Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P11021 (BiP)
 2,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GRP78/BiP, a molecular chaperone in the endoplasmic reticulum, is induced under such adverse conditions for cell survival as glucose starvation. Induction of GRP78 has been shown to coincide with G1 cell cycle arrest, which is an important cellular defense system. In this study, we investigated involvement of GRP78 in the mechanism of growth arrest by using human epidermoid carcinoma A431 cells. Under a chemical stress condition with 2-deoxyglucose, GRP78 was induced 3-4-fold. In the stressed cells, an underglycosylated form of epidermal growth factor receptor (EGFR) was produced and the mature form was decreased. We found that the molecular chaperone GRP78 in the endoplasmic reticulum formed a stable complex with the underglycosylated EGFR but did not with the mature form. This complex formation occurred specifically under the stress conditions, and the complex was dissociated upon removal of the stress. Treatment of the GRP78-underglycosylated EGFR complex with ATP resulted in a release of the underglycosylated EGFR from GRP78, indicating that the complex could be formed through the chaperone function of GRP78. In accordance with the complex formation with endoplasmic reticulum-resident GRP78, the underglycosylated EGFR could not be translocated to the cell surface. As a result, EGF could not induce expression of cyclin D3, a G1 cyclin, in the stressed cells, whereas it did in non-stressed cells. These results indicated that, in the stressed cells, GRP78 participated in down-regulation of EGF-signaling pathway by forming a stable complex with EGFR and inhibiting EGFR translocation to the cell surface.
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PMID:Down-regulation of epidermal growth factor receptor-signaling pathway by binding of GRP78/BiP to the receptor under glucose-starved stress conditions. 976 25

Proteasome inhibitors and protease inhibitors are currently being discussed to be useful to sensitize drug-resistant cancer cells to chemotherapeutic agents or to act independently as single agents on drug-resistant cancer cells. We tested the effect of the clinically applied HIV protease inhibitor nelfinavir on ovarian cancer cells. Nelfinavir efficiently induced cell death in carboplatin-sensitive (SKOV3, OV-GH-5) and carboplatin-resistant (OVCAR3, OV-GH-1) ovarian cancer cell lines as well as in cancer biopsies and ascites samples from patients with recurrent ovarian cancer. Nelfinavir significantly changed the morphology of ovarian cancer cells, resulting in formation of large ER-derived vacuoles and induced upregulation of the hsp70 heat shock family member BiP (GRP78) which accumulated within swollen ER membranes. Upregulation of BiP and phosphorylation of eIF2alpha indicated induction of the unfolded protein response, which can cause cell cycle arrest and apoptosis. Correspondingly, we observed downregulation of cell cycle regulatory proteins after nelfinavir treatment, especially that of cyclin D3, and induction of apoptosis as confirmed by annexin binding. Because nelfinavir represents an already approved drug for use in humans with HIV infection, it could rapidly be tested in clinical studies as a potential treatment strategy against drug-resistant ovarian cancer.
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PMID:Nelfinavir induces the unfolded protein response in ovarian cancer cells, resulting in ER vacuolization, cell cycle retardation and apoptosis. 1933 9