scholarly journals Nuclear factor-kB in thyroid carcinogenesis and progression: a novel therapeutic target for advanced thyroid cancer

2007 ◽  
Vol 51 (5) ◽  
pp. 843-851 ◽  
Author(s):  
Hiroyuki Namba ◽  
Vladimir Saenko ◽  
Shunichi Yamashita
Keyword(s):  
Thyroid Cancer ◽  
Transcriptional Activation ◽  
Chemotherapeutic Agents ◽  
Important Change ◽  
Jnk Pathway ◽  
In Vivo Experiments ◽  
Advanced Thyroid Cancer ◽  
Nf Kappab

Apoptosis is an essential physiological process of elimination of destined cells during the development and differentiation or after damage from external stresses such as ionizing radiation or chemotherapeutic agents. Disruption of apoptosis is proved to cause various diseases including cancer. Among numerous molecules involved in diverse anti- or pro-apoptotic signaling pathways, NF-kappaB is one of the key factors controlling anti-apoptotic responses. Its anti-apoptotic effect is thought to be mediated through not only transcriptional activation of dependent genes but also by crosstalking with the JNK pathway. Oncogenic proteins such as Ret/PTC, Ras and BRAF can induce NF-kappaB activation making it an important change in thyroid cancer. A number of specific or non-specific NF-kappaB inhibitors have been tried to take over the cascade in in vitro and in vivo experiments. These agents can induce massive apoptosis especially in combination with radio- or chemotherapy. Current results suggest that the inhibition of the NF-kappaB may be a promising strategy for advanced thyroid cancer treatment but further investigations are warranted to develop specific and clinically effective NF-kappaB inhibitors in future.

scholarly journals Targeting autophagy enhances atezolizumab-induced mitochondria-related apoptosis in osteosarcoma

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Zhuochao Liu ◽  
Hongyi Wang ◽  
Chuanzhen Hu ◽  
Chuanlong Wu ◽  
Jun Wang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Antitumor Immunity ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Specific Monoclonal Antibody ◽  
Osteosarcoma Cells ◽  
Jnk Pathway ◽  
In Vivo Experiments

AbstractIn this study, we identified the multifaceted effects of atezolizumab, a specific monoclonal antibody against PD-L1, in tumor suppression except for restoring antitumor immunity, and investigated the promising ways to improve its efficacy. Atezolizumab could inhibit the proliferation and induce immune-independent apoptosis of osteosarcoma cells. With further exploration, we found that atezolizumab could impair mitochondria of osteosarcoma cells, resulting in increased release of reactive oxygen species and cytochrome-c, eventually leading to mitochondrial-related apoptosis via activating JNK pathway. Nevertheless, the excessive release of reactive oxygen species also activated the protective autophagy of osteosarcoma cells. Therefore, when we combined atezolizumab with autophagy inhibitors, the cytotoxic effect of atezolizumab on osteosarcoma cells was significantly enhanced in vitro. Further in vivo experiments also confirmed that atezolizumab combined with chloroquine achieved the most significant antitumor effect. Taken together, our study indicates that atezolizumab can induce mitochondrial-related apoptosis and protective autophagy independently of the immune system, and targeting autophagy is a promising combinatorial approach to amplify its cytotoxicity.

scholarly journals A new member of the I kappaB protein family, I kappaB epsilon, inhibits RelA (p65)-mediated NF-kappaB transcription.

1997 ◽  
Vol 17 (10) ◽  
pp. 6184-6190 ◽  
Author(s):  
Z Li ◽  
G J Nabel
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Transcriptional Activation ◽  
Interleukin 1 ◽  
Specific Cell ◽  
Alternative Mechanism ◽  
Necrosis Factor Alpha ◽  
Nf Kappab

A novel member of the I kappaB family has been identified as a protein that associated with the p50 subunit of NF-kappaB in a yeast two-hybrid screen. Similar to previously known I kappaB proteins, this member, I kappaB epsilon, has six consecutive ankyrin repeats. I kappaB epsilon mRNA is widely expressed in different human tissues, with highest levels in spleen, testis, and lung. I kappaB epsilon interacts with different NF-kappaB proteins, including p65 (RelA), c-Rel, p50, and p52, in vitro and in vivo and inhibits the DNA-binding activity of both p50-p65 and p50-c-Rel complexes effectively. Endogenous and transfected NF-kappaB (RelA-dependent) transcriptional activation is inhibited by I kappaB epsilon. I kappaB epsilon mRNA is expressed at different levels in specific cell types and is synthesized constitutively in transformed B-cell lines. It also displays differential induction in response to tumor necrosis factor alpha, interleukin-1, or phorbol ester stimulation compared to I kappaB alpha in non-B-cell lines. Therefore, I kappaB epsilon represents a novel I kappaB family member which provides an alternative mechanism for regulation of NF-kappaB-dependent transcription.

Characterization Of In Vitro Hdm2 E3 Ubiquitin Ligase-Mediated p53 Ubiquitination

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4903-4903
Author(s):  
Bradley B Brasher ◽  
Eduardo Guillen ◽  
Ivan Tomasic ◽  
Carsten Schwerdtfeger ◽  
Francesco D Melandri
Keyword(s):  
Transcriptional Activation ◽  
Cell Function ◽  
Ring Finger ◽  
Ubiquitin Ligases ◽  
Wild Type ◽  
Western Blots ◽  
Hematopoietic Stem ◽  
In Vivo Experiments

Abstract Double minute 2 protein (Mdm2, Hdm2 in humans) is a RING-finger Ubiquitin E3 Ligase that acts as a major regulator of the tumor suppressor protein p53. Mdm2 inhibits p53 -mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. The ligase activity of Mdm2 is responsible for the ubiquitination and subsequent proteasomal degradation of p53. Mdm2 also regulates its own intracellular levels by auto-ubiquitination, and can be SUMOylated, which reportedly decreases autoubiquitination activity but increases activity toward p53. Imbalances in the p53 pathway are frequently associated with hematologic disease states. Loss of p53 function is a driving force in leukemia and lymphoma in humans and mice, while increased p53 activity can inhibit hematopoietic stem cell function and contribute to myelodysplasia. Thus, careful control of p53 activity is critical for homeostasis. Most of our understanding of p53 function in hematopoiesis is derived from in vivo experiments using genetically modified mice (Pant V., et al, Blood. 2012; 120:5118-27). While this is a powerful system for elucidating genetic pathways that influence p53 activity, there is still much to learn about the mechanisms of p53 regulation at the enzymatic level. To facilitate studies in this area, we purified recombinant Hdm2 and p53 from E.coli and developed gel-based assays to monitor both autoubiquitination and ubiquitination of protein substrates. We observed rapid autoubiquitination of Hdm2 using both wild-type and lysine-less (K0) ubiquitin, though reactions containing the former generated significantly higher molecular weight Hdm2-ubiquitin adducts. Hdm2 ubiquitination of p53 produced a discrete, ladder-like banding pattern on Western Blots regardless of whether wild-type or K0 ubiquitin was included in the reaction. This suggests that the principal product of this defined Hdm2-p53 reaction is multi-monoubiquitinated p53, as opposed to p53 modified with polyubiquitin chains. Reactions using an alternative substrate yielded different results. Hdm2 ubiquitination of Angiocidin/S5a protein generated a large smeary pattern on Western Blots instead of discrete bands. This is consistent with the Hdm2-catalyzed polyubiquitination of S5a, demonstrating that ubiquitin ligases are capable of generating different in vitro ubiquitination patterns that are dependent on the substrate utilized in the assay. These results suggest that care must be taken in experimental designs, particularly with respect to substrate and assay read out. Finally, recombinant UBE4B was included in Mdm2/p53 reactions to test the recently reported E4-ligase activity of this enzyme. Ultimately these reagents should prove useful for fully defined, in vitro studies investigating the interactions between p53 and the ubiquitin ligases and deubiquitinases that modify it in normal and diseased cellular states. Disclosures: Brasher: Boston Biochem Inc: Employment. Guillen:Boston Biochem Inc: Employment. Tomasic:Boston Biochem Inc: Employment. Schwerdtfeger:Boston Biochem Inc: Employment. Melandri:Boston Biochem Inc: Employment.

scholarly journals Distinct functional properties of IkappaB alpha and IkappaB beta.

1997 ◽  
Vol 17 (9) ◽  
pp. 5386-5399 ◽  
Author(s):  
K Tran ◽  
M Merika ◽  
D Thanos
Keyword(s):  
Transcriptional Activation ◽  
High Mobility ◽  
In Vitro Transcription ◽  
Binding Activity ◽  
High Mobility Group Protein ◽  
Dna Binding Activity ◽  
Group Protein ◽  
Nf Kappab

The biological activity of the transcription factor NF-kappaB is controlled mainly by the IkappaB alpha and IkappaB beta proteins, which restrict NF-kappaB to the cytoplasm and inhibit its DNA binding activity. Here, we carried out experiments to determine and compare the mechanisms by which IkappaB alpha and IkappaB beta inhibit NF-kappaB-dependent transcriptional activation. First, we found that in vivo IkappaB alpha is a stronger inhibitor of NF-kappaB than is IkappaB beta. This difference is directly correlated with their abilities to inhibit NF-kappaB binding to DNA in vitro and in vivo. Moreover, IkappaB alpha, but not IkappaB beta, can remove NF-kappaB from functional preinitiation complexes in in vitro transcription experiments. Second, we showed that both IkappaBs function in vivo not only in the cytoplasm but also in the nucleus, where they inhibit NF-kappaB binding to DNA. Third, the inhibitory activity of IkappaB beta, but not that of IkappaB alpha, is facilitated by phosphorylation of the C-terminal PEST sequence by casein kinase II and/or by the interaction of NF-kappaB with high-mobility group protein I (HMG I) on selected promoters. The unphosphorylated form of IkappaB beta forms stable ternary complexes with NF-kappaB on the DNA either in vitro or in vivo. These experiments suggest that IkappaB alpha works as a postinduction repressor of NF-kappaB independently of HMG I, whereas IkappaB beta functions preferentially in promoters regulated by the NF-kappaB/HMG I complexes.

scholarly journals New perspectives on the treatment of differentiated thyroid cancer

2007 ◽  
Vol 51 (4) ◽  
pp. 612-624 ◽  
Author(s):  
Sabrina Mendes Coelho ◽  
Denise Pires de Carvalho ◽  
Mário Vaisman
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapy ◽  
Thyroid Carcinoma ◽  
Kinase Inhibitors ◽  
Critical Role ◽  
New Drugs ◽  
In Vivo Studies ◽  
Advanced Thyroid Cancer

Even though differentiated thyroid carcinoma is a slow growing and usually curable disease, recurrence occurs in 20-40% and cellular dedifferentiation in up to 5% of cases. Conventional chemotherapy and radiotherapy have just a modest effect on advanced thyroid cancer. Therefore, dedifferentiated thyroid cancer represents a therapeutic dilemma and a critical area of research. Targeted therapy, a new generation of anticancer treatment, is planned to interfere with a specific molecular target, typically a protein that is believed to have a critical role in tumor growth or progression. Since many of the tumor-initiation events have already been identified in thyroid carcinogenesis, targeted therapy is a promising therapeutic tool for advanced thyroid cancer. Several new drugs are currently being tested in in vitro and in vivo studies and some of them are already being used in clinical trials, like small molecule tyrosine kinase inhibitors. In this review, we discuss the bases of targeted therapies, the principal drugs already tested and also options of redifferentiation therapy for thyroid carcinoma.

ANTITUMOR EFFECT OF COLLOIDAL SILVER BISILICATE IN EXPERIMENTAL IN VITRO AND IN VIVO STUDIES

2019 ◽  
Vol 65 (5) ◽  
pp. 760-765
Author(s):  
Margarita Tyndyk ◽  
Irina Popovich ◽  
A. Malek ◽  
R. Samsonov ◽  
N. Germanov ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Human Tumor ◽  
Significant Inhibition ◽  
In Vivo Studies ◽  
Ehrlich Carcinoma ◽  
In Vivo Experiments

The paper presents the results of the research on the antitumor activity of a new drug - atomic clusters of silver (ACS), the colloidal solution of nanostructured silver bisilicate Ag6Si2O7 with particles size of 1-2 nm in deionized water. In vitro studies to evaluate the effect of various ACS concentrations in human tumor cells cultures (breast cancer, colon carcinoma and prostate cancer) were conducted. The highest antitumor activity of ACS was observed in dilutions from 2.7 mg/l to 5.1 mg/l, resulting in the death of tumor cells in all studied cell cultures. In vivo experiments on transplanted Ehrlich carcinoma model in mice consuming 0.75 mg/kg ACS with drinking water revealed significant inhibition of tumor growth since the 14th day of experiment (maximally by 52% on the 28th day, p < 0.05) in comparison with control. Subcutaneous injections of 2.5 mg/kg ACS inhibited Ehrlich's tumor growth on the 7th and 10th days of the experiment (p < 0.05) as compared to control.

Subnuclear compartmentalization of sequence-specific transcription factors and regulation of eukaryotic gene expression

2005 ◽  
Vol 83 (4) ◽  
pp. 535-547 ◽  
Author(s):  
Gareth N Corry ◽  
D Alan Underhill
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Transcriptional Activation ◽  
Current Knowledge ◽  
Nuclear Architecture ◽  
Subnuclear Localization ◽  
Modular Structures

To date, the majority of the research regarding eukaryotic transcription factors has focused on characterizing their function primarily through in vitro methods. These studies have revealed that transcription factors are essentially modular structures, containing separate regions that participate in such activities as DNA binding, protein–protein interaction, and transcriptional activation or repression. To fully comprehend the behavior of a given transcription factor, however, these domains must be analyzed in the context of the entire protein, and in certain cases the context of a multiprotein complex. Furthermore, it must be appreciated that transcription factors function in the nucleus, where they must contend with a variety of factors, including the nuclear architecture, chromatin domains, chromosome territories, and cell-cycle-associated processes. Recent examinations of transcription factors in the nucleus have clarified the behavior of these proteins in vivo and have increased our understanding of how gene expression is regulated in eukaryotes. Here, we review the current knowledge regarding sequence-specific transcription factor compartmentalization within the nucleus and discuss its impact on the regulation of such processes as activation or repression of gene expression and interaction with coregulatory factors.Key words: transcription, subnuclear localization, chromatin, gene expression, nuclear architecture.

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