Protein–protein interactions of ASPP2: an emerging therapeutic target

MedChemComm ◽  
2014 ◽  
Vol 5 (10) ◽  
pp. 1435-1443 ◽  
Author(s):  
Anat Iosub-Amir ◽  
Assaf Friedler
Keyword(s):  
Protein Interactions ◽  
Therapeutic Target ◽  
Cancer Drugs ◽  
Protein Protein Interactions ◽  
Promising Target ◽  
Anti Cancer

ASPP2 induces apoptosis and is downregulated in many types of cancer, making it a promising target for anti-cancer drugs.

scholarly journals EEF1A2 interacts with HSP90AB1 to promote lung adenocarcinoma metastasis via enhancing TGF-β/SMAD signalling

2021 ◽  
Author(s):  
Liqing Jia ◽  
Xiaolu Ge ◽  
Chao Du ◽  
Linna Chen ◽  
Yanhong Zhou ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Protein Interactions ◽  
Elongation Factor ◽  
Protein Translation ◽  
Protein Protein Interactions ◽  
Promising Target ◽  
Tgfβ Receptor ◽  
Mesenchymal Transformation

Abstract Background Eukaryotic protein translation elongation factor 1α2 (EEF1A2) is an oncogene that promotes the progression of breast and pancreatic cancer. In this study, we aimed to elucidate the oncogenic function of EEF1A2 in the metastasis of lung adenocarcinoma (LUAD). Methods Immunohistochemistry and western blot were used to study EEF1A2 expression levels in LUAD tissues and cells, respectively. The role of EEF1A2 in LUAD progression were investigated in vitro and in vivo. We identified potential EEF1A2-binding proteins by liquid chromatography-electrospray mass spectrometry (LC-MS)/MS. Protein–protein interactions were determined by immunofluorescence and co-immunoprecipitation (Co-IP). Results In this study, we report that EEF1A2 mediates the epithelial–mesenchymal transformation (EMT), to promote the metastasis of LUAD cells in vitro and in vivo. Moreover, EEF1A2 interacts with HSP90AB1 to increase TGFβ Receptor (TβR)-I, and TβRII expression, followed by enhanced SMAD3 and pSMAD3 expression and nuclear localisation, which promotes the EMT of LUAD cells. Overexpression of EEF1A2 in cancer tissues is associated with poor prognosis and short survival of patients with LUAD. Conclusions These findings underscore the molecular functions of EEF1A2 in LUAD metastasis and indicate that EEF1A2 represents a promising target in the treatment of aggressive LUAD.

scholarly journals Exploring Protein-Protein Interactions as Drug Targets for Anti-cancer Therapy with In Silico Workflows

2017 ◽  
pp. 221-236 ◽  
Author(s):  
Alexander Goncearenco ◽  
Minghui Li ◽  
Franco L. Simonetti ◽  
Benjamin A. Shoemaker ◽  
Anna R. Panchenko
Keyword(s):  
Cancer Therapy ◽  
Protein Interactions ◽  
In Silico ◽  
Drug Targets ◽  
Protein Protein Interactions ◽  
Anti Cancer

scholarly journals Simultaneous measurement of p53:Mdm2 and p53:Mdm4 protein-protein interactions in whole cells using fluorescence labelled foci

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Y. Frosi ◽  
K. Inoue ◽  
Siti Radhiah Ramlan ◽  
D. P. Lane ◽  
T. Watanabe ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Simultaneous Measurement ◽  
Protein Complexes ◽  
Cancer Therapies ◽  
Protein Protein Interactions ◽  
Pharmaceutical Development ◽  
Whole Cells ◽  
Related Family ◽  
Anti Cancer ◽  
The Subject

AbstractIn this report we describe the development of a Fluorescent Protein-Protein Interaction-visualization (FLUOPPI) to enable the simultaneous measurement of both Mdm2:p53 and Mdm4:p53 interactions in order to assess the relative efficiencies of mimetic molecules of the p53 peptide helix against both PPIs. Mdm2 and Mdm4 overexpression frequently leads to the inactivation of non-mutated p53 in human cancers, via inhibition of its transcriptional activity, enhancing its degradation by the proteasome or by preventing its nuclear import. Development of inhibitors to disrupt the binding of one or both of these protein interactions have been the subject of intensive pharmaceutical development for anti-cancer therapies. Using the bimodal FLUOPPI system we have characterised compounds that were either monospecific for Mdm2 or bispecific for both Mdm2 and Mdm4. We have also demonstrated that the FLUOPPI assay can reliably differentiate between specific and non-specific disruption of these protein complexes via accurate assessment and normalization to the cell population under measurement. We envision that this methodology will increase the efficiency of identifying compounds that are either specific against a single PPI from a closely related family of interactions or compounds that interact across multiple related PPI pairs, depending on which is more desirable.

scholarly journals Hypoxia inducible factor (HIF) as a model for studying inhibition of protein–protein interactions

2017 ◽  
Vol 8 (6) ◽  
pp. 4188-4202 ◽  
Author(s):  
George M. Burslem ◽  
Hannah F. Kyle ◽  
Adam Nelson ◽  
Thomas A. Edwards ◽  
Andrew J. Wilson
Keyword(s):  
Drug Design ◽  
Anticancer Drug ◽  
Protein Interaction ◽  
Protein Interactions ◽  
State Of The Art ◽  
Hypoxia Inducible Factor ◽  
The State ◽  
Protein Protein Interactions ◽  
Protein Protein Interaction ◽  
Promising Target

The state of the art in identifying protein–protein interaction inhibitors of hypoxia inducible factor – a promising target for anticancer drug design – is described.

scholarly journals Tanshinone IIA Affects the Malignant Growth of Cholangiocarcinoma Cells by Inhibiting the PI3K-Akt-mTOR Pathway

2021 ◽  
Author(s):  
Huayuan Liu ◽  
Caiyun Liu ◽  
Mengya Wang ◽  
Dongxu Sun ◽  
Pengcheng Zhu ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Tanshinone Iia ◽  
Network Pharmacology ◽  
Protein Protein Interactions ◽  
Anticancer Effects ◽  
Anti Cancer ◽  
Cholangiocarcinoma Cell ◽  
And Migration ◽  
Proliferation And Migration

Abstract Purpose: In the present study, we aimed to find the target of Tanshinone IIA (Tan-IIA) in Cholangiocarcinoma by network pharmacology-based prediction and investigate the possible mechanism through experimental verification. Methods: In this study, we combined Tan-IIA-specific and Cholangiocarcinoma-specific targets with protein-protein interactions (PPI) to construct a Tan-IIA targets-Cholangiocarcinoma network, and network pharmacology approach was applied to identify potential targets and mechanisms of Tan-IIA in the treatment of Cholangiocarcinoma. The anti-cancer effects of Tan-IIA were investigated by using subcutaneous tumorigenic model in nude mice and in the human Cholangiocarcinoma cell lines in vitro. Results: Our results showed that Tan-IIA treatment considerably suppressed the proliferation and migration of Cholangiocarcinoma cells while inducing apoptosis of Cholangiocarcinoma cells. Western blot results demonstrated that the expression of PI3K, p-Akt, p-mTOR, and mTOR were inhibited by Tan-IIA. Meanwhile, After treatment with Tan-IIA, the level of Bcl2 was downregulated and cleaved caspase-3 expression increased. Further studies revealed that the anticancer effects of Tan-IIA were severely mitigated by pretreatment with a PI3K agonist.Conclusion: Our research provides a new anticancer strategy and strengthens support for the use of Tan-IIA as an anticancer drug for the treatment of CCA.

scholarly journals Defining endogenous TACC3–chTOG–clathrin–GTSE1 interactions at the mitotic spindle using induced relocalization

2020 ◽  
Author(s):  
Ellis L. Ryan ◽  
James Shelford ◽  
Teresa Massam-Wu ◽  
Richard Bayliss ◽  
Stephen J. Royle
Keyword(s):  
Protein Interactions ◽  
Membrane Trafficking ◽  
Mitotic Spindle ◽  
Binding Sites ◽  
Gene Editing ◽  
Multiprotein Complex ◽  
Protein Protein Interactions ◽  
Core Complex ◽  
Anti Cancer ◽  
Spindle Stability

A multiprotein complex containing TACC3, clathrin, and other proteins has been implicated in mitotic spindle stability. To disrupt this complex in an anti-cancer context, we need to understand the composition of the complex and the interactions between complex members and with microtubules. Induced relocalization of proteins in cells is a powerful way to analyze protein-protein interactions and additionally monitoring where and when these interactions occur. We used CRISPR/Cas9 gene-editing to add tandem FKBP-GFP tags to each complex member. The relocalization of endogenous tagged protein from the mitotic spindle to mitochondria and assessment of the effect on other proteins allowed us to establish that TACC3 and clathrin are core complex members and that chTOG and GTSE1 are ancillary to the complex, respectively binding to TACC3 and clathrin, but not each other. PIK3C2A, a membrane trafficking protein that binds clathrin, was previously proposed to also bind TACC3 and stabilize the TACC3–chTOG–clathrin–GTSE1 complex during mitosis. We show that PIK3C2A is not on the mitotic spindle and that knockout of this gene had no effect on the localization of the complex. We therefore conclude that PIK3C2A is not a member of the TACC3–chTOG–clathrin–GTSE1 complex. This work establishes that targeting the TACC3–clathrin interface or their microtubule-binding sites are the two strategies most likely to disrupt spindle stability mediated by this multiprotein complex.

Analysis of Protein Biology to Increase Efficacy of Aurora Kinase Inhibitors for Multiple Myeloma Therapy.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1699-1699
Author(s):  
Robert P. Evans ◽  
Kim Laginha ◽  
Linda M. Pilarski ◽  
Andrew Belch ◽  
Tony Reiman
Keyword(s):  
Multiple Myeloma ◽  
Cancer Cells ◽  
Protein Interactions ◽  
Kinase Inhibitors ◽  
Aurora Kinase ◽  
Protein Protein Interactions ◽  
Aurora Kinases ◽  
Aurora Kinase Inhibitors ◽  
Anti Cancer ◽  
Novel Protein

Abstract Despite improvement in therapeutic regimes which have extended survival of patients with multiple myeloma, the search for novel targets to further advance treatment options continues. It is critical to the success of targeted cancer therapy that the rational selection of drugs be derived from the molecular and cellular biology of protein targets. Furthermore, studies have indicated that focused combination drug therapy could produce remarkable improvement in patient outcomes. Aurora kinases A/B/C (AURK), components of the centrosome and important for cell cycle function, are promising new targets in the treatment of numerous types of cancer. We have previously validated AURKs as a therapeutic target in pre-clinical models of multiple myeloma. In this study our aim is to better define the biology of AURKs in both normal and malignant cells, with the goal of identifying rational strategies for improving the therapeutic potential of Aurora kinase inhibitors (AKIs) as anti-cancer agents. We use a systematic two-pronged approach to map post-translational modifications and novel protein-protein interactions that define the interactome of AURKs. We also examine whether Aurora kinase interactions and posttranslational modifications are significantly different in cancer cells compared to normal cells. Increased understanding of Aurora kinase biology will help develop mechanisms to intensify the anti-cancer effects of AKIs. SUMOylation is a recently discovered posttranslational modification of numerous proteins that has been linked to many cancer types. A small ubiquitin-like modifier (SUMO) group is conjugated at the canonical ubiquitin site of a protein to alter its function, stability or sub-cellular localization. We believe that Aurora kinases may be differentially SUMOylated in cancer cells compared to normal cells, and that SUMOylation of Aurora kinases in cancer cells may alter their function and their susceptibility to AKI therapy. Here we have determined putative SUMOylation sites of all three AURKs in silico and also have evidence of AURK SUMOylation using an in vitro assay and also in human HEK293 cells. Furthermore, the gene encoding the central SUMO conjugating enzyme - UBC9 - is expressed at higher levels in CD138+ malignant plasma cells compared to other CD138−bone marrow cells in myeloma patients. As part of our strategy, we have also used Tandem Affinity Purification (TAP) technology to identify novel protein-protein interactions of Aurora kinases. In the initial stage, we have established stable expressing clones in a human cancer cell line and a normal line that express TAP-tagged AURKA/B or C. In pilot experiments we have successfully isolated pure recombinant AURKA along with interacting proteins using the TAP method. Using mass spectrometry (MS/MS) protein ID, we have identified putative protein interaction partners with AURKA which have implications in general cancer biology and centrosomal structure. In the future, these interactions will be validated using conventional biochemical methods before being tested in myeloma cell lines.

INSIDE INDUSTRY

2013 ◽  
Vol 17 (03) ◽  
pp. 55-63 ◽  
Keyword(s):  
Protein Interactions ◽  
3D Cell Culture ◽  
Network Services ◽  
Cancer Therapies ◽  
Protein Protein Interactions ◽  
Detection Technology ◽  
Anti Cancer ◽  
Collaboration Agreement ◽  
New Discovery

Cognoptix licenses AD detection technology. 3D cell culture firm Reinnervate and specialist Oncology CRO Oncotest GmbH enter collaboration agreement. Medicago awarded contract from the U.S. Department of Defence. Clinical Network Services acquires New Zealand partner BELTAS' business assets. VABIOTECH licenses cell-based Japanese encephalitis technology from Inviragen. University of Illinois licenses novel anti-cancer therapies to StemPar Sciences. Adimab announces new discovery collaboration with Kyowa Hakko Kirin. Priaxon enters collaboration with GSK on protein-protein-interactions. Lantheus Medical Imaging and FUJIFILM RI Pharma renew long-term license and distribution agreement.

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