scholarly journals Elevated Expression of Zinc Finger Protein 703 Promotes Cell Proliferation and Metastasis through PI3K/AKT/GSK-3β Signalling in Oral Squamous Cell Carcinoma

2017 ◽  
Vol 44 (3) ◽  
pp. 920-934 ◽  
Author(s):  
Hao Wang ◽  
Xubin Deng ◽  
Jinshan Zhang ◽  
Zhilin Ou ◽  
Jiajie Mai ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Specific Inhibitor ◽  
Finger Protein ◽  
Proliferation And Metastasis ◽  
Gsk 3Β

Background/Aims: Zinc finger protein 703 (ZNF703), initially identified as a novel oncogene in human breast cancer, is a member of the NET/NlZ family of zinc finger transcription factors. It is recognized that the overexpression of ZNF703 is associated with various types of human cancers, but the role and molecular mechanism of ZNF703 in oral squamous cell carcinoma (OSCC) are unknown. Methods: ZNF703 expression levels were examined in OSCC tissues and non-cancerous tissues by qRT-PCR and immunohistochemistry (IHC). The molecular mechanisms of ZNF703 and its effects on cell growth and metastasis were explored in vitro and in vivo using the CCK8 assay, colony formation assay, cell cycle analysis, migration and invasion assays, wound-healing assay, western blotting and xenograft experiments in nude mice. Results: In this study, ZNF703 was found to be upregulated in OSCC tissues compared to that in normal tissues at both mRNA and protein levels, and its expression level was closely correlated with the overall survival of patients with OSCC. Silencing of the ZNF703 gene in OSCC cells significantly inhibited cell growth and metastasis in vitro and in vivo. Conversely, the overexpression of ZNF703 in OSCC cells promoted cancer growth and metastasis in vitro. Mechanistically, ZNF703 activated the PI3K/AKT/GSK-3β signalling pathway and its downstream effectors, thus regulating the cell cycle and epithelial-mesenchymal transition (EMT). Furthermore, the promotive effects of ZNF703 on cellular proliferation and metastasis could be rescued by LY294002 (a PI3K-specific inhibitor) and MK2206 (an Akt-specific inhibitor). Conclusion: The results show that ZNF703 promotes cell growth and metastasis through PI3K/Akt/GSK-3β signalling in OSCC and that it may be a promising target in the treatment of patients with OSCC.

scholarly journals Correlation between functional and binding activities of designer zinc-finger proteins

2007 ◽  
Vol 403 (1) ◽  
pp. 177-182 ◽  
Author(s):  
Jong Seok Kang
Keyword(s):  
Binding Affinity ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Zinc Finger Proteins ◽  
Sequence Specificity ◽  
Binding Assays ◽  
Finger Protein ◽  
Vitro Binding

Rapid progress in the ability to develop and utilize zinc-finger proteins with customized sequence specificity have led to their increasing use as tools for modulation of target gene transcription in the post-genomic era. In the present paper, a series of in vitro binding assays and in vivo reporter analyses were used to demonstrate that a zinc-finger protein can effectively specify a base at each position of the target site in vivo and that functional activity of the zinc-finger protein as either a transcriptional repressor or activator is positively correlated with its binding affinity. In addition, this correlation can be extended to artificial engineered zinc-finger proteins. These data suggest that the binding affinity of designer zinc-finger proteins with novel specificity might be a determinant for their ability to regulate transcription of a gene of interest.

A feel for the template: zinc finger protein transcription factors and chromatin

2002 ◽  
Vol 80 (3) ◽  
pp. 321-333 ◽  
Author(s):  
Fyodor D Urnov
Keyword(s):  
Transcription Factors ◽  
Zinc Finger ◽  
Binding Sites ◽  
Transcriptional Control ◽  
Hormone Receptors ◽  
Zinc Finger Protein ◽  
Finger Protein ◽  
Cell Biol

Transcription factors and chromatin collaborate in bringing the eukaryotic genome to life. An important, and poorly understood, aspect of this collaboration involves targeting the regulators to correct binding sites in vivo. An implicit and insufficiently tested assumption in the field has been that chromatin simply obstructs most sites and leaves only a few functionally relevant ones accessible. The major class of transcription factors in all metazoa, zinc finger proteins (ZFPs), can bind to chromatin in vitro (as clearly shown for Sp1, GATA-1 and -4, and the nuclear hormone receptors, for example). Data on the accessibility of DNA within heterochromatin to nonhistone regulators (E.A. Sekinger and D.S. Gross. 2001. Mol. Cell 105: 403–414; C. Jolly et al. 2002. J. Cell. Biol. 156: 775–781) and the ability of the basal transcription machinery to reside within highly condensed chromatin (most recently, R. Christova and T. Oelgeschlaeger. 2002. Nat. Cell Biol. 4: 79–82) further weaken the argument that chromatin acts as an across-the-board deterrent to ZFP binding. These proteins, however, do not bind promiscuously in vivo, and recent data on human cells (C.E. Horak et al. 2002. Proc. Natl. Acad. Sci. U.S.A. 99: 2924–2929) confirm earlier data on budding yeast (B. Ren et al. 2000. Science (Washington, D.C.), 290: 2306–2309) that primary DNA sequence, i.e., density of binding sites per unit DNA length, is not the primary determinant of where a ZFP transcription factor will bind in vivo. This article reviews these data and uses ZFP transcription factors as a model system to compare in vitro binding to chromatin by transcription factors with their in vivo behavior in gene regulation. DNA binding domain structure, nonrandom nucleoprotein organization of chromatin at target promoters, and cooperativity of regulator action may all contribute to target site selection in vivo.Key words: zinc finger protein, chromatin, transcriptional control, nucleosome.

IL-7R–dependent survival and differentiation of early T-lineage progenitors is regulated by the BTB/POZ domain transcription factor Miz-1

Blood ◽  
2011 ◽  
Vol 117 (12) ◽  
pp. 3370-3381 ◽  
Author(s):  
Ingrid Saba ◽  
Christian Kosan ◽  
Lothar Vassen ◽  
Tarik Möröy
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Strong Reduction ◽  
Expression Levels ◽  
Cell Numbers ◽  
Finger Protein

Abstract T cells originate from early T lineage precursors that have entered the thymus and differentiate through well-defined steps. Mice deficient for the BTB/POZ domain of zinc finger protein-1 (Miz-1) almost entirely lack early T lineage precursors and have a CD4−CD8− to CD4+CD8+ block causing a strong reduction in thymic cellularity. Miz-1ΔPOZ pro-T cells cannot differentiate in vitro and are unable to relay signals from the interleukin-7R (IL-7R). Both STAT5 phosphorylation and Bcl-2 up-regulation are perturbed. The high expression levels of SOCS1 found in Miz-1ΔPOZ cells probably cause these alterations. Moreover, Miz-1 can bind to the SOCS1 promoter, suggesting that Miz-1 deficiency causes a deregulation of SOCS1. Transgenic overexpression of Bcl-2 or inhibition of SOCS1 restored pro-T cell numbers and their ability to differentiate, supporting the hypothesis that Miz-1 is required for the regulation of the IL-7/IL-7R/STAT5/Bcl-2 signaling pathway by monitoring the expression levels of SOCS1.

Repeated CT elements bound by zinc finger proteins control the absolute and relative activities of the two principal human c-myc promoters

1993 ◽  
Vol 13 (9) ◽  
pp. 5710-5724
Author(s):  
E DesJardins ◽  
N Hay
Keyword(s):  
Zinc Finger ◽  
Tandem Repeats ◽  
Zinc Finger Protein ◽  
Consensus Sequence ◽  
Regulatory Region ◽  
Maximal Activity ◽  
Single Copy ◽  
Promoter Usage

Transcription of the human proto-oncogene c-myc is governed by two tandem principal promoters, termed P1 and P2. In general, the downstream promoter, P2, is predominant, which is in contrast to the promoter occlusion phenomenon usually observed in genes containing tandem promoters. A shift in human c-myc promoter usage has been observed in some tumor cells and in certain physiological conditions. However, the mechanisms that regulate promoter usage are not well understood. The present studies identify regulators which are required to promote transcription from both human c-myc promoters, P1 and P2, and have a role in determining their relative activities in vivo. A novel regulatory region located 101 bp upstream of P1 was characterized and contains five tandem repeats of the consensus sequence CCCTCCCC (CT element). The integrity of the region containing all five elements is required to promote transcription from P1 and for maximal activity from P2 in vivo. A single copy of this same element, designated CT-I2, also appears in an inverted orientation 53 bp upstream of the P2 transcription start site. This element has an inhibitory effect on P1 transcription and is required for P2 transcription. The transcription factor Sp1 was identified as the factor that binds specifically to the tandem CT elements upstream of P1 and to the CT-I2 element upstream of P2. In addition, the recently cloned zinc finger protein ZF87, or MAZ, was also able to bind these same elements in vitro. The five tandem CT elements can be functionally replaced by a heterologous enhancer that only in the absence of CT-I2 reverses the promoter usage, similar to what is observed in the translocated c-myc allele of Burkitt's lymphoma cells.

The zinc finger protein GLI transforms primary cells in cooperation with adenovirus E1A

1991 ◽  
Vol 11 (3) ◽  
pp. 1724-1728 ◽  
Author(s):  
J M Ruppert ◽  
B Vogelstein ◽  
K W Kinzler
Keyword(s):  
Zinc Finger ◽  
Nude Mice ◽  
Zinc Finger Protein ◽  
Primary Cells ◽  
Adenovirus E1a ◽  
In Vitro Transformation ◽  
Finger Protein ◽  
Protein Functions

The GLI gene was previously isolated by virtue of its amplification in human glioblastomas. We have now found that GLI expression can result in the in vitro transformation of both primary and secondary rodent cells. When coexpressed with adenovirus E1A, the GLI protein functions analogously to RAS, resulting in the formation of dense foci of cells which are tumorigenic in nude mice.

scholarly journals Menadione reduces CDC25B expression and promotes tumor shrinkage in gastric cancer

2020 ◽  
Vol 13 ◽  
pp. 175628481989543
Author(s):  
Amanda Braga Bona ◽  
Danielle Queiroz Calcagno ◽  
Helem Ferreira Ribeiro ◽  
José Augusto Pereira Carneiro Muniz ◽  
Giovanny Rebouças Pinto ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Specific Inhibitor ◽  
Gastric Carcinogenesis ◽  
In Vivo Experiments ◽  
Cycle Arrest

Background: Gastric cancer is one of the most incident types of cancer worldwide and presents high mortality rates and poor prognosis. MYC oncogene overexpression is a key event in gastric carcinogenesis and it is known that its protein positively regulates CDC25B expression which, in turn, plays an essential role in the cell division cycle progression. Menadione is a synthetic form of vitamin K that acts as a specific inhibitor of the CDC25 family of phosphatases. Methods: To better understand the menadione mechanism of action in gastric cancer, we evaluated its molecular and cellular effects in cell lines and in Sapajus apella, nonhuman primates from the new world which had gastric carcinogenesis induced by N-Methyl-N-nitrosourea. We tested CDC25B expression by western blot and RT-qPCR. In-vitro assays include proliferation, migration, invasion and flow cytometry to analyze cell cycle arrest. In in-vivo experiments, in addition to the expression analyses, we followed the preneoplastic lesions and the tumor progression by ultrasonography, endoscopy, biopsies, histopathology and immunohistochemistry. Results: Our tests demonstrated menadione reducing CDC25B expression in vivo and in vitro. It was able to reduce migration, invasion and proliferation rates, and induce cell cycle arrest in gastric cancer cell lines. Moreover, our in-vivo experiments demonstrated menadione inhibiting tumor development and progression. Conclusions: We suggest this compound may be an important ally of chemotherapeutics in the treatment of gastric cancer. In addition, CDC25B has proven to be an effective target for investigation and development of new therapeutic strategies for this malignancy.

Effect and mechanism of YB-1 knockdown on glioma cell growth, migration, and apoptosis

2020 ◽  
Vol 52 (2) ◽  
pp. 168-179 ◽  
Author(s):  
Huilin Gong ◽  
Shan Gao ◽  
Chenghuan Yu ◽  
Meihe Li ◽  
Ping Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Glioma Cell ◽  
Cell Transformation ◽  
Malignant Cell ◽  
Protein Levels ◽  
Glioma Progression

Abstract Y-box binding protein 1 (YB-1) is manifested as its involvement in cell proliferation and differentiation and malignant cell transformation. Overexpression of YB-1 is associated with glioma progression and patient survival. The aim of this study is to investigate the influence of YB-1 knockdown on glioma cell progression and reveal the mechanisms of YB-1 knockdown on glioma cell growth, migration, and apoptosis. It was found that the knockdown of YB-1 decreased the mRNA and protein levels of YB-1 in U251 glioma cells. The knockdown of YB-1 significantly inhibited cell proliferation, colony formation, and migration in vitro and tumor growth in vivo. Proteome and phosphoproteome data revealed that YB-1 is involved in glioma progression through regulating the expression and phosphorylation of major proteins involved in cell cycle, adhesion, and apoptosis. The main regulated proteins included CCNB1, CCNDBP1, CDK2, CDK3, ADGRG1, CDH-2, MMP14, AIFM1, HO-1, and BAX. Furthermore, it was also found that YB-1 knockdown is associated with the hypo-phosphorylation of ErbB, mTOR, HIF-1, cGMP-PKG, and insulin signaling pathways, and proteoglycans in cancer. Our findings indicated that YB-1 plays a key role in glioma progression in multiple ways, including regulating the expression and phosphorylation of major proteins associated with cell cycle, adhesion, and apoptosis.

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