Regulation of deleted in liver cancer 1 tumor suppressor by protein-protein interactions and phosphorylation

Several C2 domain-containing proteins play key roles in tumorigenesis, signal transduction, and mediating protein–protein interactions. Tandem C2 domains nuclear protein (TC2N) is a tandem C2 domain-containing protein that is differentially expressed in several types of cancers and is closely associated with tumorigenesis and tumor progression. Notably, TC2N has been identified as an oncogene in lung and gastric cancer but as a tumor suppressor gene in breast cancer. Recently, a large number of tumor-associated antigens (TAAs), such as heat shock proteins, alpha-fetoprotein, and carcinoembryonic antigen, have been identified in a variety of malignant tumors. Differences in the expression levels of TAAs between cancer cells and normal cells have led to these antigens being investigated as diagnostic and prognostic biomarkers and as novel targets in cancer treatment. In this review, we summarize the clinical characteristics of TC2N-positive cancers and potential mechanisms of action of TC2N in the occurrence and development of specific cancers. This article provides an exploration of TC2N as a potential target for the diagnosis and treatment of different types of cancers.

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Protein-protein interactions among signaling pathways may become new therapeutic targets in liver cancer (Review)

Oncology Reports ◽

10.3892/or.2015.4464 ◽

2015 ◽

Vol 35 (2) ◽

pp. 625-638 ◽

Cited By ~ 5

Author(s):

XIAO ZHANG ◽

YULAN WANG ◽

JIAYI WANG ◽

FENYONG SUN

Keyword(s):

Liver Cancer ◽

Signaling Pathways ◽

Protein Interactions ◽

Therapeutic Targets ◽

Protein Protein Interactions ◽

Cancer Review ◽

New Therapeutic Targets

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Gain-of-Function Mutations in p53 in Cancer Invasiveness and Metastasis

International Journal of Molecular Sciences ◽

10.3390/ijms21041334 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1334 ◽

Cited By ~ 6

Author(s):

Katarzyna A. Roszkowska ◽

Slawomir Gizinski ◽

Maria Sady ◽

Zdzislaw Gajewski ◽

Maciej B. Olszewski

Keyword(s):

Tumor Suppressor ◽

Protein Interactions ◽

Molecular Mechanisms ◽

Human Cancer ◽

P53 Protein ◽

Missense Mutations ◽

Protein Protein Interactions ◽

Gain Of Function ◽

Suppressor Activity ◽

Cancer Invasiveness

Forty years of research has proven beyond any doubt that p53 is a key regulator of many aspects of cellular physiology. It is best known for its tumor suppressor function, but it is also a regulator of processes important for maintenance of homeostasis and stress response. Its activity is generally antiproliferative and when the cell is damaged beyond repair or intensely stressed the p53 protein contributes to apoptosis. Given its key role in preventing cancer it is no wonder that it is the most frequently mutated gene in human cancer. Surprisingly, a subset of missense mutations occurring in p53 (gain-of-function) cause it to lose its suppressor activity and acquire new functionalities that turn the tumor suppressor protein into an oncoprotein. A solid body of evidence exists demonstrating increased malignancy of cancers with mutated p53 in all aspects considered “hallmarks of cancer”. In this review, we summarize current findings concerning the cellular processes altered by gain-of-function mutations in p53 and their influence on cancer invasiveness and metastasis. We also present the variety of molecular mechanisms regulating these processes, including microRNA, direct transcriptional regulation, protein–protein interactions, and more.

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Impact of Reactive Oxygen and Nitrogen Species Produced by Plasma on Mdm2–p53 Complex

International Journal of Molecular Sciences ◽

10.3390/ijms22179585 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9585

Author(s):

Pankaj Attri ◽

Hirofumi Kurita ◽

Kazunori Koga ◽

Masaharu Shiratani

Keyword(s):

Tumor Suppressor ◽

Protein Interactions ◽

Structural Changes ◽

Md Simulations ◽

Tumor Suppressor Protein ◽

Protein Protein Interactions ◽

Tumor Suppressor Protein P53 ◽

Protein P53 ◽

Before And After ◽

High Flexibility

The study of protein–protein interactions is of great interest. Several early studies focused on the murine double minute 2 (Mdm2)–tumor suppressor protein p53 interactions. However, the effect of plasma treatment on Mdm2 and p53 is still absent from the literature. This study investigated the structural changes in Mdm2, p53, and the Mdm2–p53 complex before and after possible plasma oxidation through molecular dynamic (MD) simulations. MD calculation revealed that the oxidized Mdm2 bounded or unbounded showed high flexibility that might increase the availability of tumor suppressor protein p53 in plasma-treated cells. This study provides insight into Mdm2 and p53 for a better understanding of plasma oncology.

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The E3 ubiquitin-protein ligase MDM2 is a novel interactor of the von Hippel-Lindau tumor suppressor

10.1101/2020.04.28.066084 ◽

2020 ◽

Author(s):

Antonella Falconieri ◽

Giovanni Minervini ◽

Raissa Bortolotto ◽

Damiano Piovesan ◽

Raffaele Lopreiato ◽

...

Keyword(s):

Tumor Suppressor ◽

Protein Interactions ◽

Hypoxia Inducible Factor ◽

Protein Protein Interactions ◽

Von Hippel Lindau ◽

Intrinsically Disordered ◽

Tetramerization Domain ◽

Specific Association ◽

Cycle Regulation

AbstractMutations of the von Hippel-Lindau (pVHL) tumor suppressor are causative of a familiar predisposition to develop different types of cancer. pVHL is mainly known for its role in regulating hypoxia-inducible factor 1-α (HIF-1α) degradation, thus modulating the hypoxia response. There are different pVHL isoforms, including pVHL30 and pVHL19. However, little is known about isoform-specific functions and protein-protein interactions. Integrating in silico predictions with in vitro and in vivo assays, we describe a novel interaction between pVHL and mouse double minute 2 homolog (MDM2). Importantly, we found that pVHL30, and not pVHL19, forms a complex with MDM2, and that the N-terminal acidic tail of pVHL30 is required for its association with MDM2. Further, we demonstrate that an intrinsically disordered region upstream of the tetramerization domain of MDM2 is responsible for its isoform-specific association with pVHL30. This region is highly conserved in higher mammals, including primates, similarly to what has been already proposed for the N-terminal tail of pVHL30. Finally, we show that overexpression of pVHL30 and MDM2 together reduces cell proliferation, suggesting a synergistic effect of these E3 ubiquitin ligases. Collectively, our data support the idea that pVHL30 plays a role in MDM2 regulation, suggesting a wider interplay among hypoxia sensing and cell cycle regulation.

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Small-molecule modulation of p53 protein-protein interactions

Biological Chemistry ◽

10.1515/hsz-2019-0405 ◽

2020 ◽

Vol 401 (8) ◽

pp. 921-931 ◽

Cited By ~ 1

Author(s):

Ave Kuusk ◽

Helen Boyd ◽

Hongming Chen ◽

Christian Ottmann

Keyword(s):

Tumor Suppressor ◽

Small Molecules ◽

Small Molecule ◽

Protein Interactions ◽

P53 Protein ◽

Tumor Suppressor Protein ◽

Protein Protein Interactions ◽

Mdm2 Protein ◽

Protein Protein Interaction ◽

Altered Proteins

AbstractSmall-molecule modulation of protein-protein interactions (PPIs) is a very promising but also challenging area in drug discovery. The tumor suppressor protein p53 is one of the most frequently altered proteins in human cancers, making it an attractive target in oncology. 14-3-3 proteins have been shown to bind to and positively regulate p53 activity by protecting it from MDM2-dependent degradation or activating its DNA binding affinity. PPIs can be modulated by inhibiting or stabilizing specific interactions by small molecules. Whereas inhibition has been widely explored by the pharmaceutical industry and academia, the opposite strategy of stabilizing PPIs still remains relatively underexploited. This is rather interesting considering the number of natural compounds like rapamycin, forskolin and fusicoccin that exert their activity by stabilizing specific PPIs. In this review, we give an overview of 14-3-3 interactions with p53, explain isoform specific stabilization of the tumor suppressor protein, explore the approach of stabilizing the 14-3-3σ-p53 complex and summarize some promising small molecules inhibiting the p53-MDM2 protein-protein interaction.

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Virtual Docking of VBP1 with HBX and NFκB Protein to Study the Activation of NFκB in the Regulatory Mechanism of Liver Cancer

Current Journal of Applied Science and Technology ◽

10.9734/cjast/2021/v40i3931593 ◽

2021 ◽

pp. 21-28

Author(s):

Mamta Sagar ◽

Padma Saxena ◽

Suruchi Singh ◽

Ravindra Nath ◽

Pramod W. Ramteke

Keyword(s):

Amino Acids ◽

Liver Cancer ◽

Protein Interactions ◽

Protein Protein Interactions ◽

Von Hippel Lindau ◽

Hbv Replication ◽

Protein Ligand Interactions ◽

B Virus ◽

Ligand Interactions ◽

The Common

Molecular docking is an efficient way to study protein-protein and protein-ligand interactions in virtual mode, this provides structural annotations of molecular interactions, required in the drug discovery process. The Cartesian FFT approach in ‘Hex’ spherical polar Fourier (SPF) uses rotational correlations, this method is used here to study protein-protein interactions. Hepatitis B virus (HBV) X protein (HBx) is essential for virus infection and has been used in the development of therapeutics for liver cancer. It can interact with many cellular proteins. It interferes with cell viability and stimulates HBV replication. The von Hippel-Lindau binding protein 1(VBP1) has an important role in HBx-mediated nuclear factor kappa B (NFkB) stimulation. VBP1 and HBx function as coactivators in the activation of NFκB binding. Docking results revealed that HBx and NFkB bind with VBP1 at the common site on amino acids positions Arg 161, Glu 92, and Arg 82, which may have a role in HBx-mediated NFκB activation. Lowest energy complex VBP1- NFkB1 was obtained at -883.70 Kcal/mol. The amino acids involved in interaction among HBx, VBP1, and NFκB proteins, may be involved in transcriptional regulation and has significance in normal and abnormal regulation. These amino acid interactions may be associated with the manifestation of Liver cancer.

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