Translationally controlled tumour protein (TCTP) is a novel glucose-regulated protein that is important for survival of pancreatic beta cells (original) (raw)
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Endocrinology, 2014
The perinatal period is critical for -cell mass establishment, which is characterized by a transient burst in proliferation to increase -cell mass in response to the need for glucose homeostasis throughout life. In adulthood, the ability of -cells to grow, proliferate, and expand their mass is also characteristic of pathological states of insulin resistance. Translationally controlled tumorassociated protein (TCTP), an evolutionarily highly conserved protein that is implicated in cell growth and proliferation, has been identified as a novel glucose-regulated survival-supporting protein in pancreatic -cells. In this study, the enhanced -cell proliferation detected both during the perinatal developmental period and in insulin-resistant states in high-fat diet-fed mice was found to parallel the expression of TCTP in pancreatic -cells. Specific knockout of TCTP in -cells led to increased expression of total and nuclear Forkhead box protein O1 and tumor suppressor protein 53, and decreased expression of p70S6 kinase phosphorylation and cyclin D2 and cyclindependent kinase 2. This resulted in decreased -cell proliferation and growth, reduced -cell mass, and insulin secretion. Together, these effects led to hyperglycemia. These observations suggest that TCTP is essential for -cell mass expansion during development and -cell adaptation in response to insulin resistance.
The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation
TCTP/tpt1 - Remodeling Signaling from Stem Cell to Disease, 2017
The Translational Controlled Tumour Protein TCTP (gene symbol TPT1, also called P21, P23, Q23, fortilin or histamine-releasing factor, HRF) is a highly conserved protein present in essentially all eukaryotic organisms and involved in many fundamental cell biological and disease processes. It was first discovered about 35 years ago, and it took an extended period of time for its multiple functions to be revealed, and even today we do not yet fully understand all the details. Having witnessed most of this history, in this chapter, I give a brief overview and review the current knowledge on the structure, biological functions, disease involvements and cellular regulation of this protein. TCTP is able to interact with a large number of other proteins and is therefore involved in many core cell biological processes, predominantly in the response to cellular stresses, such as oxidative stress, heat shock, genotoxic stress, imbalance of ion metabolism as well as other conditions. Mechanistically, TCTP acts as an anti-apoptotic protein, and it is involved in DNA-damage repair and in cellular autophagy. Thus, broadly speaking, TCTP can be considered a cytoprotective protein. In addition, TCTP facilitates cell division through stabilising the mitotic spindle and cell growth through modulating growth signalling pathways and through its interaction with the proteosynthetic machinery of the cell. Due to its activities, both as an anti-apoptotic protein and in promoting cell growth and division, TCTP is also essential in the early development of both animals and plants. Apart from its involvement in various biological processes at the cellular level, TCTP can also act as an extracellular protein and as such has been involved in modulating whole-body defence processes, namely in the mammalian immune system. Extracellular TCTP, typically in its dimerised form, is able to induce the release of cytokines and other signalling molecules from various types of immune cells. There are also several examples, where TCTP was shown to be involved in antiviral/antibacterial defence in lower animals. In plants, the protein appears to have a protective effect against phytotoxic stresses, such as flooding, draught, too high or low temperature, salt stress or exposure to heavy metals. The finding for the latter stress condition is corroborated by earlier reports that TCTP levels are considerably up-regulated upon exposure of earthworms to high levels of heavy metals. Given the involvement of TCTP in many biological processes aimed at maintaining cellular or whole-body homeostasis, it is not surprising that dysregulation of TCTP levels may promote a range of disease processes, foremost cancer. Indeed a large body of evidence now supports a role of TCTP in at least the most predominant types of human cancers. Typically, this can be ascribed to both the anti-apoptotic activity of the protein and to its function in promoting cell growth and division. However, TCTP also appears to be involved in the later stages of cancer progression, such as invasion and metastasis. Hence, high TCTP levels in tumour tissues are often associated with a poor patient outcome. Due to its multiple roles in cancer progression, TCTP has been proposed as a potential target for the development of new anti-cancer strategies in recent pilot studies. Apart from its role in cancer, TCTP dysregulation has been reported to contribute to certain processes in the development of diabetes, as well as in diseases associated with the cardiovascular system. Since cellular TCTP levels are highly regulated, e.g. in response to cell stress or to growth signalling, and because deregulation of this protein contributes to many disease processes, a detailed understanding of regulatory processes that impinge on TCTP levels is required. The last section of this chapter summarises our current knowledge on the mechanisms that may be involved in the regulation of TCT
Journal of Biological Chemistry, 2009
Recently, we identified Txnip (thioredoxin-interacting protein) as a mediator of glucotoxic beta cell death and discovered that lack of Txnip protects against streptozotocin-and obesityinduced diabetes by preventing beta cell apoptosis and preserving endogenous beta cell mass. Txnip has therefore become an attractive target for diabetes therapy, but although we have found that txnip transcription is highly induced by glucose through a unique carbohydrate response element, the factors controlling this effect have remained unknown. Using transient transfection experiments, we now show that overexpression of the carbohydrate response element-binding protein (ChREBP) transactivates the txnip promoter, whereas ChREBP knockdown by small interfering RNA completely blunts glucose-induced txnip transcription. Moreover, chromatin immunoprecipitation demonstrated that glucose leads to a dose-and time-dependent recruitment of ChREBP to the txnip promoter in vivo in INS-1 beta cells as well as human islets. Furthermore, we found that the co-activator and histone acetyltransferase p300 co-immunoprecipitates with ChREBP and also binds to the txnip promoter in response to glucose. Interestingly, this is associated with specific acetylation of histone H4 and recruitment of RNA polymerase II as measured by chromatin immunoprecipitation. Thus, with this study we have identified ChREBP as the transcription factor that mediates glucose-induced txnip expression in human islets and INS-1 beta cells and have characterized the chromatin modification associated with glucose-induced txnip transcription. In addition, the results reveal for the first time that ChREBP interacts with p300. This may explain how ChREBP induces H4 acetylation and sheds new light on glucose-mediated regulation of chromatin structure and transcription.
The glucose-regulated proteins: stress induction and clinical applications
Trends in Biochemical Sciences, 2001
A protective mechanism used by cells to adapt to stress of the endoplasmic reticulum (ER) is the induction of members of the glucose-regulated protein (Grp) family. The induction of mammalian Grp proteins in response to ER stress involves a complex network of regulators and novel mechanisms. The elucidation of Grp function and regulation opens up new therapeutic approaches to diseases associated with ER stress and cancer.
2011
Background: We studied the RNA expression of the genes in response to glucose from 5 mM (condition of normoglycemia) to 20 mM (condition of hyperglycemia/diabetes) by microarray analysis in breast cancer derived cell line MDA-MB-231. We identified the thioredoxin-interacting protein (TXNIP), whose RNA level increased as a gene product particularly sensitive to the variation of the level of glucose in culture media. We investigated the kinesis of the TXNIP RNA and protein in response to glucose and the relationship between this protein and the related thioredoxin (TRX) in regulating the level of reactive oxygen species (ROS) in MDA-MB-231 cells. Methods: MDA-MB-231 cells were grown either in 5 or 20 mM glucose chronically prior to plating. For glucose shift (5/20), cells were plated in 5 mM glucose and shifted to 20 mM at time 0. Cells were analyzed with Affymetrix Human U133A microarray chip and gene expression profile was obtained. Semi-quantitative RT-PCR and Western blot was used to validate the expression of TXNIP RNA and protein in response to glucose, respectively. ROS were detected by CM-H2DCFDA (5-6-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate) and measured for mean fluorescence intensity with flow cytometry. TRX activity was assayed by the insulin disulfide reducing assay. Results: We found that the regulation of TXNIP gene expression by glucose in MDA-MB-231 cells occurs rapidly within 6 h of its increased level (20 mM glucose) and persists through the duration of the conditions of hyperglycemia. The increased level of TXNIP RNA is followed by increased level of protein that is associated with increasing levels of ROS and reduced TRX activity. The inhibition of the glucose transporter GLUT1 by phloretin notably reduces TXNIP RNA level and the inhibition of the p38 MAP kinase activity by SB203580 reverses the effects of TXNIP on ROS-TRX activity. Conclusion: In this study we show that TXNIP is an oxidative stress responsive gene and its expression is exquisitely regulated by glucose level in highly metastatic MDA-MB-231 cells.
Journal of Clinical Investigation, 1996
This study demonstrates that rat islet  cells constitutively express an apoptotic program which is activated when mRNA or protein synthesis is blocked. Apoptotic  cells were detectable by electron microscopy after treatment with actinomycin D or cycloheximide. With a fluorescence microscopic assay both agents were found to increase the number of apoptotic  cells dose-and time-dependently, up to 70% after 1 wk of culture; virtually no apoptotic  cells occurred in control preparations or in conditions leading to primary necrosis. Thus, survival of  cells seems dependent on synthesis of proteins which suppress an endogenous suicide program. This mechanism explains earlier observed effects of glucose on survival of cultured  cells. Glucose is known to dose-dependently increase the percentage of  cells in active biosynthesis and the percentage that survives during culture. It is now demonstrated that the glucose-induced survival of  cells cultured for 1 wk results from a dose-dependent reduction in the percentage of  cells dying in apoptosis (49% at 3 mM glucose, 40% at 6 mM, 9% at 10 mM). Thus, intercellular differences in glucose sensitivity appear responsible for the heterogeneity in  cell sensitivity to apoptotic conditions. These data indicate that glucose promotes survival of  cells by activating synthesis of proteins which suppress apoptosis. The present model allows for further investigation of the regulation of apoptosis in  cells and the identification of agents which induce or prevent  cell death. ( J. Clin. Invest. 1996. 98:1568-1574.) Key words: apoptosis • insulin • endocrine pancreas • diabetes • islets of Langerhans 1. Abbreviations used in this paper: AMD, actinomycin D; CHX, cycloheximide; HO 342, Hoechst 33342; PI, propidium iodide.
Proteome Science, 2009
Background: Development of type 2 diabetes mellitus (T2DM) is characterized by aberrant insulin secretory patterns, where elevated insulin levels at non-stimulatory basal conditions and reduced hormonal levels at stimulatory conditions are major components. To delineate mechanisms responsible for these alterations we cultured INS-1E cells for 48 hours at 20 mM glucose in absence or presence of 0.5 mM palmitate, when stimulatory secretion of insulin was reduced or basal secretion was elevated, respectively. Results: After culture, cells were protein profiled by SELDI-TOF-MS and 2D-PAGE. Differentially expressed proteins were discovered and identified by peptide mass fingerprinting. Complimentary protein profiles were obtained by the two approaches with SELDI-TOF-MS being more efficient in separating proteins in the low molecular range and 2D-PAGE in the high molecular range. Identified proteins included alpha glucosidase, calmodulin, gars, glucose-6-phosphate dehydrogenase, heterogenous nuclear ribonucleoprotein A3, lon peptidase, nicotineamide adenine dinucleotide hydrogen (NADH) dehydrogenase, phosphoglycerate kinase, proteasome p45, rab2, pyruvate kinase and t-complex protein. The observed glucose-induced differential protein expression pattern indicates enhanced glucose metabolism, defense against reactive oxygen species, enhanced protein translation, folding and degradation and decreased insulin granular formation and trafficking. Palmitate-induced changes could be related to altered exocytosis. Conclusion: The identified altered proteins indicate mechanism important for altered β-cell function in T2DM.
Hyperglycemia impairs cytotrophoblast function via stress signaling
OBJECTIVE: Diabetes mellitus is a risk factor for preeclampsia. Cytotrophoblast (CTB) invasion is facilitated from the conversion of plasminogen to plasmin by urokinase plasminogen activator (uPA), regulated by plasminogen activator inhibitor 1 (PAI-1), and may be inhibited in preeclampsia. This study assessed signaling mechanisms of hyperglycemia-induced CTB dysfunction.
Glucose dependence of the regulated secretory pathway in αTC1-6 cells
Endocrinology, 2005
We have investigated the effects of chronically elevated glucose concentrations on the pancreatic ␣-cell line ␣TC1-6. We show that basal glucagon secretion and proglucagon gene expression were increased in response to high glucose levels. The extent of acute stimulated secretion of glucagon was also increased in response to high glucose, as was the transcription of the prohormone processing enzymes PC1/3 and PC2. The secretion of GLP-1, a proglucagon-derived peptide produced by cleavage of proglucagon by PC1/3, was also increased in response to high glucose. Gene expression profiling experiments showed that a number of components of the regulated secretory pathway were up-regulated at high glucose concentrations, including processing enzymes and exocytotic proteins. Immunoblot analysis showed that the expression of the exocytotic SNARE proteins, as well as that of PC1/3, chromogranin A, and 7B2, were all increased after chronic exposure to high glucose levels. Immunocytochemistry showed no changes in the expression of the mature ␣-cell markers glucagon and brn-4 and no induction of the immature ␣-cell marker pdx-1. We conclude that chronically elevated glucose concentrations up-regulate the regulated secretory response of the ␣-cell. (Endocrinology 146: 4514-4523, 2005
Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential
Nature Reviews Cancer, 2014
The glucose-regulated proteins (GRPs) GRP78 (also known as BiP and HSPA5), GRP94 (also known as GP96 and HSP90B1), GRP170 (also known as ORP150 and HYOU1) and GRP75 (also known as mortalin and HSPA9) are stress-inducible molecular chaperones that belong to the heat shock protein (HSP) family (BOX 1). Unlike most of the HSPs, which reside mainly in the cytosol and the nucleus, these GRPs are found in the endoplasmic reticulum (ER) or the mitochondria, which are important organelles for the regulation of protein quality control and metabolic balance 1-4. In their traditional chaperone roles, these GRPs facilitate protein folding and assembly, as well as the export of misfolded proteins for degradation. Coupled with their Ca 2+ binding functions, they maintain the integrity and homeo stasis of the ER and the mitochondria under physiological and pathological conditions. GRP overexpression is widely reported in cancer cell lines and is associated with aggressive growth and invasive properties 5,6 (see Supplementary information S1 (table)). During the past decade, exciting discoveries have been made in identifying common and distinctive functions of these GRPs in cancer. GRP78 regulates the balance between cancer cell viability and apoptosis by sustaining ER protein folding capacity and by maintaining ER stress sensors and ER-associated pro-apoptotic machineries in their inactive state 7. GRP94 is essential for the processing of proteins that have been implicated in tumorigenesis, such as insulin-like growth factor 1 (IGF1), Toll-like receptors (TLRs) and integrins 4. GRP170, which has an ADP-ATP exchange function, is both a co-chaperone for GRP78 and an independent chaperone, and it is crucial for vascular endothelial growth factor A (VEGFA) processing and maturation 2,8,9. GRP75 interacts with the tumour suppressor p53, thereby inactivating the capacity of p53 to function as a transcription factor and inducing apoptosis 10. Furthermore, these GRPs, which are traditionally thought to exclusively reside in the ER lumen, can be actively translocated to other cellular locations and can be secreted, and they have additional functions that control signalling, proliferation, invasion, apoptosis, inflammation and immunity 11-14. ER stress, as well as the development of therapeutic resistance, actively promotes the cell surface expression of GRP78, which functions as an upstream regulator of the PI3K-AKT oncogenic signalling pathway 15-17. GRP78 is also a downstream target of AKT activation 18,19. At the cell surface, GRP94 and GRP170 function in antigen presentation, and their secreted forms have the ability to elicit innate and adaptive immune responses, which could be useful in the development of cancer vaccines 1,2,20. Through the use of cancer cell lines, xenografts and conditional knockout mouse models, the important roles of these GRPs in cancer are being established 5,20,21. Promising therapeutics that are specifically directed against the GRPs, including conjugated peptides and toxins, antibodies, small molecules and microRNAs, are being developed 5,20,22. Thus, these GRPs represent novel