scholarly journals New insights into plasma cell differentiation and unfolded protein response in multiple myeloma: role of DEPTOR and IRE1

2020 ◽  
Author(s):  
Dalia Quwaider
Keyword(s):  
Multiple Myeloma ◽  
Cell Differentiation ◽  
Unfolded Protein Response ◽  
Plasma Cell ◽  
Plasma Cell Differentiation ◽  
Unfolded Protein ◽  
Protein Response

Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1

10.1038/ni907 ◽  
2003 ◽  
Vol 4 (4) ◽  
pp. 321-329 ◽  
Author(s):  
Neal N. Iwakoshi ◽  
Ann-Hwee Lee ◽  
Prasanth Vallabhajosyula ◽  
Kevin L. Otipoby ◽  
Klaus Rajewsky ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
Unfolded Protein Response ◽  
Plasma Cell ◽  
Plasma Cell Differentiation ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

The Human Plasma Cell Gene Expression Program.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3242-3242
Author(s):  
John De Vos ◽  
Dirk Hose ◽  
Thierry Reme ◽  
Hartmut Goldschmidt ◽  
Jean-Francois Rossi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Cell Differentiation ◽  
Plasma Cell ◽  
Expression Profile ◽  
Plasma Cells ◽  
Plasma Cell Differentiation ◽  
Unfolded Protein ◽  
The Mean ◽  
Protein Response

Abstract Seven purified peripheral blood memory B-cells (BM), seven in-vitro-generated polyclonal plasmablastic cells (PPC) and seven purified bone marrow mature plasma cells (BMPC) were studied by oligonucleotide microarrays. All samples were obtained from healthy volunteers. The gene expression profiling of these samples was determined with Affymetrix pan genomic U133A + B arrays (44 928 oligonucleotide probesets). We determined that 2313 genes were differentially expressed between these three B cell categories (P 〈 0.01 by a Kruskal-Wallis test and a ratio between two categories 〉 3). These 2313 genes were classified into six categories, according to the expression profile: early plasma cell genes (EPC), late plasma cell genes (LPC), genes lost early during plasma cell differentiation (LEPC), genes lost late during plasma cell differentiation (LLPC), genes upregulated only in plasmablasts (PBO) and genes lost only in plasmablasts (LPBO). As expected, Ig transcripts where essentially classified as EPC. As a corollary, genes involved in protein synthesis or degradation, transmembrane transporters and metabolism genes were overrepresented in EPC genes. Interestingly, genes involved in intercellular communication and extracellular matrix were enriched in LPC, highlighting the fact that mature plasma cells develop tight interactions with the bone marrow environment. Of note, genes involved in cell cycle are upregulated mainly in plasmablasts, whereas antiapoptotic genes are lost in plasmablasts only. Mains genes known to be involved in plasma cell differentiation display an expression profile in agreement with published data, as illustrated for transcription factors in Figure 1, validating this DNA microarray dataset. However most of these 2313 genes have either never been described yet or have no yet been linked to plasma cell differentiation. The description of those genes among our genome whose expression vary most during plasma cell differentiation will be an essential step in understanding the biology of a cell type essential to immune defenses and involved in deadly diseases. Figure 1: Transcription factors involved in plasma cell differentiation. Color indicates the expression profile category. For each gene is given the ratio of the mean expression value in plasma cell samples (PPC and BMPC) to the mean expression value in BM. UPR: Unfolded Protein Response. Figure 1:. Transcription factors involved in plasma cell differentiation. Color indicates the expression profile category. For each gene is given the ratio of the mean expression value in plasma cell samples (PPC and BMPC) to the mean expression value in BM. UPR: Unfolded Protein Response.

scholarly journals The Role of AP-1 Transcription Factors in Plasma Cell Biology and Multiple Myeloma Pathophysiology

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2326
Author(s):  
Fengjuan Fan ◽  
Klaus Podar
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Transcription Factors ◽  
Cell Differentiation ◽  
Plasma Cell ◽  
Cell Biology ◽  
Hematologic Malignancy ◽  
Family Members ◽  
Plasma Cell Differentiation

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the clonal expansion of malignant plasma cells within the bone marrow. Activator Protein-1 (AP-1) transcription factors (TFs), comprised of the JUN, FOS, ATF and MAF multigene families, are implicated in a plethora of physiologic processes and tumorigenesis including plasma cell differentiation and MM pathogenesis. Depending on the genetic background, the tumor stage, and cues of the tumor microenvironment, specific dimeric AP-1 complexes are formed. For example, AP-1 complexes containing Fra-1, Fra-2 and B-ATF play central roles in the transcriptional control of B cell development and plasma cell differentiation, while dysregulation of AP-1 family members c-Maf, c-Jun, and JunB is associated with MM cell proliferation, survival, drug resistance, bone marrow angiogenesis, and bone disease. The present review article summarizes our up-to-date knowledge on the role of AP-1 family members in plasma cell differentiation and MM pathophysiology. Moreover, it discusses novel, rationally derived approaches to therapeutically target AP-1 TFs, including protein-protein and protein-DNA binding inhibitors, epigenetic modifiers and natural products.

scholarly journals Blocking of Transient Receptor Potential Vanilloid 1 (TRPV1) promotes terminal mitophagy in multiple myeloma, disturbing calcium homeostasis and targeting ubiquitin pathway and bortezomib-induced unfolded protein response

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Katia Beider ◽  
Evgenia Rosenberg ◽  
Valeria Dimenshtein-Voevoda ◽  
Yaarit Sirovsky ◽  
Julia Vladimirsky ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Unfolded Protein Response ◽  
Cell Lines ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Unfolded Protein ◽  
Transient Receptor ◽  
Protein Response

Abstract Background Chemoresistance remains a major treatment obstacle in multiple myeloma (MM). Novel new therapies are thus in need. Transient Receptor Potential Vanilloid type 1 (TRPV1) is a calcium-permeable ion channel that has been demonstrated to be expressed in solid tumors. Calcium channels have been shown to be involved in the regulation of cell proliferation, chemoresistance, migration and invasion. The aim of the current study was to evaluate its possible role in MM. Methods Pharmacological inhibitor was used to evaluate the role of TRPV1 in MM cell lines and primary MM cells. Flow cytometry, molecular analysis, fluorescent microscopy, proteomic analysis and xenograft in vivo model of MM with BM involvement were employed to assess the effect of TRPV1 inhibition and decipher its unique mechanism of action in MM. Results TRPV1 was found to be expressed by MM cell lines and primary MM cells. TRPV1 inhibition using the antagonist AMG9810-induced MM cell apoptosis and synergized with bortezomib, overcoming both CXCR4-dependent stroma-mediated and acquired resistance. In accordance, AMG9810 suppressed the expression and activation of CXCR4 in MM cells. TRPV1 inhibition increased mitochondrial calcium levels with subsequent mitochondrial ROS accumulation and depolarization. These effects were reversed by calcium chelation, suggesting the role of calcium perturbations in oxidative stress and mitochondrial destabilization. Furthermore, AMG9810 abolished bortezomib-induced accumulation of mitochondrial HSP70 and suppressed protective mitochondrial unfolded protein response. Proteomics revealed unique molecular signature related to the modification of ubiquitin signaling pathway. Consequently, 38 proteins related to the ubiquitylation machinery were downregulated upon combined bortezomib/AMG9810 treatment. Concomitantly, AMG9810 abolished bortezomib-induced ubiquitination of cytosolic and mitochondrial proteins. Furthermore, bortezomib/AMG9810 treatment induced mitochondrial accumulation of PINK1, significantly reduced the mitochondrial mass and promoted mitochondrial-lysosomal fusion, indicating massive mitophagy. Finally, in a recently developed xenograft model of systemic MM with BM involvement, bortezomib/AMG9810 treatment effectively reduced tumor burden in the BM of MM-bearing mice. Conclusions Altogether, our results unravel the mechanism mediating the strong synergistic anti-MM activity of bortezomib in combination with TRPV1 inhibition which may be translated into the clinic.

scholarly journals Confounding Roles of ER Stress and the Unfolded Protein Response in Skeletal Muscle Atrophy

2021 ◽  
Vol 22 (5) ◽  
pp. 2567
Author(s):  
Yann S. Gallot ◽  
Kyle R. Bohnert
Keyword(s):  
Skeletal Muscle ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Smooth Endoplasmic Reticulum ◽  
Skeletal Muscle Atrophy ◽  
Unfolded Protein ◽  
The Individual ◽  
The Unfolded Protein Response ◽  
Protein Response

Skeletal muscle is an essential organ, responsible for many physiological functions such as breathing, locomotion, postural maintenance, thermoregulation, and metabolism. Interestingly, skeletal muscle is a highly plastic tissue, capable of adapting to anabolic and catabolic stimuli. Skeletal muscle contains a specialized smooth endoplasmic reticulum (ER), known as the sarcoplasmic reticulum, composed of an extensive network of tubules. In addition to the role of folding and trafficking proteins within the cell, this specialized organelle is responsible for the regulated release of calcium ions (Ca2+) into the cytoplasm to trigger a muscle contraction. Under various stimuli, such as exercise, hypoxia, imbalances in calcium levels, ER homeostasis is disturbed and the amount of misfolded and/or unfolded proteins accumulates in the ER. This accumulation of misfolded/unfolded protein causes ER stress and leads to the activation of the unfolded protein response (UPR). Interestingly, the role of the UPR in skeletal muscle has only just begun to be elucidated. Accumulating evidence suggests that ER stress and UPR markers are drastically induced in various catabolic stimuli including cachexia, denervation, nutrient deprivation, aging, and disease. Evidence indicates some of these molecules appear to be aiding the skeletal muscle in regaining homeostasis whereas others demonstrate the ability to drive the atrophy. Continued investigations into the individual molecules of this complex pathway are necessary to fully understand the mechanisms.

scholarly journals A Role for the DnaJ Homologue Scj1p in Protein Folding in the Yeast Endoplasmic Reticulum

1998 ◽  
Vol 143 (4) ◽  
pp. 921-933 ◽  
Author(s):  
Susana Silberstein ◽  
Gabriel Schlenstedt ◽  
Pam A. Silver ◽  
Reid Gilmore
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Physiological Role ◽  
Carboxypeptidase Y ◽  
Reporter Protein ◽  
Unfolded Protein ◽  
A Cell ◽  
The Unfolded Protein Response ◽  
Protein Response

Members of the eukaryotic heat shock protein 70 family (Hsp70s) are regulated by protein cofactors that contain domains homologous to bacterial DnaJ. Of the three DnaJ homologues in the yeast rough endoplasmic reticulum (RER; Scj1p, Sec63p, and Jem1p), Scj1p is most closely related to DnaJ, hence it is a probable cofactor for Kar2p, the major Hsp70 in the yeast RER. However, the physiological role of Scj1p has remained obscure due to the lack of an obvious defect in Kar2p-mediated pathways in scj1 null mutants. Here, we show that the Δscj1 mutant is hypersensitive to tunicamycin or mutations that reduce N-linked glycosylation of proteins. Although maturation of glycosylated carboxypeptidase Y occurs with wild-type kinetics in Δscj1 cells, the transport rate for an unglycosylated mutant carboxypeptidase Y (CPY) is markedly reduced. Loss of Scj1p induces the unfolded protein response pathway, and results in a cell wall defect when combined with an oligosaccharyltransferase mutation. The combined loss of both Scj1p and Jem1p exaggerates the sensitivity to hypoglycosylation stress, leads to further induction of the unfolded protein response pathway, and drastically delays maturation of an unglycosylated reporter protein in the RER. We propose that the major role for Scj1p is to cooperate with Kar2p to mediate maturation of proteins in the RER lumen.

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