scholarly journals Autophagy and apoptosis are regulated by stress on Bcl2 by AMBRA1 in the endoplasmic reticulum and mitochondria

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Bojie Yang ◽  
Quansheng Liu ◽  
Yuanhong Bi
Keyword(s):  
Endoplasmic Reticulum ◽  
B Cell ◽  
Cell Fate ◽  
Cell Lymphoma ◽  
Feedback Regulation ◽  
B Cell Lymphoma ◽  
Regulatory Mechanisms ◽  
Time Duration ◽  
Cell Fate Decisions ◽  
Different Levels

Abstract Background Autophagy and apoptosis are two important physiological processes that determine cell survival or death in response to different stress signals. The regulatory mechanisms of these two processes share B-cell lymphoma-2 family proteins and AMBRA1, which are present in both the endoplasmic reticulum and mitochondria. B-cell lymphoma-2 family proteins sense different stresses and interact with AMBRA1 to regulate autophagy and apoptosis, which are respectively mediated by Beclin1 and Caspases. Therefore, we investigated how different levels of stress on B-cell lymphoma-2 family proteins that bind to AMBRA1 in the endoplasmic reticulum and mitochondria regulate the switch from autophagy to apoptosis. Methods In this paper, we considered the responses of B-cell lymphoma-2 family proteins, which bind to AMBRA1 in both the endoplasmic reticulum and mitochondria, to two different levels of stress in a model originally proposed by Kapuy et al. We investigated how these two stress levels affect the transition from autophagy to apoptosis and their effects on apoptosis activation over time. Additionally, we analyzed how the feedback regulation in this model affects the bifurcation diagrams of two levels of stress and cell fate decisions between autophagy and apoptosis. Results Autophagy is activated for minor stress in mitochondria regardless of endoplasmic reticulum stress, while apoptosis is activated for only significant stress in mitochondria. Apoptosis is only sensitive to mitochondria stress. The time duration before apoptosis activation is longer in the presence of high AMBRA1 levels with high endoplasmic reticulum and mitochondria stress. AMBRA1 can compete with B-cell lymphoma-2 family proteins to bind and activate Beclin1 and thus promote the autophagy process for a long time before apoptosis. Furthermore, apoptosis is prone to occur with increasing activation of Caspases, inactivation of Beclin1-A and the Michaelis constant of Caspases. Conclusion A novel mathematical model has been developed to understand the complex regulatory mechanisms of autophagy and apoptosis. Our model may be applied to further autophagy-apoptosis dynamic modeling experiments and simulations.

From Signalosome to Enhanceosome: The Translocation of CD40 from Membrane to Nucleus Involves Multiple Mechanisms

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3781-3781
Author(s):  
Hai-Jun Zhou ◽  
Archie Tamayo ◽  
Lan Pham ◽  
Yen-Chiu Lin-Lee ◽  
Richard J. Ford
Keyword(s):  
Endoplasmic Reticulum ◽  
B Cell ◽  
B Lymphocytes ◽  
Nuclear Localization ◽  
Cell Nucleus ◽  
Nuclear Pore Complex ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Nuclear Pore ◽  
Lymphoma Cells

Abstract CD40 plays important roles in the proliferation, survival and differentiation of lymphocytes. Constitutively active CD40 recruits TRAFs and IKKs within the lipid rafts to form a signalosome that mediates pivotal downstream proliferation and survival mechanisms involving NF-kB. Recently, we have reported that nuclear localization of CD40, through its interaction with c-Rel, promotes growth, cell cycle progression and survival in large B cell lymphoma. Our studies have opened a new paradigm in the functional role of CD40 in non-Hodgkin lymphomas of B cell origin (NHL-B). However, the mechanism about how CD40 enters nuclear still remains elusive. In this study, we show that CD40 ligation enhances its nuclear accumulation with activation of c-Rel in both normal B-lymphocytes and B cell lymphoma cells with cell fractionation assay and con-focal microscopy. Over-expression of c-Rel in B cell lymphoma cells drives CD40 into cell nucleus. We hypothesize that the route CD40 enters nucleus may involve endosome-endoplasmic reticulum-nuclear pore complex. Indeed, further studies show CD40 co-localizes with endosome marker-EEA1 and endoplasmic reticulum marker-Sec61. Furthermore, our co-immunoprecipitation assay has demonstrated CD40 interacts with Sec61. CD40 also co-localizes and immuno-precipitates with nuclear pore complex (NPC) proteins-NUP62 in normal B-lymphocytes and B lymphoma cells, which suggests NPC proteins may facilitate the nuclear translocation of CD40 protein. Overall, our study suggests that translocation of CD40 into cell nucleus involves multiple pathways. Blocking nuclear localization may modulate the function of CD40 in lymphoma cells; which could provide a new-targeted therapeutic approach for lymphoma therapy.

scholarly journals Gain-of-Function Mutations and Copy Number Increases of Notch2 in Diffuse Large B-Cell Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 695-695
Author(s):  
Suk Young Lee ◽  
Keiki Kumano ◽  
Kumi Nakazaki ◽  
Masashi Sanada ◽  
Go Yamamoto ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Notch Signaling ◽  
Cell Fate ◽  
Copy Number ◽  
Cell Lymphoma ◽  
Gene Mutations ◽  
B Cell Lymphoma ◽  
Gain Of Function ◽  
Large B Cell

Abstract [Background] Signaling through the Notch receptors, triggered by the binding of ligands expressed on neighboring cells, has a key role in determining cell fate in a variety of cell lineages, including lymphocytes. The physiologic roles of two of the four mammalian Notch genes, Notch1 and Notch2, have been clarified in mouse models. Notch1 is preferentially expressed in immature T cells and is essential for specification of early hematopoietic progenitors toward the T-cell fate and for early T-cell development in the thymus. In contrast, Notch2 is preferentially expressed in mature B cells and is required for the generation of a mature B-cell subset, known as splenic marginal zone B (MZB) cells. Deregulation of Notch1 function results in the development of T-cell acute lymphoblastic leukemia (T-ALL) in a number of mouse experimental models, and more importantly, more than 50% of childhood and 30% to 40% of adult human T-ALL cases carry Notch1 mutations that lead to deregulated activation of Notch signaling, indicating that accelerated Notch signaling contributes to the development of human neoplasms. [Results and Discussion] We screened Notch2 gene mutations at the heterodimerization and PEST domains in 109 B-cell lymphoma samples, and found mutations in 5 samples, all of which were diffuse large B-cell lymphomas (DLBCL; in DLBCL, 5 of 63 samples, ∼8%). These mutations lead to partial or complete deletion of the PEST domain, or a single amino acid substitution at the C-terminus of Notch2 protein. All five DLBCL cases with Notch2 mutations were uniformly immunohistochemically negative for CD10 and positive for BCL6 and MUM-1, whereas only 10 out of 24 Notch2 mutation-negative subjects showed this staining pattern. This observation might imply a link between Notch2 mutations and a fraction of non-germinal center B-cell-like DLBCL (non-GCB-DLBCL), according to the immunohistchemistry-based DLBCL subclassification. Interestingly, high-density oligonucleotide microarray analysis revealed that two of the five Notch2 mutation-carrying samples had an increased copy number of the mutated Notch2 allele, and in another sample of the five the total copy number of the Notch2 allele was increased. Furthermore, in the Notch activation-sensitive luciferase reporter assay in vitro, mutant Notch2 receptors showed increased activity compared with wild-type Notch2. These findings implicate Notch2 gain-of-function mutations in the pathogenesis of a subset of B-cell lymphomas, and suggest broader roles for Notch gene mutations in human cancers.

scholarly journals Modulation of Ca2+ Signaling by Anti-apoptotic B-Cell Lymphoma 2 Proteins at the Endoplasmic Reticulum–Mitochondrial Interface

2017 ◽  
Vol 7 ◽  
Author(s):  
Tim Vervliet ◽  
Eva Clerix ◽  
Bruno Seitaj ◽  
Hristina Ivanova ◽  
Giovanni Monaco ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma

scholarly journals Interleukin 10 Plays an Important Role in Neonatal Rats with Hypoxic-Ischemia Associated with B-Cell Lymphoma 2 and Endoplasmic Reticulum Protein 29

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Xue Bai ◽  
Liu-Lin Xiong ◽  
Chang-Le Fang ◽  
Hao-Li Zhou ◽  
Lu-Lu Xue ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
B Cell ◽  
Cell Lymphoma ◽  
Quantitative Polymerase Chain Reaction ◽  
B Cell Lymphoma ◽  
Interleukin 10 ◽  
Mrna Levels ◽  
Artery Ligation ◽  
Neuroprotective Effects ◽  
Endoplasmic Reticulum Protein

Interleukin 10 (IL-10) is a synthetic inhibitor of human cytokines with immunomodulatory and anti-inflammatory effects. This study was designed to investigate the expression variation of IL-10 in the multiple sites including cortex, hippocampus, and lung tissues of neonatal hypoxic-ischemic (HI) rats and explore the crucial role of IL-10 in alleviating HI brain damage. In this study, neonatal Sprague-Dawley rats were subjected to the right common carotid artery ligation, followed by 2 h of hypoxia. The expression of IL-10 in the cortex, hippocampus, and lung tissues was measured with immunohistochemistry, real-time quantitative polymerase chain reaction (RT-qPCR), and western blot (WB). Immunofluorescence double staining was performed to observe the localization of IL-10 in neurons and astrocytes. Moreover, not-targeting and targeting IL-10 siRNA lentivirus vectors were injected into the rats of the negative control (NC) and IL-10 group, respectively, and the mRNA levels of B-cell lymphoma 2 (Bcl-2) and endoplasmic reticulum protein 29 (ERp29) were detected by RT-qPCR following IL-10 silence. The results demonstrated that the IL-10 expression was markedly increased after HI and IL-10 were colocalized with neurons and astrocytes which were badly injured by HI insult. In addition, Bcl-2 and ERp29 were remarkably decreased following IL-10 mRNA interference compared with the NC group. Our findings revealed that IL-10 exerted its antiapoptotic and neuroprotective effects by regulating the expression of Bcl-2 and ERp29, indicating that IL-10 may be a promising molecule target for HIE treatment.

Abstract #812: Primary B Cell Lymphoma of Pituitary Presenting with Hypopituitarism and Dual Natremic Abnormalities

2015 ◽  
Vol 21 ◽  
pp. 153-154
Author(s):  
Abhijana Karunakaran ◽  
Kadapalakere Reddy ◽  
Anshu Alok ◽  
Manav Batra ◽  
Ajay Chaudhuri ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma
Sign in / Sign up

Export Citation Format

Share Document