Glucose-regulated protein 78 (GRP78) is elevated in embryonic mouse heart and induced following hypoglycemic stress

Barnes, Jill A.; Smoak, Ida W.

doi:10.1007/s004290000090

Cited by 40 publications

(28 citation statements)

References 48 publications

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“…In support of this notion, high levels of GRP78 were detected in the heart, somite, and neural tube of developing mouse embryos at day 9.5 and day 10.5 (2). Elevated levels of GRP78 in the testes also imply that GRP78 might play an important role in spermatogenesis (14).…”

Section: Discussionmentioning

confidence: 79%

“…1A). The expression profile of the 3kb/LacZ transgene has been shown to faithfully represent endogenous GRP78 expression in mouse embryos at E9.5 to E11.5, where GRP78 is highly elevated in the developing heart and in somite and neural tubes (2,33). LacZ activity, as detected by ␤-gal staining, was observed in both the trophectoderm (TE) and inner cell mass (ICM) of the 3kb/LacZ blastocyst (Fig.…”

Section: De Novo Transcription Of Grp78 In Blastocysts Requires the Ementioning

confidence: 89%

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GRP78/BiP Is Required for Cell Proliferation and Protecting the Inner Cell Mass from Apoptosis during Early Mouse Embryonic Development

Luo

Mao

Lee

et al. 2006

Molecular and Cellular Biology

399

362

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GRP78, also known as BiP, is a central regulator of endoplasmic reticulum (ER) homeostasis due to its multiple functional roles in protein folding, ER calcium binding, and controlling of the activation of transmembrane ER stress sensors. ER stress induction of GRP78/BiP represents a major prosurvival arm of the unfolded protein response (UPR). However, the physiological role of GRP78 in development is not known. Using a transgenic approach, we discovered that the Grp78 promoter is activated in both the trophectoderm and inner cell mass (ICM) of embryos at embryonic day 3.5 via a mechanism requiring the ER stress elements. To reveal the function of the GRP78 in vivo, we created a tri-loxP Grp78 mutant allele, which was further crossed with EIIA-cre to create a knockout allele. The Grp78 ؉/؊ mice, which express 50% of the wild-type level of the GRP78 protein, are viable. Interestingly, the heterozygous Grp78 cells up-regulate the ER proteins GRP94 and protein disulfide isomerase at both the transcript and protein levels, while other UPR targets such as CHOP and XBP-1 are not affected. Further studies revealed that mouse embryonic fibroblasts from Grp78 ؉/؊ mice are capable of responding to ER stress. However, Grp78؊/؊ embryos that are completely devoid of GRP78 lead to peri-implantation lethality. These embryos do not hatch from the zona pellucida in vitro, fail to grow in culture, and exhibit proliferation defects and a massive increase in apoptosis in the ICM, which is the precursor of embryonic stem cells. These findings provide the first evidence that GRP78 is essential for embryonic cell growth and pluripotent cell survival.The unfolded protein response (UPR), which is conserved from yeast to human, triggers multiple pathways to allow cells to respond to stress conditions that target the endoplasmic reticulum (ER) (17). The ER is the site for the synthesis of secretory and membrane proteins and lipids and is also a major intracellular calcium storage compartment. As such, ER homeostasis is critical for the survival of eukaryotic cells. The 78-kDa glucose-regulated protein GRP78, also referred to as the immunoglobulin binding protein BiP, is a stress-inducible ER chaperone that belongs to the HSP70 family (15,27). GRP78 is composed of three domains: the ATPase domain, the peptide-binding domain, and a C-terminal domain with unknown function (21). GRP78 binds to the unfolded peptides through the peptide-binding domain and uses the energy from hydrolyzing ATP to promote proper folding and to prevent aggregation (22). GRP78 also possesses the capacity to bind Ca 2ϩ , which helps to immobilize Ca 2ϩ and maintain ER calcium homeostasis (26). Furthermore, GRP78 serves as a master modulator for the UPR network by binding to the ER stress sensors PERK, Ire1p, and ATF6 and inhibiting their activation (3, 43). Furthermore, due to its antiapoptotic property, stress induction of GRP78 represents an important prosurvival arm of the UPR, with implications for cancer progression, drug resistance, neuroprotection, and diabete...

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Section: Discussionmentioning

confidence: 79%

Section: De Novo Transcription Of Grp78 In Blastocysts Requires the Ementioning

confidence: 89%

GRP78/BiP Is Required for Cell Proliferation and Protecting the Inner Cell Mass from Apoptosis during Early Mouse Embryonic Development

Luo

Mao

Lee

et al. 2006

Molecular and Cellular Biology

399

362

View full text Add to dashboard Cite

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“…Tsang et al (2007) report delayed terminal differentiation in hypertrophic chondrocytes of the growth plate in response to ER stress, brought on by the retention of collagen type X in the ER. Additionally, it is reported that grp78 is upregulated during early mouse development in the heart, somites, and other tissues, and that its expression decreases during later phases of development (Barnes and Smoak 2000). It has also been suggested that the GRP family of proteins serve as detectors for the level of activity of cellular secretion (Kozutsumi et al 1988).…”

Section: Discussionmentioning

confidence: 99%

Advanced Osteoarthritis in Humans Is Associated With Altered Collagen VI Expression and Upregulation of ER-stress Markers Grp78 and Bag-1

Nugent

Speicher

Gradisar

et al. 2009

J Histochem Cytochem.

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; and Summa Health Systems, Akron, Ohio (IG) S U M M A R Y To test the hypothesis that a perturbation of endoplasmic reticulum (ER) function is involved in the pathogenesis of osteoarthritis (OA), articular cartilage was isolated from non-OA patients secondary to resection of osteo-or chondrosarcomas. Intra-joint samples of minimal and advanced osteoarthritic cartilage were isolated from patients undergoing total knee arthroplasty and scored for disease severity. Glucose-regulated protein-78 (grp78) and bcl-2-associated athanogene-1 (bag-1) were detected via immunofluorescence as markers of non-homeostatic ER function. Additionally, the expression of type VI collagen and its integrin receptor, NG2, was determined to examine cartilage matrix health and turnover. There was an upregulation of grp78 in advanced OA, and variable expression in minimal OA. Non-OA cartilage was consistently grp78 negative. The downstream regulator bag-1 was also upregulated in OA compared with normal cartilage. Collagen VI was mainly cellassociated in non-OA cartilage, with a more widespread distribution observed in OA cartilage along with increased intracellular staining intensity. The collagen VI integral membrane proteoglycan receptor NG2 was downregulated in advanced OA compared with its patientmatched minimally involved cartilage sample. These results suggest that chondrocytes exhibit ER stress during OA, in association with upregulation of a large secreted molecule, type VI collagen. (J Histochem Cytochem 57:923-931, 2009) K E Y W O R D S osteoarthritis cartilage ER stress bag-1 grp78 collagen VI NG2 OSTEOARTHRITIS (OA) IS A PROGRESSIVE DISEASE, with changes in chondrocyte gene expression and extracellular matrix (ECM) composition occurring before macroscopic structural damage is observed (Hamerman 1989). Articular chondrocytes in OA exhibit a hypermetabolic phenotype, with studies describing highly proliferative clonal chondrocytes, along with the upand downregulation of ECM molecules such as aggrecan

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“…For example, reduction of ER Ca increases GRP78 in H9c2 cardiac myocytes 13 and activates ATF6 and the GRP78 promoter in cardiac myocyte cultures. 14 GRP78 is also elevated in the embryonic mouse myocardium, 15,16 and XBP1 knockout mice die in utero from cardiac myocyte apoptosis, 17 suggesting a requirement for the UPR during cardiac development. GRP78 is induced in mouse hearts on transverse aortic constriction, 18 suggesting UPR activation by pressure overload.…”

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confidence: 99%

Activation of the Unfolded Protein Response in Infarcted Mouse Heart and Hypoxic Cultured Cardiac Myocytes

Thuerauf

Marcinko

Gude

et al. 2006

Circulation Research

275

241

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Abstract-Endoplasmic reticulum (ER) stresses that reduce ER protein folding activate the unfolded protein response (UPR). One effector of the UPR is the transcription factor X-box binding protein-1 (XBP1), which is expressed on ER stress-mediated splicing of the XBP1 mRNA. XBP1 induces certain ER-targeted proteins, eg, glucose-regulated protein 78 (GRP78), that help resolve the ER stress and foster cell survival. In this study, we determined whether hypoxia can activate the UPR in the cardiac context. Neonatal rat ventricular myocyte cultures subjected to hypoxia (16 hours) exhibited increased XBP1 mRNA splicing, XBP1 protein expression, GRP78 promoter activation, and GRP78 protein levels; however, the levels of these UPR markers declined during reoxygenation, suggesting that the UPR is activated during hypoxia but not during reoxygenation. When cells were infected with a recombinant adenovirus (AdV) encoding dominant-negative XBP1 (AdV-XBP1dn), UPR markers were reduced; however, hypoxia/reoxygenation-induced apoptosis increased. Confocal immunocytofluorescence demonstrated that hypoxia induced GRP78 in neonatal rat and isolated adult mouse ventricular myocytes. Moreover, mouse hearts subjected to in vivo myocardial infarction exhibited increased GRP78 expression in cardiac myocytes near the infarct, but not in healthy cells distal to the infarct. These results indicate that hypoxia activates the UPR in cardiac myocytes and that XBP1-inducible proteins may contribute to protecting the myocardium during hypoxic stress.

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Glucose-regulated protein 78 (GRP78) is elevated in embryonic mouse heart and induced following hypoglycemic stress

Cited by 40 publications

References 48 publications

GRP78/BiP Is Required for Cell Proliferation and Protecting the Inner Cell Mass from Apoptosis during Early Mouse Embryonic Development

GRP78/BiP Is Required for Cell Proliferation and Protecting the Inner Cell Mass from Apoptosis during Early Mouse Embryonic Development

Advanced Osteoarthritis in Humans Is Associated With Altered Collagen VI Expression and Upregulation of ER-stress Markers Grp78 and Bag-1

Activation of the Unfolded Protein Response in Infarcted Mouse Heart and Hypoxic Cultured Cardiac Myocytes

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