citation statements)

References 43 publications

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“…Another common mechanism of cell desensitization to glucocorticoids is mediated by a negative feedback loop via GR molecular chaperone FKBP51 (also called FK506-binding protein 5 36 ). FKBP51 sequesters GR in cytoplasm and prevents its nuclear translocation.…”

Section: Combination Of a Selective Activator Of The Glucocorticoid Receptor Compound A With A Proteasome Inhibitor As A Novel Strategy Fmentioning

confidence: 99%

Combination of a selective activator of the glucocorticoid receptor Compound A with a proteasome inhibitor as a novel strategy for chemotherapy of hematologic malignancies

Lesovaya¹,

Yemelyanov

Кирсанов³

et al. 2012

Cell Cycle

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Glucocorticoids are widely used for the treatment of hematological malignancies; however, their chronic use results in numerous metabolic side effects. Thus, the development of selective glucocorticoid receptor (GR) activators (SEGRA) with improved therapeutic index is important. GR regulates gene expression via (1) transactivation that requires GR homodimer binding to gene promoters and is linked to side effects and (2) transrepression-mediated via negative GR interaction with other transcription factors. Novel GR modulator Compound A (CpdA) prevents GR dimerization, retains glucocorticoid anti-inflammatory activity and has fewer side effects compared with glucocorticoids in vivo. Here we tested CpdA anticancer activity in human T- and B-lymphoma and multiple myeloma cells expressing GR and their counterparts with silenced GR. We found that CpdA in GR-dependent manner strongly inhibited growth and viability of human T-, B-lymphoma and multiple myeloma cells. Furthermore, primary leukemia cell cultures from T-ALL patients appeared to be equally sensitive to glucocorticoid dexamethasone and CpdA. It is known that GR expression is controlled by proteasome. We showed that pretreatment of lymphoma CEM and NCEB cells with proteasome-inhibitor Bortezomib resulted in GR accumulation and enhanced ligand properties of CpdA, shifting GR activity toward transrepression evaluated by inhibition of NFкB and AP-1 transcription factors. We also revealed remarkable GR-dependent cooperation between CpdA and Bortezomib in suppressing growth and survival of T- and B-lymphoma and multiple myeloma MM.1S cells. Overall, our data provide the rationale for novel GR-based therapy for hematological malignancies based on combination of SEGRA with proteasome inhibitors.

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Section: Combination Of a Selective Activator Of The Glucocorticoid Receptor Compound A With A Proteasome Inhibitor As A Novel Strategy Fmentioning

confidence: 99%

Combination of a selective activator of the glucocorticoid receptor Compound A with a proteasome inhibitor as a novel strategy for chemotherapy of hematologic malignancies

Lesovaya¹,

Yemelyanov

Кирсанов³

et al. 2012

Cell Cycle

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“…This immunophilin has been referred to in the literature by a variety of acronyms, such as hsp56(Yemefa/. 1992), p59 (Lebeau etal., 1992), FKBP-52 (Peattie et al, 1992), HBI (Callebaut etal., 1992), FKBP-51 (Wiederrecht et al, 1992), and FKBP-59 (Tai et al, 1992), yet it is becoming clear that all of these terms relate to the same or derivative protein species. The original finding that hsp56 associates with various steroid receptor complexes (Renoir et al, 1990;Sanchez et al, 1990;Tai et al, 1986), taken together with the recent demonstration that hsp56 binds to FK506 (Yem et al, 1992), suggests that hsp56 in vivo may have a dual role in mammalian biochemistry.…”

mentioning

confidence: 99%

An active FK506-binding domain of 17,000 daltons is isolated following limited proteolysis of chicken thymus HSP56

Yem¹,

Reardon²,

Leone³

et al. 1993

Biochemistry

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We have previously identified hsp56, a protein component of steroid receptor complexes, as an FK506 binding protein [Yem et al. (1992) J. Biol. Chem. 267, 2868-2871]. We now report that hsp56 is also found to be a major immunophilin in chicken thymus, by virtue of binding to FK506-Affi-Gel-10 as well as positive cross-reactivity with a polyclonal antiserum directed against human hsp56. Limited digests of purified chicken hsp56 with endoproteinase Lys C result in the production of a unique polypeptide having a mass of about 17 kDa (p17), as judged by Western blotting. Peptide mapping provided additional proof that p17 is a fragment which comprises the entire FK506 binding domain I of chicken hsp56, terminating with an Arg-Lys which might represent a processing site. Binding of radiolabeled dihydro FK506 to p17 is saturable with a calculated KD of 42 nM. Since size exclusion chromatography of drug-p17 complexes indicates that the active species is a homodimer with a mass of 30-40 kDa, the stoichiometry calculated for the drug-protein complex is approximately 1:1. Furthermore, unlike FKBP-12, chicken p17 bound to FK506 does not bind to calcineurin-calmodulin complexes. This work demonstrates the excision of a domain from an hsp56 protein that is active in binding FK506 and functionally distinct from FKBP-12, a protein of similar size and structure.

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“…Tacrolismus (FK506) binding protein 5 (FKBP51) is a 51 kDA chaperon molecule and an endogenous cytosolic peptidyl-prolyl isomerase counted among the immunophilin protein family [285,286] with others [287,288]. Immunophilins had been described as receptor molecules for immunosuppressive drugs, such as cyclophilin 40 (CyP40), FK506-binding proteins FKBP51 and FK506-binding protein 4 (FKBP52), protein phosphatase 5 (PP5), and heat shock protein 90 (Hsp90) [289].…”

Section: Developing Targeted Therapy Not As Easy As Advertisedmentioning

confidence: 99%

Synopsis: Special Issue on “Disruption of signaling homeostasis induced crosstalk in the carcinogenesis paradigmEpistemology of the origin of cancer”

Brücher

Jamall

2019

4open

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It is increasingly evident that carcinogenesis, in the vast majority of cancers, cannot be explained simply through an accumulation of somatic mutations, or epigenetics, the stem cell theory, or the Warburg effect. Here, decades of thinking based on incorrect assumptions has resulted in an incorrect hypothesis on the origin of cancer. Many papers studying DNA, genetics, RNA, miRNA, proteomics, and epigenetics have increased our understanding of biology. Our paradigm, though more complex, is more reliable and plausible. It states that cancer originates from a disruption of homeostasis. This essential biological phenomenon, homeostasis, maintains the interrelationships of various signaling pathways and induced crosstalk which modify cellular functions together with the interactions of surrounding cells and structures such that the equilibrium lies towards the optimal health of the organism. This Special Issue “Disruption of signaling homeostasis induced crosstalk in the carcinogenesis paradigm Epistemology of the origin of cancer” provides compelling evidence that carcinogenesis is explained by a six-step sequence of events for the vast majority of cancers. These six steps include, (1) a pathogenic stimulus followed by (2) chronic inflammation, from which develops (3) fibrosis with associated remodeling in the cellular microenvironment. From these changes a (4) pre-cancerous niche develops which triggers the deployment of (5) a chronic stress escape strategy, and when this fails to resolve, and (6) the transition of a normal cell to a cancer cell occurs. This paradigm provides opportunities to move away from a symptom-oriented understanding of cancer and is much closer to a cause-based understanding, which opens the door for early preventative strategies to mitigate cancer as a disease, and to interdict metastases. This is underpinned by the fact that an independent recently published proof of this paradigm showed how a stimulus trigger the proposed multi-sequence cascade of events as abrupt involution-induced chronic inflammation, followed by fibrosis with remodeling, which describes the pre-cancerous niche followed by hyperplasia, metaplasia, and cancer.

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Characterization of high molecular weight FK-506 binding activities reveals a novel FK-506-binding protein as well as a protein complex.

Cited by 108 publications

References 43 publications

Combination of a selective activator of the glucocorticoid receptor Compound A with a proteasome inhibitor as a novel strategy for chemotherapy of hematologic malignancies

Combination of a selective activator of the glucocorticoid receptor Compound A with a proteasome inhibitor as a novel strategy for chemotherapy of hematologic malignancies

An active FK506-binding domain of 17,000 daltons is isolated following limited proteolysis of chicken thymus HSP56

Synopsis: Special Issue on “Disruption of signaling homeostasis induced crosstalk in the carcinogenesis paradigmEpistemology of the origin of cancer”

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