Prevention of cytokine withdrawal-induced apoptosis by Mcl-1 requires interaction between Mcl-1 and Bim

2010 ◽  
Vol 88 (5) ◽  
pp. 809-818 ◽  
Author(s):  
Sarwat Jamil ◽  
Shih Wei Wang ◽  
Lise Bondy ◽  
Shadi Mojtabavi ◽  
Vincent Duronio
Keyword(s):  
Normal Growth ◽  
Growth Conditions ◽  
Mitochondrial Pathway ◽  
Hemopoietic Cells ◽  
Primary Bone ◽  
Induced Apoptosis ◽  
Apoptotic Effects ◽  
Mutant Forms ◽  
Pest Region ◽  
Primary Bone Marrow

Growth factor withdrawal from hemopoietic cells results in activation of the mitochondrial pathway of apoptosis. Members of the Bcl-2 family regulate this pathway, with anti-apoptotic members counteracting the effects of pro-apoptotic members. We investigated the effect on Mcl-1 function of mutation at a conserved threonine 163 residue (T163) in its proline, glutamate, serine, and threonine rich (PEST) region. Under normal growth conditions, Mcl-1 half-life increased with alteration of T163 to glutamic acid, but decreased with mutation to alanine. However, both T163 mutants exhibited greater pro-survival effects compared with the wild type, which can be explained by an increased stability of the T163A mutant in cytokine-starved conditions. Both the mutant forms exhibited prolonged binding to pro-apoptotic Bim in cytokine-deprived cells. The extent to which Mcl-1 mutants were able to exert their anti-apoptotic effects correlated with their ability to associate with Bim. We further observed that primary bone marrow derived macrophages survived following cytokine withdrawal as long as Bim and Mcl-1 remained associated. In our study, we were unable to detect a role for GSK-3-mediated regulation of Mcl-1 expression. Based on these results we propose that upon cytokine withdrawal, survival of hemopoietic cells depends on association between Mcl-1 and Bim. Furthermore, alteration of T163 of Mcl-1 may change the protein such that its association with Bim is affected, resulting in prolonged association and increased survival.

scholarly journals Renal Mesangial Cells Isolated from Sphingosine Kinase 2 Transgenic Mice Show Reduced Proliferation and are More Sensitive to Stress-Induced Apoptosis

2018 ◽  
Vol 47 (6) ◽  
pp. 2522-2533
Author(s):  
Sandra Beyer ◽  
Stephanie Schwalm ◽  
Josef Pfeilschifter ◽  
Andrea Huwiler
Keyword(s):  
Cell Growth ◽  
Transgenic Mice ◽  
Mesangial Cells ◽  
Normal Growth ◽  
Growth Conditions ◽  
Mitochondrial Pathway ◽  
Cell Functions ◽  
Transgenic Cells ◽  
Induced Apoptosis

Background/Aims: Sphingosine 1-phosphate (S1P) is considered as a key molecule regulating various cell functions including cell growth and death. It is produced by two sphingosine kinases (SK) denoted as SK-1 and SK-2. Whereas SK-1 has been extensively studied and has been appointed a role in promoting cell growth, the function of SK-2 is controversial, and both pro-proliferative and pro-apoptotic functions have been suggested. In this study we investigated whether renal mesangial cells isolated from transgenic mice overexpressing the human Sphk2 gene (hSK2-tg) showed an altered cell response towards growth-inducing and apoptotic stimuli. Methods: hSK2-tg mice were generated by using a Quick KnockinR strategy. Renal mesangial cells were isolated by a differential sieving method and further cultivated in vitro. Lipids were quantified by mass spectrometry. Protein expression was determined by Western blot analysis, cell proliferation was determined by 3H-thymidine incorporation, and apoptosis was determined by a DNA fragmentation ELISA. Results: We show here that kidneys and mesangial cells from hSK2-tg mice express the hSK2 as well as the endogenous mouse mSK2. hSK2 and mSK2 predominantly resided in the cytosol of quiescent transgenic cells. However, S1P accumulated strongly in the nucleus and only minimally in the cytosol of transgenic cells. Functionally, hSK2-tg cells proliferated less than control cells under normal growth conditions and were also more sensitive towards stress-induced apoptosis. On the molecular level, this was reflected by reduced ERK and Akt/PKB activation, and upon staurosporine treatment, by a sensitized mitochondrial pathway as manifested by reduced anti-apoptotic Bcl-XL expression and increased cleavage of caspase-9, downstream caspase-3 and PARP-1. Conclusion: Altogether, these data demonstrate that SK-2 exerts an antiproliferative and apoptosis-sensitizing effect in renal mesangial cells which suggests that selective inhibitors of SK-2 may promote proliferation and reduce apoptosis and this may have impact on the outcome of proliferation-associated diseases such as mesangioproliferative glomerulonephritis.

scholarly journals Agaricus blazeiExtract Induces Apoptosis through ROS-Dependent JNK Activation Involving the Mitochondrial Pathway and Suppression of Constitutive NF-κB in THP-1 Cells

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Mun-Ock Kim ◽  
Dong-Oh Moon ◽  
Jin Myung Jung ◽  
Won Sup Lee ◽  
Yung Hyun Choi ◽  
...  
Keyword(s):  
Mitochondrial Pathway ◽  
Ros Generation ◽  
Gene Products ◽  
Oxygen Species ◽  
Agaricus Blazei ◽  
Anti Cancer ◽  
Induced Apoptosis ◽  
Jnk Activation ◽  
Apoptotic Effects ◽  
Apoptotic Mechanism

Agaricus blazeiis widely accepted as a traditional medicinal mushroom, and it has been known to exhibit immunostimulatory and anti-cancer activity. However, the apoptotic mechanism in cancer cells is poorly understood. In this study, we have investigated whetherA. blazeiextract (ABE) exerts antiproliferative and apoptotic effects in human leukemic THP-1 cells. We observed that ABE-induced apoptosis is associated with the mitochondrial pathway, which is mediated by reactive oxygen species (ROS) generation and prolonged c-Jun N-terminal kinase (JNK) activation. In addition, the ABE treatment resulted in the accumulation of cytochromecin the cytoplasm, an increase in caspase activity, and an upregulation of Bax and Bad. With those results in mind, we found that ABE decreases constitutive NF-κB activation and NF-κB-regulated gene products such as IAP-1 and -2. We concluded that ABE induces apoptosis with ROS-dependent JNK activation and constitutive activated NF-κB inhibition in THP-1 cells.

scholarly journals Activation of JNK-dependent Pathway Is Required for HIV Viral Protein R-induced Apoptosis in Human Monocytic Cells

2006 ◽  
Vol 282 (7) ◽  
pp. 4288-4300 ◽  
Author(s):  
Sasmita Mishra ◽  
Jyoti P. Mishra ◽  
Ashok Kumar
Keyword(s):  
Viral Protein ◽  
Cell Types ◽  
Mitochondrial Pathway ◽  
Dependent Manner ◽  
Small Interfering Rnas ◽  
Monocytic Cells ◽  
Viral Protein R ◽  
Jnk Inhibitors ◽  
Induced Apoptosis ◽  
Apoptotic Effects

Human immunodeficiency virus (HIV) accessory protein viral protein R (Vpr) plays a key role in virus replication and induces cell cycle arrest and apoptosis in various cell types including T cells and neuronal and tumor cells following infection with Vpr-expressing HIV isolates or exposure to the extracellular Vpr protein. The C-terminal Vpr peptide encompassing amino acids 52–96 (Vpr-(52–96)) is required for exerting the apoptotic effects, whereas the N-terminal Vpr-(1–45) peptide is responsible for virus transcription. We demonstrate that Vpr-(52–96) induced apoptosis in human promonocytic THP-1 cells and primary monocytes through the mitochondrial pathway in a caspase-dependent manner. To understand the regulation of Vpr-induced apoptosis, we investigated the signaling pathways, particularly the MAPKs, and the transcription factors involved. Although both Vpr-(52–96) and Vpr-(1–45) peptides induced phosphorylation of all the three members of the MAPKs, Vpr-(52–96)-activated JNK selectively induced apoptosis in monocytic cells through the mitochondrial pathway as determined by using JNK inhibitors SP60025, dexamethasone, curcumin, and JNK-specific small interfering RNAs. Furthermore Vpr-(52–96)-induced apoptosis was mediated by inhibition of downstream antiapoptotic Bcl2 and c-IAP1 genes whose expression could be restored following pretreatment with JNK-specific inhibitors. Overall the results suggest that Vpr-(52–96)-activated JNK plays a key role in inducing apoptosis through the down-regulation of antiapoptotic Bcl2 and c-IAP1 genes.

Apoptotic Effects of N-(2-hydroxyphenyl)-2-propylpentanamide on U87-MG and U-2 OS Cells and Antiangiogenic Properties

2020 ◽  
Vol 20 ◽  
Author(s):  
Paola Castillo-Juárez ◽  
Sebastián C. Sanchez ◽  
Alma D. Chávez-Blanco ◽  
Humberto Mendoza-Figueroa ◽  
José Correa-Basurto
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Histone Deacetylases ◽  
Biochemical Mechanism ◽  
Antiproliferative Effects ◽  
Human Osteosarcoma ◽  
Antiproliferative Agent ◽  
Induced Apoptosis ◽  
Apoptotic Effects

Background and Objective: Histone deacetylases (HDACs) are important therapeutic targets for many types of human cancers. A derivative of valproic acid, N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA), has antiproliferative properties on some cancer cell lines and inhibits the HDAC1 isoform. Materials and Methods: In this work, HO-AAVPA was tested as an antiproliferative agent in U87-MG (human glioblastoma) and U-2 OS cells (human osteosarcoma), which are types of cancer that are difficult to treat, and its antiangiogenic properties were explored. Results: HO-AAVPA had antiproliferative effects at 48 h with an IC50 = 0.655 mM in U87-MG cells and an IC50 = 0.453 mM in U-2 OS cells. Additionally, in the colony formation assay, HO-AAVPA decreased the number of colonies by approximately 99% in both cell lines and induced apoptosis by 31.3% in the U-2 OS cell line and by 78.2% in the U87-MG cell line. Additionally, HO-AAVPA reduced the number of vessels in chorioallantoid membranes (CAMs) by approximately 67.74% and IL-6 levels in both cell lines suggesting that the biochemical mechanism on cancer cell of HO-AAVPA is different compared to VPA. Conclusion: HO-AAVPA has antiproliferative effects on glioblastoma and osteosarcoma and antiangiogenic properties.

scholarly journals Versatile Physiological Functions of Plant GSK3-Like Kinases

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 697
Author(s):  
Juan Mao ◽  
Wenxin Li ◽  
Jing Liu ◽  
Jianming Li
Keyword(s):  
Stress Responses ◽  
Glycogen Synthase ◽  
Plant Stress ◽  
Normal Growth ◽  
Growth Conditions ◽  
Genetic Studies ◽  
Physiological Functions ◽  
Environmental Signals ◽  
Plant Stress Responses ◽  
Diverse Plant

The plant glycogen synthase kinase 3 (GSK3)-like kinases are highly conserved protein serine/threonine kinases that are grouped into four subfamilies. Similar to their mammalian homologs, these kinases are constitutively active under normal growth conditions but become inactivated in response to diverse developmental and environmental signals. Since their initial discoveries in the early 1990s, many biochemical and genetic studies were performed to investigate their physiological functions in various plant species. These studies have demonstrated that the plant GSK3-like kinases are multifunctional kinases involved not only in a wide variety of plant growth and developmental processes but also in diverse plant stress responses. Here we summarize our current understanding of the versatile physiological functions of the plant GSK3-like kinases along with their confirmed and potential substrates.

Lamotrigine Attenuates Proteasome Inhibition-Induced Apoptosis by Suppressing the Activation of the Mitochondrial Pathway and the Caspase-8- and Bid-Dependent Pathways

2016 ◽  
Vol 41 (10) ◽  
pp. 2503-2516 ◽  
Author(s):  
Yoon Jeong Nam ◽  
Arum Kim ◽  
Min Sung Lee ◽  
Yong Kyoo Shin ◽  
Dong Suep Sohn ◽  
...  
Keyword(s):  
Proteasome Inhibition ◽  
Mitochondrial Pathway ◽  
Caspase 8 ◽  
Induced Apoptosis

Stachyose-induced apoptosis of Caco-2 cells via the caspase-dependent mitochondrial pathway

2015 ◽  
Vol 6 (3) ◽  
pp. 765-771 ◽  
Author(s):  
Guidong Huang ◽  
Jian Mao ◽  
Zhongwei Ji ◽  
Aisikaer Ailati
Keyword(s):  
Colon Cancer ◽  
Cell Growth ◽  
Cancer Cell ◽  
Mitochondrial Pathway ◽  
Colon Cancer Cell ◽  
Cancer Cell Growth ◽  
Induced Apoptosis

Some studies have shown that stachyose, as prebiotics, can prevent indirectly colon cancer cell growth by promoting the proliferation of probiotics or producing beneficial materials in the intestine.

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