scholarly journals Emerging roles of DYRK2 in cancer

2020 ◽  
pp. jbc.REV120.015217
Author(s):  
Vasudha Tandon ◽  
Laureano de la Vega ◽  
Sourav Banerjee
Keyword(s):  
Tumour Suppressor ◽  
26S Proteasome ◽  
Heat Shock Factor 1 ◽  
Lung Cancers ◽  
Nuclear Stability ◽  
Spatio Temporal ◽  
Temporal Interactions

Over the last decade, the CMGC-kinase, DYRK2, has been reported as a tumour-suppressor across various cancers triggering major anti-tumour and pro-apoptotic signals in breast, colon, liver, ovary, brain, and lung cancers, while lower DYRK2 expression apparently correlated with poorer prognosis in patients. Contrary to this, various medicinal chemistry studies reported robust anti-proliferative properties of DYRK2 inhibitors while unbiased ‘omics’ and GWAS based studies identified DYRK2 as a highly overexpressed kinase in various patient tumour samples. A major paradigm shift occurred in the last four years when DYRK2 was found to regulate proteostasis in cancer via a two-pronged mechanism. DYRK2 phosphorylated and activated the 26S proteasome to enhance degradation of mis-folded/tumour-suppressor proteins while also promoting the nuclear stability and transcriptional activity of its substrate, heat-shock factor 1 (HSF1) triggering protein folding. Together, DYRK2 regulates proteostasis and promotes pro-tumorigenic survival for specific cancers. Indeed, potent and selective small molecule inhibitors of DYRK2 exhibit in vitro and in vivo anti-tumour activity in triple negative breast cancer (TNBC) and myeloma models. Thus, with conflicting and contradictory reports across different cancers, the overarching role of DYRK2 remains enigmatic. Specific cancer (sub)types coupled to spatio-temporal interactions with substrates could decide the pro- or anti-cancer role of DYRK2. The current review aims to provide a balanced and critical appreciation of the literature-to-date highlighting top substrates such as p53, c-Myc, c-Jun, HSF1, proteasome or NOTCH1, to discuss DYRK2 inhibitors available to the scientific community, and to shed light on this duality of pro- and anti-tumorigenic roles of DYRK2.

Role of ESCRT component HD-PTP/PTPN23 in cancer

2017 ◽  
Vol 45 (3) ◽  
pp. 845-854 ◽  
Author(s):  
Marie-Claude Gingras ◽  
Jalal M. Kazan ◽  
Arnim Pause
Keyword(s):  
Plasma Membrane ◽  
Cancer Susceptibility ◽  
Tumour Suppressor ◽  
Tumour Suppressor Genes ◽  
Surface Receptors ◽  
Endosomal Sorting ◽  
Bona Fide

Sustained cellular signalling originated from the receptors located at the plasma membrane is widely associated with cancer susceptibility. Endosomal sorting and degradation of the cell surface receptors is therefore crucial to preventing chronic downstream signalling and tumorigenesis. Since the Endosomal Sorting Complexes Required for Transport (ESCRT) controls these processes, ESCRT components were proposed to act as tumour suppressor genes. However, the bona fide role of ESCRT components in tumorigenesis has not been clearly demonstrated. The ESCRT member HD-PTP/PTPN23 was recently identified as a novel haplo-insufficient tumour suppressor in vitro and in vivo, in mice and humans. In this mini-review, we outline the role of the ESCRT components in cancer and summarize the functions of HD-PTP/PTPN23 in tumorigenesis.

scholarly journals A Spatio-Temporal Model and Inference Tools for Longitudinal Count Data on Multicolor Cell Growth

2018 ◽  
Vol 14 (2) ◽  
Author(s):  
PuXue Qiao ◽  
Christina Mølck ◽  
Davide Ferrari ◽  
Frédéric Hollande
Keyword(s):  
Cell Growth ◽  
Image Data ◽  
Real Data ◽  
Cell Types ◽  
Spatial Autoregressive ◽  
Spatio Temporal ◽  
Different Cell Types ◽  
Temporal Interactions

AbstractMulticolor cell spatio-temporal image data have become important to investigate organ development and regeneration, malignant growth or immune responses by tracking different cell types both in vivo and in vitro. Statistical modeling of image data from common longitudinal cell experiments poses significant challenges due to the presence of complex spatio-temporal interactions between different cell types and difficulties related to measurement of single cell trajectories. Current analysis methods focus mainly on univariate cases, often not considering the spatio-temporal effects affecting cell growth between different cell populations. In this paper, we propose a conditional spatial autoregressive model to describe multivariate count cell data on the lattice, and develop inference tools. The proposed methodology is computationally tractable and enables researchers to estimate a complete statistical model of multicolor cell growth. Our methodology is applied on real experimental data where we investigate how interactions between cancer cells and fibroblasts affect their growth, which are normally present in the tumor microenvironment. We also compare the performance of our methodology to the multivariate conditional autoregressive (MCAR) model in both simulations and real data applications.

scholarly journals DNA hypermethylation contributes to colorectal cancer metastasis by regulating the binding of CEBPB and TFCP2 to the CPEB1 promoter

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Keke Shao ◽  
Weilin Pu ◽  
Jianfeng Zhang ◽  
Shicheng Guo ◽  
Fei Qian ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Transcription Factor ◽  
Cell Lines ◽  
Binding Protein ◽  
Tumour Suppressor ◽  
Tumour Suppressor Genes ◽  
Suppressor Genes

Abstract Background Aberrant DNA methylation has been firmly established as a factor contributing to the pathogenesis of colorectal cancer (CRC) via its capacity to silence tumour suppressor genes. However, the methylation status of multiple tumour suppressor genes and their roles in promoting CRC metastasis are not well characterised. Methods We explored the methylation and expression profiles of CPEB1 (the gene encoding cytoplasmic polyadenylation element-binding protein 1), a candidate CRC tumour suppressor gene, using The Cancer Genome Atlas (TCGA) database and validated these results in both CRC cell lines and cells from Han Chinese CRC patients (n = 104). The functional role of CPEB1 in CRC was examined in experiments performed in vitro and in vivo. A candidate transcription factor capable of regulating CPEB1 expression was predicted in silico and validated by luciferase reporter, DNA pull-down, and electrophoretic mobility shift assays. Results Hypermethylation and decreased expression of CPEB1 in CRC tumour tissues were revealed by TCGA database. We also identified a significant inverse correlation (Pearson’s R = − 0.43, P < 0.001) between promoter methylation and CPEB1 expression. We validated these results in CRC samples and two CRC cell lines. We also demonstrated that up-regulation of CPEB1 resulted in significantly decreased tumour growth, migration, invasion, and tumorigenicity and promoted tumour cell apoptosis both in vitro and in vivo. We identified the transcription factors CCAAT enhancer-binding protein beta (CEBPB) and transcription factor CP2 (TFCP2) as critical regulators of CPEB1 expression. Hypermethylation of the CPEB1 promoter resulted in a simultaneous increase in the capacity for TFCP2 binding and a decreased likelihood of CEBPB binding, both of which led to diminished expression of CPEB1. Conclusions Our results identified a novel tumour-suppressive role of CPEB1 in CRC and found that hypermethylation of the CPEB1 promoter may lead to diminished expression due to decreased chromatin accessibility and transcription factor binding. Collectively, these results suggest a potential role for CPEB1 in the diagnosis and treatment of CRC.

scholarly journals BBX21, an Arabidopsis B-box protein, directly activates HY5 and is targeted by COP1 for 26S proteasome-mediated degradation

2016 ◽  
Vol 113 (27) ◽  
pp. 7655-7660 ◽  
Author(s):  
Dongqing Xu ◽  
Yan Jiang ◽  
Jigang Li ◽  
Fang Lin ◽  
Magnus Holm ◽  
...  
Keyword(s):  
Salt Tolerance ◽  
26S Proteasome ◽  
Light Signaling ◽  
Dependent Manner ◽  
Positive Regulator ◽  
Molecular Base ◽  
Precise Role

BBX21 (also known as SALT TOLERANCE HOMOLOG 2), a B-box (BBX)-containing protein, has been previously identified as a positive regulator of light signaling; however, the precise role of BBX21 in regulating seedling photomorphogenesis remains largely unclear. In this study, we report that CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1) interacts with BBX21 in vivo and is able to ubiquitinate BBX21 in vitro. Thus, BBX21 is targeted for 26S proteasome-mediated degradation in dark-grown Arabidopsis seedlings in a COP1-dependent manner. Moreover, we show that BBX21 binds to the T/G-box in the ELONGATED HYPOCOTYL 5 (HY5) promoter and directly activates HY5 expression in the light. Transgenic seedlings overexpressing BBX21 exhibit dramatically shortened hypocotyls in the light, and this phenotype is dependent on a functional HY5. Taken together, our data suggest a molecular base underlying BBX21-mediated seedling photomorphogenesis, indicating that BBX21 is a pivotal component involved in the COP1-HY5 regulatory hub.

Inhibition of NF-κB activation in vitro and in vivo: Role of 26S proteasome

1999 ◽  
pp. 345-363 ◽  
Author(s):  
Matthew B. Grisham ◽  
Vito J. Palombella ◽  
Peter J. Elliott ◽  
Elaine M. Conner ◽  
Stephen Brand ◽  
...  
Keyword(s):  
26S Proteasome

scholarly journals Phosphatase UBLCP1 controls proteasome assembly

Open Biology ◽  
2017 ◽  
Vol 7 (5) ◽  
pp. 170042 ◽  
Author(s):  
Shuangwu Sun ◽  
Sisi Liu ◽  
Zhengmao Zhang ◽  
Wang Zeng ◽  
Chuang Sun ◽  
...  
Keyword(s):  
Atpase Activity ◽  
Essential Role ◽  
26S Proteasome ◽  
Core Particle ◽  
Proteasome Subunit ◽  
Bona Fide ◽  
Proteasome Regulation

Ubiquitin-like domain-containing C-terminal domain phosphatase 1 (UBLCP1), an FCP/SCP phosphatase family member, was identified as the first proteasome phosphatase. UBLCP1 binds to proteasome subunit Rpn1 and dephosphorylates the proteasome in vitro . However, it is still unclear which proteasome subunit(s) are the bona fide substrate(s) of UBLCP1 and the precise mechanism for proteasome regulation remains elusive. Here, we show that UBLCP1 selectively binds to the 19S regulatory particle (RP) through its interaction with Rpn1, but not the 20S core particle (CP) or the 26S proteasome holoenzyme. In the RP, UBLCP1 dephosphorylates the subunit Rpt1, impairs its ATPase activity, and consequently disrupts the 26S proteasome assembly, yet it has no effects on the RP assembly from precursor complexes. The Rpn1-binding and phosphatase activities of UBLCP1 are essential for its function on Rpt1 dephosphorylation and proteasome activity both in vivo and in vitro . Our study establishes the essential role of the UBLCP1/Rpn1/Rpt1 complex in regulating proteasome assembly.

The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

2012 ◽  
Vol 82 (3) ◽  
pp. 228-232 ◽  
Author(s):  
Mauro Serafini ◽  
Giuseppa Morabito
Keyword(s):  
Antioxidant Capacity ◽  
Dietary Intervention ◽  
Ex Vivo ◽  
The Body ◽  
Dietary Polyphenols ◽  
Enzymatic Antioxidant ◽  
Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

Anti-obesity role of Aster glehni extract: in vivo and in vitro effects

Planta Medica ◽  
2012 ◽  
Vol 78 (11) ◽  
Author(s):  
HM Lee ◽  
TG Ahn ◽  
CW Kim ◽  
HJ An
Keyword(s):  
In Vitro Effects

A Molecular Approach to Immunoscintigraphy: A Study of the T-Antigen Conformation on the Surface of Tumors

1987 ◽  
Vol 26 (01) ◽  
pp. 1-6 ◽  
Author(s):  
S. Selvaraj ◽  
M. R. Suresh ◽  
G. McLean ◽  
D. Willans ◽  
C. Turner ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Tumor Cell ◽  
T Antigen ◽  
Human Carcinomas ◽  
Animal Tumor ◽  
Synthetic Antigens

The role of glycoconjugates in tumor cell differentiation has been well documented. We have examined the expression of the two anomers of the Thomsen-Friedenreich antigen on the surface of human, canine and murine tumor cell membranes both in vitro and in vivo. This has been accomplished through the synthesis of the disaccharide terminal residues in both a and ß configuration. Both entities were used to generate murine monoclonal antibodies which recognized the carbohydrate determinants. The determination of fine specificities of these antibodies was effected by means of cellular uptake, immunohistopathology and immunoscintigraphy. Examination of pathological specimens of human and canine tumor tissue indicated that the expressed antigen was in the β configuration. More than 89% of all human carcinomas tested expressed the antigen in the above anomeric form. The combination of synthetic antigens and monoclonal antibodies raised specifically against them provide us with invaluable tools for the study of tumor marker expression in humans and their respective animal tumor models.

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