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

BE2 is a cell surface monomeric 78-kDa protein (BE2-78) expressed on the malignant lymphocytes of cutaneous T-cell lymphoma and adult T-cell leukemia, on some lymphocytes from patients with acquired immunodeficiency syndrome and on Epstein-Barr virus-transformed B cells. BE2-78 positivity of cutaneous T-cell lymphoma tumor cells is a useful diagnostic and prognostic determinant in evaluating patients with that disorder. The BE2-78 protein was isolated from Epstein Barr virus-transformed B cells, purified by 1- and 2-dimensional electrophoresis and then sequenced. The sequence of 4 isolated peptide fragments was highly homologous with the 78-kDa heat shock protein, BiP, an endoplasmic reticulum chaperone. The similarity between BiP and BE2-78 was supported by the demonstration that BE2-78, like BiP, avidly binds to ATP. However, polyclonal and monoclonal reagents that recognize cytoplasmic 70- and 78-kDa heat shock proteins do not detect the BE2-78 antigen on the cell surface of cutaneous T-cell lymphoma or Epstein Barr virus-transformed lymphocytes, and peptide mapping demonstrates sequence divergence, suggesting that either they are distinct or conformationally different molecules. Our results indicate that BE2-78 is a cell surface heat shock protein. The possibility that malignant or transformed lymphocytes may express cell surface molecules with the capacity to bind a spectrum of exogenous or endogenous peptides has potential implications for tumor immunology.
 ...
PMID:A lymphocyte cell surface heat shock protein homologous to the endoplasmic reticulum chaperone, immunoglobulin heavy chain binding protein BIP. 918 14

Phylogenetic analyses indicated that a series of paralogous gene pairs, found in two extensive regions on human chromosomal bands 6p21.3 and 9q33-34, were created by at least two independent duplications. The duplicated genes on chromosomal band 6p21.3 include the genes for type 11 collagen alpha2 subunit (COL11A2), NOTCH4 (mouse int-3 homologue), 70 kDa heat shock protein (HSPA1A, HSPA1B, and HSPA1L), valyl-tRNA synthetase 2 (VARS2), complement components (C2 and C4), pre-B cell leukemia transcription factor 2 (PBX2), retinoid X receptor beta (RXRB), NAT/RING3, and four other proteins. Their paralogous genes on chromosomal band 9q33-34 are genes for type 5 collagen alpha1 subunit (COL5A1), NOTCH1, 78 kDa glucose-regulated protein (HSPA5), valyl-tRNA synthetase 1 (VARS1), complement component V (C5), PBX3, retinoid X receptor alpha (RXRA), ORFX/RING3L, and others. Among these, the genes for collagen, complement components, NAT/RING3, PBX, and RXR appear to have been duplicated around the time of vertebrate emergence, supporting the idea that they were duplicated simultaneously at that time. Another group of genes that includes NOTCH and HSP appear to have diverged long before that time. A comparison of the physical maps of these two regions revealed that the genes which duplicated in the same period were arranged in almost the same order in the two regions, with the assumption of a few chromosomal rearrangements. We propose a possible model for the evolution of these regions, taking into account the molecular mechanisms of regional duplication, gene duplication, translocation, and inversion. We also propose that a comparative mapping of paralogous genes within the human genome would be useful for identifying new genes.
 ...
PMID:Evolutionary significance of intra-genome duplications on human chromosomes. 946 76

RBL-2H3 rat basophilic leukemia cells were homogenized and fractionated. A fraction F3 obtained by differential centrifugation was 6-fold enriched in [3H]-inositol 1,4,5-trisphosphate (InsP3) binding activity, while the NADH-cytochrome c oxidoreductase and sulphatase-C activities were only 3.8- and 2.9-fold enriched, respectively. Furthermore, the three InsP3 receptor (InsP3R) isoforms, two sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) isoforms (2b and 3) as well as four Ca2+ binding proteins (calreticulin, calnexin, protein disulfide isomerase (PDI) and BiP), were present in this fraction. Fraction F3 was, therefore, further purified on a discontinuous sucrose density gradient, and the 3 resulting fractions were analyzed. The InsP3 binding sites were distributed over the gradient and did not co-migrate with the RNA. We examined the relative content of the three InsP3R isoforms, of both SERCA2b and 3, as well as that of the four Ca2+ binding proteins in fraction F3 and the sucrose density gradient fractions. InsP3R-1 and InsP3R-2 showed a similar distribution, with the highest level in the light and intermediate density fractions. InsP3R-3 distributed differently, with the highest level in the intermediate density fraction. Both SERCA isoforms distributed similarly to InsP3R-1 and InsP3R-2. SERCA3 was present at a very low level in the high density fraction. Calreticulin and BiP showed a pattern similar to that of InsP3R-1 and InsP3R-2 and the SERCAs. PDI was clearly enriched in the light density fraction while calnexin was broadly distributed. These results indicate a heterogeneous distribution of the three InsP3R isoforms, the two SERCA isoforms and the four Ca2+ binding proteins investigated. This heterogeneity may underlie specialization of the Ca2+ stores and the subsequent initiation of intracellular Ca2+ signals.
 ...
PMID:Distribution of inositol 1,4,5-trisphosphate receptor isoforms, SERCA isoforms and Ca2+ binding proteins in RBL-2H3 rat basophilic leukemia cells. 950 97

We previously demonstrated that mink cells undergo apoptosis after MCF13 murine leukemia virus (MLV) infection. In this study, we observed that virus-infected mink epithelial cells had significantly larger amounts of steady-state levels of MCF13 MLV envelope precursor protein (gPr80(env)) than did Mus dunni fibroblasts, which are resistant to virus-induced cytopathicity. Infection of mink cells with the noncytopathic NZB-9 MLV did not result in the accumulation of gPr80(env). MCF13 MLV infection of mink cells produced low cell surface expression of envelope glycoprotein and less efficient spread of infectious virus. Western blot analysis of mink epithelial cells infected with MCF13 MLV showed an increase in GRP78/BiP, which was not observed for either mink cells infected with NZB-9 MLV or M. dunni fibroblasts infected with MCF13 MLV. MCF13 MLV infection of mink cells also resulted in a significant upregulation of CHOP/GADD153. These results indicate that the accumulation of MCF13 MLV gPr80(env) triggers endoplasmic reticulum stress, which may mediate apoptosis in mink epithelial cells.
 ...
PMID:Mink epithelial cell killing by pathogenic murine leukemia viruses involves endoplasmic reticulum stress. 1547 49

The pro-oxidant effect of L-ascorbic acid (LAA) is toxic to leukemia cells. LAA induces the oxidation of glutathione to its oxidized form (GSSG) and this is followed by a concentration-dependent H(2)O(2) accumulation, which occurs in parallel to the induction of apoptosis. To identify early protein targets of LAA in leukemia cells, we used a differential proteomics approach in NB4 human leukemia cells treated with 0.5 mM of LAA for 30 min. This exposure was determined to efficiently block cellular proliferation and to activate oxidative stress-inducible apoptosis. We identified nine proteins that sensitively reacted to LAA treatment by using two-dimensional (2-D) gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight-MS. A subunit of protein-disulfide isomerase (a thiol/disulfide exchange catalyst) and immunoglobulin-heavy-chain binding protein (BiP, identical to Hsp70 chaperone) showed quantitative expression profile differences. A myeloid leukemia associated antigen protein (a tropomyosin isoform) showed changes in pI as a result of phosphorylation. Our studies demonstrate for the first time that the addition of LAA to cells results in an immediate change in the intracellular thiol/disulfide condition and that this includes an increase in the GSH oxidation with changes in the superfamily of thiol/disulfide exchange catalysts. These results suggest that LAA oxidizes intracellular reduced glutathione and modulates disulfide bond formation in proteins.
 ...
PMID:A proteomic approach to the identification of early molecular targets changed by L-ascorbic acid in NB4 human leukemia cells. 1692 50

Trichosanthin (TCS), a traditional Chinese medicine, exerts antitumor activities by inducing apoptosis in many different tumor cell lines. However, the mechanisms remain obscure. The present study focused on various caspase pathways that may be involved in TCS-induced apoptosis in leukemia HL-60 cells. Key caspases in both intrinsic and extrinsic pathways including caspase-8, -9 and -3 were activated upon TCS treatment. Additionally, TCS treatment induced upregulation of BiP and CHOP and also activated caspase-4, which for the first time strongly supported the involvement of endoplasmic reticulum stress pathway in TCS-induced apoptosis. Interestingly, although caspase-8 was activated, Fas/Fas ligand pathway was not involved as evidenced by a lack of induction of Fas or Fas ligand and a lack of inhibitory effect of anti-Fas blocking antibody on TCS-induced apoptosis. Instead, caspase-8 was activated in a caspase-9 and -4 dependent manner. The involvement of mitochondria was demonstrated by the reduction of mitochondrial membrane potential and release of cytochrome c and Smac besides the activation of caspase-9. Further investigation confirmed that caspase-3 was the major executioner caspase downstream to caspase-9, -4 and -8. Taken together, our results suggested that TCS-induced apoptosis in HL-60 cells was mainly mediated by mitochondrial and ER stress signaling pathways via caspase-3.
 ...
PMID:Trichosanthin induced apoptosis in HL-60 cells via mitochondrial and endoplasmic reticulum stress signaling pathways. 1757 May 95

Recent studies have suggested that neuronal apoptosis in cerebral ischemia could arise from dysfunction of endoplasmic reticulum (ER) and mitochondria. B-cell lymphoma/leukemia-2 gene (Bcl-2) has been described as an inhibitor both in programmed cell death (PCD) and ER dysfunction during apoptosis, and the Bcl-2 family play a key role in regulating the PCD, both locally at the ER and from a distance at the mitochondrial membrane. However, its signal pathways and concrete mechanisms in endoplasmic reticulum-initiated apoptosis remain incompletely understood. We therefore investigate whether ischemia/reperfusion (I/R) causes neuronal apoptosis in part via cross-talk between ER and mitochondria or not, and how the overexpression of Bcl-2 prevents this form of cell death. Here we show that analogous I/R-induced cell death occurs consequent to interactions of ER stress and mitochondrial death pathways. The participation of the mitochondrial pathway was demonstrated by the release of cytochrome C (cyt C) from mitochondrial into cytoplasmic fractions and caspase-9 cleavage. The involvement of ER stress was further supported by the observable increase of glucose-regulated protein 78(GRP78)/BiP expression and caspase-12 activity. Furthermore, prior to these changes, swelling of the ER lumen and dissociation of ribosomes from rough ER were detected by electron microscopy. Bcl-2 overexpression inhibits the release of cyt C and the activation of caspase-9/-8/-3 but not caspase-12 based on the results of Western blot. These suggest that cross-talk between ER and mitochondria participate in neuronal damage after ischemia/reperfusion. Bcl-2 overexpression could suppress I/R-induced neuronal apoptosis via influencing mitochondrial integrity.
 ...
PMID:The protection of Bcl-2 overexpression on rat cortical neuronal injury caused by analogous ischemia/reperfusion in vitro. 1872 55

A small group of ecotropic murine retroviruses cause a spongiform neurodegenerative disease manifested by tremor, paralysis, and wasting. The neurovirulence of these viruses has long been known to be determined by the sequence of the viral envelope protein, although the nature of the neurotoxicity remains to be clarified. Studies on the neurovirulent viruses FrCas(NC) and Moloney murine leukemia virus ts1 indicate that the nascent envelope protein misfolds, is retained in the endoplasmic reticulum (ER), and induces an unfolded protein response. In the present study we constructed a series of viruses with chimeric envelope genes containing segments from virulent and avirulent retroviruses. Each of the viruses studied was highly neuroinvasive but differed in the severity of the neurological disease they induced. Only viruses that contained the receptor-binding domain (RBD) of the neurovirulent virus induced neurological disease. Likewise, only viruses containing the RBD of the neurovirulent virus exhibited increased binding of the ER chaperone BiP to the envelope precursor protein and induced the unfolded protein response. Thus, the RBD determined both neurovirulence and folding instability. Among viruses carrying the neurovirulent RBD, the severity of the disease was increased when envelope sequences from the neurovirulent virus outside the RBD were also present. Interestingly, these sequences appeared to further increase the degree of folding instability (BiP binding) of the viral envelope protein. These results provide strong support for the hypothesis that this spongiform neurodegenerative disease represents a virus-induced protein folding disorder.
 ...
PMID:The degree of folding instability of the envelope protein of a neurovirulent murine retrovirus correlates with the severity of the neurological disease. 1933 54

The unfolded protein response (UPR) is an evolutionarily conserved mechanism to allow cells to adapt to stress targeting the endoplasmic reticulum (ER). Induction of ER chaperone GRP78/BiP increases protein folding capacity; as such it represents a major survival arm of UPR. Considering the central importance of the UPR in regulating cell survival and death, evidence is emerging that cells evolve feedback regulatory pathways to modulate the key UPR executors, however, the precise mechanisms remain to be elucidated. Here, we report the fortuitous discovery of GRP78va, a novel isoform of GRP78 generated by alternative splicing (retention of intron 1) and alternative translation initiation. Bioinformatic and biochemical analyses revealed that expression of GRP78va is enhanced by ER stress and is notably elevated in human leukemic cells and leukemia patients. In contrast to the canonical GRP78 which is primarily an ER lumenal protein, GRP78va is devoid of the ER signaling peptide and is cytosolic. Through specific knockdown of endogenous GRP78va by siRNA without affecting canonical GRP78, we showed that GRP78va promotes cell survival under ER stress. We further demonstrated that GRP78va has the ability to regulate PERK signaling and that GRP78va is able to interact with and antagonize PERK inhibitor P58(IPK). Our study describes the discovery of GRP78va, a novel cytosolic isoform of GRP78/BiP, and the first characterization of the modulation of UPR signaling via alternative splicing of nuclear pre-mRNA. Our study further reveals a novel survival mechanism in leukemic cells and other cell types where GRP78va is expressed.
 ...
PMID:Regulation of PERK signaling and leukemic cell survival by a novel cytosolic isoform of the UPR regulator GRP78/BiP. 1971 40

The rapid proliferation of cancer cells mandates a high protein turnover. The endoplasmic reticulum (ER) is intimately involved in protein processing. An accumulation of unfolded or misfolded proteins in the ER leads to a cascade of transcriptional and translational events collectively called the unfolded protein response (UPR). Protein disulfide isomerase (PDI) is one of the most abundant ER proteins and maintains a sentinel function in organizing accurate protein folding. Treatment of cells with O(2)-[2,4-dinitro-5-(N-methyl-N-4-carboxyphenylamino)phenyl]1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (PABA/NO) resulted in a dose-dependent increase in intracellular nitric oxide that caused S-glutathionylation of various proteins. Within 4 h, PABA/NO activated the UPR and led to translational attenuation as measured by the phosphorylation and activation of the ER transmembrane kinase, pancreatic ER kinase, and its downstream effector eukaryotic initiation factor 2 in human leukemia (HL60) and ovarian cancer cells (SKOV3). Cleavage of the transcription factor X-box protein 1 and transcriptional activation of the ER resident proteins BiP, PDI, GRP94, and ERO1 (5- to 10-fold induction) also occurred. Immunoprecipitation of PDI showed that whereas nitrosylation was undetectable, PABA/NO treatment caused S-glutathionylation of PDI. Mass spectroscopy analysis showed that single cysteine residues within each of the catalytic sites of PDI had a mass increase [+305.3 Da] consistent with S-glutathionylation. Circular dichroism confirmed that S-glutathionylation of PDI results in alterations in the alpha-helix content of PDI and is concurrent with inhibition of its isomerase activity. Thus, it appears that S-glutathionylation of PDI is an upstream signaling event in the UPR and may be linked with the cytotoxic potential of PABA/NO.
 ...
PMID:Nitrosative stress-induced s-glutathionylation of protein disulfide isomerase leads to activation of the unfolded protein response. 1977 42


1 2 Next >>