Faculty Opinions recommendation of Multiple signaling pathways promote B lymphocyte stimulator dependent B-cell growth and survival.

2008 ◽  
Author(s):  
E Charles Snow
Keyword(s):  
Cell Growth ◽  
B Cell ◽  
Signaling Pathways ◽  
B Lymphocyte ◽  
Growth And Survival ◽  
B Lymphocyte Stimulator ◽  
Multiple Signaling ◽  
Cell Growth And Survival

scholarly journals Multiple signaling pathways promote B lymphocyte stimulator–dependent B-cell growth and survival

Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 750-760 ◽  
Author(s):  
Robert T. Woodland ◽  
Casey J. Fox ◽  
Madelyn R. Schmidt ◽  
Peter S. Hammerman ◽  
Joseph T. Opferman ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Growth ◽  
B Cell ◽  
Signaling Pathways ◽  
B Lymphocyte ◽  
Marginal Zone B Cells ◽  
Growth And Survival ◽  
B Lymphocyte Stimulator ◽  
Cell Growth And Survival

We investigated the mechanism by which B lymphocyte stimulator (BLyS)/BAFF, a tumor necrosis factor superfamily ligand, promotes B-cell survival and resistance to atrophy. BLyS stimulation activates 2 independent signaling pathways, Akt/mTOR and Pim 2, associated with cell growth and survival. BLyS blocks the cell volume loss (atrophy) that freshly isolated B cells normally undergo when maintained in vitro while concurrently increasing glycolytic activity and overall metabolism. This atrophy resistance requires Akt/mTOR. We used a genetic approach to resolve the contributions of Akt/mTOR and Pim kinase pathways to BLyS-mediated survival. Pim 2–deficient B cells are readily protected from death by BLyS stimulation, but this protection is completely abrogated by treatment with the mTOR inhibitor rapamycin. Furthermore, rapamycin treatment in vivo significantly reduces both follicular and marginal zone B cells in Pim-deficient but not healthy hosts. BLyS-dependent survival requires the antiapoptotic protein Mcl-1. Mcl-1 protein levels rise and fall in response to BLyS addition and withdrawal, respectively, and conditional deletion of the Mcl-1 gene renders B cells refractory to BLyS-mediated protection. Because BlyS is required for the normal homeostasis of all B cells, these data suggest a therapeutic strategy simultaneously inhibiting mTOR and Pim 2 could target pathogenic B cells.

Recruitment of the SWI/SNF Chromatin Remodeling Complex by NFATc1 in the Transcriptional Regulation of the C-MYC Oncogene in Aggressive B-Cell Lymphomas

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3808-3808 ◽  
Author(s):  
Lan V. Pham ◽  
Archito Tamayo ◽  
Hai-Jun Zhou ◽  
Yen-Chiu Lin-Lee ◽  
Lingchen Fu ◽  
...  
Keyword(s):  
Cell Growth ◽  
Protein Expression ◽  
B Cell ◽  
Binding Site ◽  
Chromatin Remodeling ◽  
B Cell Lymphoma ◽  
Lymphoma Cell ◽  
Growth And Survival ◽  
Myc Oncogene ◽  
Cell Growth And Survival

Abstract The NFAT (nuclear factor of activated T-cells) family of transcription factors functions as integrators of multiple signaling pathways by binding to chromatin in combination with other transcription factors and coactivators to regulate genes central for cell growth and survival in hematopoietic cells. Recent experimental evidence has implicated the calcineurin/NFAT signaling pathway for involvement in the pathogenesis of various malignancies, including large B-cell lymphoma (LBCL), a non-Hodgkin’s lymphoma subgroup that is generally responsive to conventional cancer therapies (R-CHOP), but relapse is common that subsequently leads to therapeutic resistance. Although we have shown previously that NFAT family member NFATc1 is constitutively activated and has the ability to maintain cell growth and survival in LBCL cell lines and primary cells, the molecular mechanism(s) underlying how NFATc1 regulates cell growth and survival in LBCL is still unclear. In this study, we demonstrate that the well-known oncogene c-myc is transcriptionally regulated by the transcription factor NFATc1 in LBCL, through a chromatin remodeling mechanism that involves the recruitment of the SWI/SNF chromatin-remodeling complex. In aggressive B-cell lymphoma cell lines, c-myc oncogene protein expression was shown to correlate with NFATc1 protein expression. We further showed that NFATc1 binds to a specific DNA binding element within the proximal c-myc promoter and up-regulates c-myc transcription. The SWI/SNF proteins Brg-1 and Brm, chromatin-remodeling proteins that utilize ATP hydrolysis for energy to modify chromatin structure in order to regulate gene expression, also were shown to bind to the NFAT binding site on the c-myc promoter. Confocal microscopic analysis showed that NFATc1 colocalizes with Brg-1, and co-immunoprecipitation assays showed that Brg-1 interacts with NFATc1. Both proteins interact with the c-myc promoter within the NFAT binding site, as demonstrated by chromatin-immunoprecipitation (ChIP) analysis. Induction of a constitutively active mutant of NFATc1 (caNFATc1) in an NFATc1 negative lymphoma cell line induces c-myc protein expression. Constitutively active NFATc1 also enhances Brg-1 binding to the c-myc promoter when analyzed by ChIP-qPCR assays, suggesting that NFATc1 recruits Brg-1 to the NFAT binding site in the c-myc promoter. Down-regulation of NFATc1 by chemical inhibitors (FK-506) or by validated shRNA of NFATc1, inhibited c-myc protein expression and in-vitro lymphoma cell growth. Our data indicates a novel control mechanism for the transcriptional regulation of c-myc in the pathophysiology of aggressive lymphoma B cells and suggests that targeting NFATc1 could have therapeutic value.

Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival

Blood ◽  
2004 ◽  
Vol 103 (2) ◽  
pp. 689-694 ◽  
Author(s):  
Anne J. Novak ◽  
Jaime R. Darce ◽  
Bonnie K. Arendt ◽  
Brandon Harder ◽  
Kathy Henderson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
B Lymphocyte ◽  
Regulatory Elements ◽  
Proliferative Potential ◽  
Altered Expression ◽  
Growth And Survival ◽  
B Cell Maturation ◽  
Number Of Patients ◽  
B Lymphocyte Stimulator

Abstract Multiple myeloma (MM) is a progressive disease that is thought to result from multiple genetic insults to the precursor plasma cell that ultimately affords the tumor cell with proliferative potential despite its differentiated phenotype and resistance to undergoing apoptosis. Altered expression of antiapoptotic factors as well as growth factors have been described in a significant number of patients. However, the key regulatory elements that control myeloma development and progression remain largely undefined. Because of the knowledge that B-lymphocyte stimulator (BLyS), a tumor necrosis factor (TNF) family member shown to be critical for maintenance of normal B-cell development and homeostasis, promotes the survival of malignant B cells, we began a coordinated study of BLyS and its receptors in MM. All MM cells studied expressed one or more of 3 known receptors (B-cell maturation antigen [BCMA], transmembrane activator and CAML interactor [TACI], and B-cell activating factor receptor [BAFF-R]) for BLyS; however, the pattern of expression was variable. Additionally, we provide evidence that BLyS can modulate the proliferative capacity and survival of MM cells. Finally, we provide evidence that BLyS is expressed by MM cells and is present in the bone marrow of patients with MM. Expression of BCMA, TACI, and BAFF-R by MM taken together with the ability of BLyS to support MM cell growth and survival has exciting implications because they may be potential therapeutic targets.

scholarly journals Signaling Pathway Mediating Myeloma Cell Growth and Survival

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 216
Author(s):  
Teru Hideshima ◽  
Kenneth C. Anderson
Keyword(s):  
Cell Growth ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Treatment Strategies ◽  
Myeloma Cell ◽  
Growth And Survival ◽  
Signal Transduction Networks ◽  
Accessory Cells ◽  
Different Types ◽  
Multiple Signaling

The multiple myeloma (MM) bone marrow (BM) microenvironment consists of different types of accessory cells. Both soluble factors (i.e., cytokines) secreted from these cells and adhesion of MM cells to these cells play crucial roles in activation of intracellular signaling pathways mediating MM cell growth, survival, migration, and drug resistance. Importantly, there is crosstalk between the signaling pathways, increasing the complexity of signal transduction networks in MM cells in the BM microenvironment, highlighting the requirement for combination treatment strategies to blocking multiple signaling pathways.

TRAF6 and C-myb Show Novel Functions in the Nucleus of Lymphoma B Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2376-2376 ◽  
Author(s):  
Lan V. Pham ◽  
Yen-Chiu Lin-Lee ◽  
Hai-Jun Zhou ◽  
Archito T. Tamayo ◽  
Linda C. Yoshimura ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Growth ◽  
B Cell ◽  
Cell Survival ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Tnf Receptor ◽  
Growth And Survival ◽  
Survival Pathways ◽  
Interfering Rna

Abstract The tumor necrosis factor (TNF) family (TNF-R; CD40; BAFF-R) plays a key role in neoplastic as well as normal B cell growth and survival mechanisms. TNF receptor-associated factor-6 (TRAF-6) is an adapter molecule that regulates several important signaling pathways critical for cell growth and cell survival. It is a member of seven closely related TRAF proteins that serve as signaling molecules, coupling to TNF-receptor superfamily to intracellular signaling, particularly in the CD40 Signalosome. TRAF6 has shown to be over-expressed and play an important role in cell growth and cell survival through the activation of the key transcription factor NF-kB in aggressive non-Hodgkin’s lymphoma B cells (NHL-B), common B cell neoplasm that have been increasing in recent years. Although much of TRAF-6 functions have focused primarily as an adaptor molecule in signaling pathways in the cytoplasm, the role of TRAF-6 in other cellular compartments has not been investigated. Here, we demonstrate, by confocal microscopy as well as cellular fractionation studies that TRAF-6 resides not only in the cytoplasm but also in the nucleus of lymphoma B cells. Immunoprecipitation studies show that TRAF6 is auto-ubiquitinated in the cytoplasm but not in the nucleus, suggesting that nuclear TRAF6 functions differently than cytoplasmic TRAF6. Chromatin immunoprecipitation (ChiP) cloning assays using anti-TRAF6 polyclonal antibody reveal over 200 clones, one of which contains a 130 bp fragment belonging to the proximal 5′ end of the c-myb oncogene promoter. Further experiments demonstrate that nuclear TRAF6 co-localized with SUMO1 and c-myb, suggesting that TRAF-6 may enter the nucleus through SUMO1 interaction and serve as an E3 sumo ligase, in addition to its known adapter role in cytoplasmic signaling. Over-expression studies show that TRAF6 enhances c-myb sumoylation in lymphoma B cells, where this oncogene is over-expressed. C-myb correlates with TRAF6 protein and mRNA expressions in NHL-B cells, suggesting that TRAF6 may be involved in the modulation of c-myb expression through sumoylation, regulating key genes that are regulated by c-myb. Small interfering RNA (siRNA) targeting c-myb results in inhibition of lymphoma cell survival, suggesting that SUMO1/TRAF6/c-myb interactions are important in cell survival pathways in aggressive NHL-B. Such pathways could represent novel targets for the development of therapeutic agents for aggressive B cell lymphomas.

scholarly journals Molecular mechanisms contributing to glutamine-mediated intestinal cell survival

2007 ◽  
Vol 293 (6) ◽  
pp. G1262-G1271 ◽  
Author(s):  
Shawn D. Larson ◽  
Jing Li ◽  
Dai H. Chung ◽  
B. Mark Evers
Keyword(s):  
Cell Growth ◽  
Signaling Pathways ◽  
Dna Fragmentation ◽  
Molecular Mechanisms ◽  
Intestinal Cell ◽  
Protective Mechanism ◽  
Growth And Survival ◽  
Phosphorylated Akt ◽  
Glutamine Deprivation ◽  
Cell Growth And Survival

Glutamine, the most abundant amino acid in the bloodstream, is the preferred fuel source for enterocytes and plays a vital role in the maintenance of mucosal growth. The molecular mechanisms regulating the effects of glutamine on intestinal cell growth and survival are poorly understood. Here, we show that addition of glutamine (1 mmol/l) enhanced rat intestinal epithelial (RIE)-1 cell growth; conversely, glutamine deprivation increased apoptosis as noted by increased DNA fragmentation and caspase-3 activity. To delineate signaling pathways involved in the effects of glutamine on intestinal cells, we assessed activation of extracellular signal-related kinase (ERK), protein kinase D (PKD), and phosphatidylinositol 3-kinase (PI3K)/Akt, which are important pathways in cell growth and survival. Addition of glutamine activated ERK and PKD in RIE-1 cells after a period of glutamine starvation; inhibition of ERK, but not PKD, increased cell apoptosis. Conversely, glutamine starvation alone increased phosphorylated Akt; inhibition of Akt enhanced RIE-1 cell DNA fragmentation. The role of ERK was further delineated using RIE-1 cells stably transfected with an inducible Ras. Apoptosis was significantly increased following ERK inhibition, despite Ras activation. Taken together, these results identify a critical role for the ERK signaling pathways in glutamine-mediated intestinal homeostasis. Furthermore, activation of PI3K/Akt during periods of glutamine deprivation likely occurs as a protective mechanism to limit apoptosis associated with cellular stress. Importantly, our findings provide novel mechanistic insights into the antiapoptotic effects of glutamine in the intestine.

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