Human FK506 Binding Protein 65 Is Associated with Colorectal Cancer

Olesen, Sanne H.; Christensen, Lise Lotte; Sørensen, Flemming Brandt; Cabezón, Teresa; Laurberg, Søren; Ørntoft, Torben F.; Birkenkamp‐Demtröder, Karin

doi:10.1074/mcp.m400217-mcp200

Cited by 32 publications

(33 citation statements)

References 24 publications

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“…Peptidyl-prolyl cis/trans isomerase (PPIase or rotamase) enzymes located within the ER lumen are not well characterized but have been associated with the appropriate folding of some ER cargo proteins. FKBP65 is the largest known rotamase enzyme, with four PPIase domains (Coss et al 1995), whose expression serves as a marker for cancerous transformation of colorectal cells, and also for the repair of lung tissue following injury (Olesen et al 2005;Patterson et al 2005). Humans with deleterious mutations in FKBP65 display severe defects in collagen deposition and bone development, as revealed in the heritable disease OI.…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum stress or mutation of an EF-hand Ca2+-binding domain directs the FKBP65 rotamase to an ERAD-based proteolysis

Murphy

Ramirez

Trinh

et al. 2011

Cell Stress and Chaperones

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FKBP65 is an endoplasmic reticulum (ER)-localized chaperone and rotamase, with cargo proteins that include tropoelastin and collagen. In humans, mutations in FKBP65 have recently been shown to cause a form of osteogenesis imperfecta (OI), a brittle bone disease resulting from deficient secretion of mature type I collagen. In this work, we describe the rapid proteolysis of FKBP65 in response to ER stress signals that activate the release of ER Ca 2+ stores. A large-scale screen for stress-induced cellular changes revealed FKBP65 proteins to decrease within 6-12 h of stress activation. Inhibiting IP 3 R-mediated ER Ca 2+ release blocked this response. No other ER-localized chaperone and folding mediators assessed in the study displayed this phenomenon, indicating that this rapid proteolysis of folding mediator is distinctive. Imaging and cellular fractionation confirmed the localization of FKBP65 (72 kDa glycoprotein) to the ER of untreated cells, a rapid decrease in protein levels following ER stress, and the corresponding appearance of a 30-kDa fragment in the cytosol. Inhibition of the proteasome during ER stress revealed an accumulation of FKBP65 in the cytosol, consistent with retrotranslocation and a proteasome-based proteolysis. To assess the role of Ca 2+ -binding EF-hand domains in FKBP65 stability, a recombinant FKBP65-GFP construct was engineered to ablate Ca 2+ binding at each of two EF-hand domains. Cells transfected with the wild-type construct displayed ER localization of the FKBP65-GFP protein and a proteasome-dependent proteolysis in response to ER stress. Recombinant FKBP65-GFP carrying a defect in the EF1 Ca 2+ -binding domain displayed diminished protein in the ER when compared to wild-type FKBP65-GFP. Proteasome inhibition restored mutant protein to levels similar to that of the wild-type FKBP65-GFP. A similar mutation in EF2 did not confer FKBP65 proteolysis. This work supports a model in which stress-induced changes in ER Ca 2+ stores induce the rapid proteolysis of FKBP65, a chaperone and folding mediator of collagen and tropoelastin. The destruction of this protein may identify a cellular strategy for replacement of protein folding machinery following ER stress. The implications for stress-induced changes in the handling of aggregateprone proteins in the ER-Golgi secretory pathway are discussed.

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Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum stress or mutation of an EF-hand Ca2+-binding domain directs the FKBP65 rotamase to an ERAD-based proteolysis

Murphy

Ramirez

Trinh

et al. 2011

Cell Stress and Chaperones

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“…For instance, FKBP12 was exhibited to be upregulated in malignant vascular endothelium (5) and childhood astrocytoma (6). FKBP65 expression was increased in early benign lesions compared with normal mucosa (7). FKBP52 has been demonstrated to be overexpressed in breast (8), prostate (9) and hepatocellular carcinoma tissues (10).…”

Section: Introductionmentioning

confidence: 96%

Downregulation of FKBP14 by RNA interference inhibits the proliferation, adhesion and invasion of gastric cancer cells

2017

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Abstract. FK506 binding protein (FBBP) 14 belongs to the family of FKBPs. Altered expression of FKBPs are observed in several malignancies. The present study aimed to explore the expression and biological function of FKBP14 in gastric cancer. FKBP14 expression levels in 40 gastric cancer samples and matched control samples were evaluated using quantitative polymerase chain reaction. Cell proliferation was evaluated using Cell Counting kit-8 assay. A cell adhesion and a Transwell assay were performed to detect cell adhesion and invasion. Protein expression was determined using western blot analysis. It was found that FKBP14 expression in gastric cancer tissues was elevated compared with normal tissues. Silencing of FKBP14 expression in the gastric cancer MKN-45 and AGS cell lines, which have a higher expression level of FKBP14 compared with four other gastric cancer cell lines, significantly inhibited cellular proliferation, adhesion and invasion. In addition, the protein levels of proliferating cell nuclear antigen, matrix metalloproteinase 2 and the epithelial-mesenchymal-transition (EMT) markers β-catenin, Snail1 and Twist were repressed in gastric cancer cells with FKBP14 silenced. In conclusion, FKBP14 may act as an oncogene by suppressing cellular proliferation, adhesion and invasion and EMT in gastric carcinogenesis. FKBP14 may be a diagnosis marker and potential therapeutic target in gastric cancer.

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“…Ten micrograms of protein per lane were loaded on a 12% NuPAGE gel (Invitrogen Corp., Carlsbad, Calif., USA) and electrophoretically blotted to a PVDF-plus membrane as previously described [17]. After blocking with 5% skimmed milk and 0.1% Tween-20 in PBS buffer, the secretagogin protein was detected using a specific polyclonal rabbit anti-human secretagogin antibody diluted 1:3,000 (L. Wagner, Austria) followed by the secondary HRP-conjugated goat anti-rabbit IgG (DakoCytomation, Glostrup, Denmark).…”

Section: Methodsmentioning

confidence: 99%

Secretagogin Is a Novel Marker for Neuroendocrine Differentiation

et al. 2005

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Our previous microarray-based studies identified secretagogin to be highly expressed in normal colon mucosa compared to basal expression in colon adenocarcinomas. The aim of this study was to analyze the differential expression of secretagogin in normal mucosa, adenocarcinomas, and neuroendocrine tumors. Western blotting, immunohistochemistry, immunofluorescence microscopy and ELISA were applied. Western blot analysis detected a 32-kDa secretagogin band in samples from normal mucosa. Immunohistochemical analyses on tissue specimens showed that secretagogin is exclusively expressed in neuroendocrine cells and nerve cells in normal mucosa of the digestive tract. Tissues adjacent to benign hyperplasic polyps and adenomas showed a decreased number of secretagogin-expressing neuroendocrine cells. Secretagogin co-localized with neuroendocrine markers (chromogranin A, neuron-specific enolase, synaptophysin) in neuroendocrine cells in crypts of normal mucosa, and in tumor cells of carcinoids. Secretagogin was strongly expressed in the cytosol and the nucleus of 19 well-differentiated neuroendocrine carcinoids and carcinoid metastases, as well as in neuroendocrine tumors from the lung, pancreas and adrenal gland. Secretagogin was detected in plasma from carcinoid patients with distant metastasis. Combined immunohistochemical analysis of secretagogin and FK506-binding protein 65, a protein de novo synthesized in adenocarcinomas, distinguished well-differentiated carcinoids, adenocarcinoids and undifferentiated carcinomas. We conclude that secretagogin is a novel marker for neuroendocrine differentiation.

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Human FK506 Binding Protein 65 Is Associated with Colorectal Cancer

Cited by 32 publications

References 24 publications

Endoplasmic reticulum stress or mutation of an EF-hand Ca2+-binding domain directs the FKBP65 rotamase to an ERAD-based proteolysis

Endoplasmic reticulum stress or mutation of an EF-hand Ca2+-binding domain directs the FKBP65 rotamase to an ERAD-based proteolysis

Downregulation of FKBP14 by RNA interference inhibits the proliferation, adhesion and invasion of gastric cancer cells

Secretagogin Is a Novel Marker for Neuroendocrine Differentiation

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