scholarly journals Loss of the Notch effector RBPJ promotes tumorigenesis

2014 ◽  
Vol 212 (1) ◽  
pp. 37-52 ◽  
Author(s):  
Iva Kulic ◽  
Gordon Robertson ◽  
Linda Chang ◽  
Jennifer H.E. Baker ◽  
William W. Lockwood ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Growth ◽  
Target Genes ◽  
Human Cancer ◽  
Global Analysis ◽  
Notch Pathway ◽  
Gene Promoters ◽  
Human Cancer Cell Lines ◽  
Immunodeficient Mice ◽  
Cell Death Pathway

Aberrant Notch activity is oncogenic in several malignancies, but it is unclear how expression or function of downstream elements in the Notch pathway affects tumor growth. Transcriptional regulation by Notch is dependent on interaction with the DNA-binding transcriptional repressor, RBPJ, and consequent derepression or activation of associated gene promoters. We show here that RBPJ is frequently depleted in human tumors. Depletion of RBPJ in human cancer cell lines xenografted into immunodeficient mice resulted in activation of canonical Notch target genes, and accelerated tumor growth secondary to reduced cell death. Global analysis of activated regions of the genome, as defined by differential acetylation of histone H4 (H4ac), revealed that the cell death pathway was significantly dysregulated in RBPJ-depleted tumors. Analysis of transcription factor binding data identified several transcriptional activators that bind promoters with differential H4ac in RBPJ-depleted cells. Functional studies demonstrated that NF-κB and MYC were essential for survival of RBPJ-depleted cells. Thus, loss of RBPJ derepresses target gene promoters, allowing Notch-independent activation by alternate transcription factors that promote tumorigenesis.

scholarly journals Id2 Promotes Apoptosis by a Novel Mechanism Independent of Dimerization to Basic Helix-Loop-Helix Factors

1998 ◽  
Vol 18 (9) ◽  
pp. 5435-5444 ◽  
Author(s):  
Monica Florio ◽  
Maria-Clemencia Hernandez ◽  
Hui Yang ◽  
Hui-Kuo Shu ◽  
John L. Cleveland ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Target Genes ◽  
Specific Binding ◽  
Helix Loop Helix ◽  
Cell Death Pathway ◽  
Id Proteins ◽  
Enhanced Expression ◽  
Positive Regulators ◽  
Hlh Transcription Factors

ABSTRACT Members of the helix-loop-helix (HLH) family of Id proteins have demonstrated roles in the regulation of differentiation and cell proliferation. Id proteins inhibit differentiation by HLH-mediated heterodimerization with basic HLH transcription factors. This blocks their sequence-specific binding to DNA and activation of target genes that are often expressed in a tissue-specific manner. Id proteins can also act as positive regulators of cell proliferation. The different mechanisms proposed for Id-mediated promotion of entry into S phase also involve HLH-mediated interactions affecting regulators of the G1/S transition. We have found that Id2 augments apoptosis in both interleukin-3 (IL-3)-dependent 32D.3 myeloid progenitors and U2OS osteosarcoma cells. We could not detect a similar activity for Id3. In contrast to the effects of Id2 on differentiation and cell proliferation, Id2-mediated apoptosis is independent of HLH-mediated dimerization. The ability of Id2 to promote cell death resides in its N-terminal region and is associated with the enhanced expression of a known component of the programmed cell death pathway, the proapoptotic gene BAX.

scholarly journals The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Margaret E Torrence ◽  
Michael R MacArthur ◽  
Aaron M Hosios ◽  
Alexander J Valvezan ◽  
John M Asara ◽  
...  
Keyword(s):  
Target Genes ◽  
Human Cancer ◽  
Amino Acid Uptake ◽  
Acid Uptake ◽  
Glutathione Synthesis ◽  
Human Cancer Cell Lines ◽  
Downstream Target ◽  
Mtorc1 Signaling ◽  
Transcriptional Changes ◽  
Established Role

The mechanistic target of rapamycin complex 1 (mTORC1) stimulates a coordinated anabolic program in response to growth-promoting signals. Paradoxically, recent studies indicate that mTORC1 can activate the transcription factor ATF4 through mechanisms distinct from its canonical induction by the integrated stress response (ISR). However, its broader roles as a downstream target of mTORC1 are unknown. Therefore, we directly compared ATF4-dependent transcriptional changes induced upon insulin-stimulated mTORC1 signaling to those activated by the ISR. In multiple mouse embryo fibroblast (MEF) and human cancer cell lines, the mTORC1-ATF4 pathway stimulated expression of only a subset of the ATF4 target genes induced by the ISR, including genes involved in amino acid uptake, synthesis, and tRNA charging. We demonstrate that ATF4 is a metabolic effector of mTORC1 involved in both its established role in promoting protein synthesis and in a previously unappreciated function for mTORC1 in stimulating cellular cystine uptake and glutathione synthesis.

scholarly journals Comparison of Cellular Death Pathways after mTHPC-mediated Photodynamic Therapy (PDT) in Five Human Cancer Cell Lines

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 702 ◽  
Author(s):  
Carsten Lange ◽  
Christiane Lehmann ◽  
Martin Mahler ◽  
Patrick J. Bednarski
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Photodynamic Therapy ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
Cell Death Mechanisms

One of the most promising photosensitizers (PS) used in photodynamic therapy (PDT) is the porphyrin derivative 5,10,15,20-tetra(m-hydroxyphenyl)chlorin (mTHPC, temoporfin), marketed in Europe under the trade name Foscan®. A set of five human cancer cell lines from head and neck and other PDT-relevant tissues was used to investigate oxidative stress and underlying cell death mechanisms of mTHPC-mediated PDT in vitro. Cells were treated with mTHPC in equitoxic concentrations and illuminated with light doses of 1.8–7.0 J/cm2 and harvested immediately, 6, 24, or 48 h post illumination for analyses. Our results confirm the induction of oxidative stress after mTHPC-based PDT by detecting a total loss of mitochondrial membrane potential (Δψm) and increased formation of ROS. However, lipid peroxidation (LPO) and loss of cell membrane integrity play only a minor role in cell death in most cell lines. Based on our results, apoptosis is the predominant death mechanism following mTHPC-mediated PDT. Autophagy can occur in parallel to apoptosis or the former can be dominant first, yet ultimately leading to autophagy-associated apoptosis. The death of the cells is in some cases accompanied by DNA fragmentation and a G2/M phase arrest. In general, the overall phototoxic effects and the concentrations as well as the time to establish these effects varies between cell lines, suggesting that the cancer cells are not all dying by one defined mechanism, but rather succumb to an individual interplay of different cell death mechanisms. Besides the evaluation of the underlying cell death mechanisms, we focused on the comparison of results in a set of five identically treated cell lines in this study. Although cells were treated under equitoxic conditions and PDT acts via a rather unspecific ROS formation, very heterogeneous results were obtained with different cell lines. This study shows that general conclusions after PDT in vitro require testing on several cell lines to be reliable, which has too often been ignored in the past.

Ectopic expression of Flt3 kinase inhibits proliferation and promotes cell death in different human cancer cell lines

2012 ◽  
Vol 28 (4) ◽  
pp. 201-212 ◽  
Author(s):  
Eystein Oveland ◽  
Line Wergeland ◽  
Randi Hovland ◽  
James B. Lorens ◽  
Bjørn Tore Gjertsen ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Ectopic Expression ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines

scholarly journals A putative PPAR beta/delta agonist induces cell death in human cancer cell lines

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
David Kelly Strom ◽  
Dalon Li ◽  
Hanna Brinkman ◽  
Stephanie Gleason ◽  
Sarah Hershberger ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines

scholarly journals The SMAC mimetic BV6 induces cell death and sensitizes different cell lines to TNF-α and TRAIL-induced apoptosis

2016 ◽  
Vol 241 (18) ◽  
pp. 2015-2022 ◽  
Author(s):  
Mohamed El-Mesery ◽  
Mohamed E Shaker ◽  
Abdelaziz Elgaml
Keyword(s):  
Cell Death ◽  
Immune System ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
Tnf Α ◽  
Smac Mimetic

The inhibitors of apoptosis proteins are implicated in promoting cancer cells survival and resistance toward immune surveillance and chemotherapy. Second mitochondria-derived activator of caspases (SMAC) mimetics are novel compounds developed to mimic the inhibitory effect of the endogenous SMAC/DIABLO on these IAPs. Here, we examined the potential effects of the novel SMAC mimetic BV6 on different human cancer cell lines. Our results indicated that BV6 was able to induce cell death in different human cancer cell lines. Mechanistically, BV6 dose dependently induced degradation of IAPs, including cIAP1 and cIAP2. This was coincided with activating the non-canonical NF -kappa B (NF-κB) pathway, as indicated by stabilizing NF-κB-inducing kinase (NIK) for p100 processing to p52. More interestingly, BV6 was able to sensitize some of the resistant cancer cell lines to apoptosis induced by the death ligands tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) that are produced by different cells of the immune system. Such cell death enhancement was mediated by inducing an additional cleavage of caspase-9 to augment that of caspase-8 induced by death ligands. This eventually led to more processing of the executioner caspase-3 and poly (ADP-ribose) polymerase (PARP). In conclusion, therapeutic targeting of IAPs by BV6 might be an effective approach to enhance cancer regression induced by immune system. Our data also open up the future possibility of using BV6 in combination with other antitumor therapies to overcome cancer drug resistance.

scholarly journals FOXA1 defines cancer cell specificity

2016 ◽  
Vol 2 (3) ◽  
pp. e1501473 ◽  
Author(s):  
Gaihua Zhang ◽  
Yongbing Zhao ◽  
Yi Liu ◽  
Li-Pin Kao ◽  
Xiao Wang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Target Genes ◽  
Human Cancer ◽  
Cell Types ◽  
Human Cancer Cell Lines ◽  
Chromatin Immunoprecipitation Sequencing ◽  
Pioneer Transcription Factor ◽  
Specific Regulation

A transcription factor functions differentially and/or identically in multiple cell types. However, the mechanism for cell-specific regulation of a transcription factor remains to be elucidated. We address how a single transcription factor, forkhead box protein A1 (FOXA1), forms cell-specific genomic signatures and differentially regulates gene expression in four human cancer cell lines (HepG2, LNCaP, MCF7, and T47D). FOXA1 is a pioneer transcription factor in organogenesis and cancer progression. Genomewide mapping of FOXA1 by chromatin immunoprecipitation sequencing annotates that target genes associated with FOXA1 binding are mostly common to these cancer cells. However, most of the functional FOXA1 target genes are specific to each cancer cell type. Further investigations using CRISPR-Cas9 genome editing technology indicate that cell-specific FOXA1 regulation is attributable to unique FOXA1 binding, genetic variations, and/or potential epigenetic regulation. Thus, FOXA1 controls the specificity of cancer cell types. We raise a “flower-blooming” hypothesis for cell-specific transcriptional regulation based on these observations.

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