scholarly journals Methionine adenosyltransferases in cancers: Mechanisms of dysregulation and implications for therapy

2017 ◽  
Vol 243 (2) ◽  
pp. 107-117 ◽  
Author(s):  
Lauren Y Maldonado ◽  
Diana Arsene ◽  
José M Mato ◽  
Shelly C Lu
Keyword(s):  
Protein Interactions ◽  
Mammalian Cells ◽  
Human Cancer ◽  
Methionine Adenosyltransferase ◽  
Therapeutic Interventions ◽  
Cancer Development ◽  
Growth And Survival ◽  
Liver Cancers ◽  
Mat Genes

Methionine adenosyltransferase genes encode enzymes responsible for the biosynthesis of S-adenosylmethionine, the principal biological methyl donor and precursor of polyamines and glutathione. Mammalian cells express three genes – MAT1A, MAT2A, and MAT2B – with distinct expression and functions. MAT1A is mainly expressed in the liver and maintains the differentiated states of both hepatocytes and bile duct epithelial cells. Conversely, MAT2A and MAT2B are widely distributed in non-parenchymal cells of the liver and extrahepatic tissues. Increasing evidence suggests that methionine adenosyltransferases play significant roles in the development of cancers. Liver cancers, namely hepatocellular carcinoma and cholangiocarcinoma, involve dysregulation of all three methionine adenosyltransferase genes. MAT1A reduction is associated with increased oxidative stress, progenitor cell expansion, genomic instability, and other mechanisms implicated in tumorigenesis. MAT2A/MAT2B induction confers growth and survival advantage to cancerous cells, enhancing tumor migration. Highlighted examples from colon, gastric, breast, pancreas and prostate cancer studies further underscore methionine adenosyltransferase genes’ role beyond the liver in cancer development. In this subset of extra-hepatic cancers, MAT2A and MAT2B are induced via different regulatory mechanisms. Understanding the role of methionine adenosyltransferase genes in tumorigenesis helps identify attributes of these genes that may serve as valuable targets for therapy. While S-adenosylmethionine, and its metabolite, methylthioadenosine, have been largely explored as therapeutic interventions, targets aimed at regulation of MAT gene expression and methionine adenosyltransferase protein–protein interactions are now surfacing as potential effective strategies for treatment and chemoprevention of cancers. Impact statement This review examines the role of methionine adenosyltransferases (MATs) in human cancer development, with a particular focus on liver cancers in which all three MAT genes are implicated in tumorigenesis. An overview of MAT genes, isoenzymes and their regulation provide context for understanding consequences of dysregulation. Highlighting examples from liver, colon, gastric, breast, pancreas and prostate cancers underscore the importance of understanding MAT’s tumorigenic role in identifying future targets for cancer therapy.

The role of chromosomal alterations in human cancer development

2007 ◽  
Vol 102 (2) ◽  
pp. 320-331 ◽  
Author(s):  
Patrizia Gasparini ◽  
Gabriella Sozzi ◽  
Marco A. Pierotti
Keyword(s):  
Human Cancer ◽  
Cancer Development ◽  
Chromosomal Alterations

scholarly journals The PI3K Pathway As Drug Target in Human Cancer

2010 ◽  
Vol 28 (6) ◽  
pp. 1075-1083 ◽  
Author(s):  
Kevin D. Courtney ◽  
Ryan B. Corcoran ◽  
Jeffrey A. Engelman
Keyword(s):  
Human Cancer ◽  
Pi3k Pathway ◽  
Pi3k Signaling ◽  
Phosphatidylinositol 3 Kinase ◽  
Cancer Cell Growth ◽  
Growth And Survival ◽  
Genes Encoding ◽  
Signaling Axis ◽  
Rapid Pace

The phosphatidylinositol 3-kinase (PI3K) signaling axis impacts on cancer cell growth, survival, motility, and metabolism. This pathway is activated by several different mechanisms in cancers, including somatic mutation and amplification of genes encoding key components. In addition, PI3K signaling may serve integral functions for noncancerous cells in the tumor microenvironment. Consequently, therapeutics targeting the PI3K pathway are being developed at a rapid pace, and preclinical and early clinical studies are beginning to suggest specific strategies to effectively use them. However, the central role of PI3K signaling in a large array of diverse biologic processes raises concerns about its use in therapeutics and increases the need to develop sophisticated strategies for its use. In this review, we will discuss how PI3K signaling affects the growth and survival of tumor cells. From this vantage, we will consider how inhibitors of the PI3K signaling cascade, either alone or in combination with other therapeutics, can most effectively be used for the treatment of cancer.

scholarly journals The emerging role of SPOP protein in tumorigenesis and cancer therapy

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Yizuo Song ◽  
Yichi Xu ◽  
Chunyu Pan ◽  
Linzhi Yan ◽  
Zhi-wei Wang ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Human Cancer ◽  
Critical Role ◽  
Cancer Type ◽  
Nuclear Speckle ◽  
Ring E3 Ligase ◽  
Promising Therapeutic Target ◽  
Liver Cancers ◽  
Ring E3

AbstractThe nuclear speckle-type pox virus and zinc finger (POZ) protein (SPOP), a representative substrate-recognition subunit of the cullin-RING E3 ligase, has been characterized to play a dual role in tumorigenesis and cancer progression. Numerous studies have determined that SPOP suppresses tumorigenesis in a variety of human malignancies such as prostate, lung, colon, gastric, and liver cancers. However, several studies revealed that SPOP exhibited oncogenic function in kidney cancer, suggesting that SPOP could exert its biological function in a cancer type-specific manner. The role of SPOP in thyroid, cervical, ovarian, bone and neurologic cancers has yet to be determined. In this review article, we describe the structure and regulation of SPOP in human cancer. Moreover, we highlight the critical role of SPOP in tumorigenesis based on three major categories: physiological evidence (animal models), pathological evidence (human cancer specimens) and biochemical evidence (downstream ubiquitin substrates). Furthermore, we note that SPOP could be a promising therapeutic target for cancer treatment.

scholarly journals RING1 Interacts with Multiple Polycomb-Group Proteins and Displays Tumorigenic Activity

1999 ◽  
Vol 19 (1) ◽  
pp. 57-68 ◽  
Author(s):  
David P. E. Satijn ◽  
Arie P. Otte
Keyword(s):  
Gene Expression ◽  
Protein Interactions ◽  
Mammalian Cells ◽  
Protein Complexes ◽  
Cellular Transformation ◽  
Polycomb Group ◽  
Expression Levels ◽  
Self Association

ABSTRACT Polycomb-group (PcG) proteins form large multimeric protein complexes that are involved in maintaining the transcriptionally repressive state of genes. Previously, we reported that RING1 interacts with vertebrate Polycomb (Pc) homologs and is associated with or is part of a human PcG complex. However, very little is known about the role of RING1 as a component of the PcG complex. Here we undertake a detailed characterization of RING1 protein-protein interactions. By using directed two-hybrid and in vitro protein-protein analyses, we demonstrate that RING1, besides interacting with the human Pc homolog HPC2, can also interact with itself and with the vertebrate PcG protein BMI1. Distinct domains in the RING1 protein are involved in the self-association and in the interaction with BMI1. Further, we find that the BMI1 protein can also interact with itself. To better understand the role of RING1 in regulating gene expression, we overexpressed the protein in mammalian cells and analyzed differences in gene expression levels. This analysis shows that overexpression of RING1 strongly represses En-2, a mammalian homolog of the well-characterized Drosophila PcG target geneengrailed. Furthermore, RING1 overexpression results in enhanced expression of the proto-oncogenes c-jun and c-fos. The changes in expression levels of these proto-oncogenes are accompanied by cellular transformation, as judged by anchorage-independent growth and the induction of tumors in athymic mice. Our data demonstrate that RING1 interacts with multiple human PcG proteins, indicating an important role for RING1 in the PcG complex. Further, deregulation of RING1 expression leads to oncogenic transformation by deregulation of the expression levels of certain oncogenes.

The multifaceted role of sortilin/neurotensin receptor 3 in human cancer development

2021 ◽  
Author(s):  
Fatemeh Ghaemimanesh ◽  
Majid Mehravar ◽  
Saeideh Milani ◽  
Ensieh M. Poursani ◽  
Kioomars Saliminejad
Keyword(s):  
Human Cancer ◽  
Cancer Development ◽  
Neurotensin Receptor

The unfolding role of ceramide in coordinating retinoid-based cancer therapy

2021 ◽  
Vol 478 (19) ◽  
pp. 3621-3642
Author(s):  
Botheina Ghandour ◽  
Ghassan Dbaibo ◽  
Nadine Darwiche
Keyword(s):  
Cancer Therapy ◽  
Tumor Suppressor ◽  
Therapeutic Interventions ◽  
Tumor Promoter ◽  
Cancer Development ◽  
Sphingolipid Metabolism ◽  
Retinoid Signaling ◽  
Combination Treatments ◽  
Ceramide Generation

Sphingolipid-mediated regulation in cancer development and treatment is largely ceramide-centered with the complex sphingolipid metabolic pathways unfolding as attractive targets for anticancer drug discovery. The dynamic interconversion of sphingolipids is tightly controlled at the level of enzymes and cellular compartments in response to endogenous or exogenous stimuli, such as anticancer drugs, including retinoids. Over the past two decades, evidence emerged that retinoids owe part of their potency in cancer therapy to modulation of sphingolipid metabolism and ceramide generation. Ceramide has been proposed as a ‘tumor-suppressor lipid' that orchestrates cell growth, cell cycle arrest, cell death, senescence, autophagy, and metastasis. There is accumulating evidence that cancer development is promoted by the dysregulation of tumor-promoting sphingolipids whereas cancer treatments can kill tumor cells by inducing the accumulation of endogenous ceramide levels. Resistance to cancer therapy may develop due to a disrupted equilibrium between the opposing roles of tumor-suppressor and tumor-promoter sphingolipids. Despite the undulating effect and complexity of sphingolipid pathways, there are emerging opportunities for a plethora of enzyme-targeted therapeutic interventions that overcome resistance resulting from perturbed sphingolipid pathways. Here, we have revisited the interconnectivity of sphingolipid metabolism and the instrumental role of ceramide-biosynthetic and degradative enzymes, including bioactive sphingolipid products, how they closely relate to cancer treatment and pathogenesis, and the interplay with retinoid signaling in cancer. We focused on retinoid targeting, alone or in combination, of sphingolipid metabolism nodes in cancer to enhance ceramide-based therapeutics. Retinoid and ceramide-based cancer therapy using novel strategies such as combination treatments, synthetic retinoids, ceramide modulators, and delivery formulations hold promise in the battle against cancer

scholarly journals Dynamic Regulation of RNA Structure in Mammalian Cells

2018 ◽  
Author(s):  
Lei Sun ◽  
Furqan Fazal ◽  
Pan Li ◽  
James P. Broughton ◽  
Byron Lee ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Rna Structure ◽  
Mammalian Cells ◽  
Rna Binding ◽  
Structural Information ◽  
Rna Structures ◽  
Rna Modifications ◽  
Dynamic Regulation ◽  
Comparative Structure

RNA structure is intimately connected to each step of gene expression. Recent advances have enabled transcriptome-wide maps of RNA secondary structure, termed RNA structuromes. However, previous whole-cell analyses lacked the resolution to unravel the dynamic regulation of RNA structure across subcellular states. Here we reveal the RNA structuromes in three compartments — chromatin, nucleoplasm and cytoplasm. The cytotopic structuromes substantially expand RNA structural information, and enable detailed investigation of the central role of RNA structure in linking transcription, translation, and RNA decay. Through comparative structure analysis, we develop a resource to visualize the interplay of RNA-protein interactions, RNA chemical modifications, and RNA structure, and predict both direct and indirect reader proteins of RNA modifications. We validate the novel role of the RNA binding protein LIN28A as an N6-methyladenosine (m6A) modification “anti-reader”. Our results highlight the dynamic nature of RNA structures and its functional significance in gene regulation.

scholarly journals The Role of Histone Lysine Methylation in the Response of Mammalian Cells to Ionizing Radiation

2021 ◽  
Vol 12 ◽  
Author(s):  
Elena Di Nisio ◽  
Giuseppe Lupo ◽  
Valerio Licursi ◽  
Rodolfo Negri
Keyword(s):  
Cell Lines ◽  
Protein Interactions ◽  
Mammalian Cells ◽  
Bioinformatic Analysis ◽  
Mrna Levels ◽  
Lysine Methylation ◽  
Histone Lysine Methylation ◽  
Cellular Processes ◽  
Histone Lysine

Eukaryotic genomes are wrapped around nucleosomes and organized into different levels of chromatin structure. Chromatin organization has a crucial role in regulating all cellular processes involving DNA-protein interactions, such as DNA transcription, replication, recombination and repair. Histone post-translational modifications (HPTMs) have a prominent role in chromatin regulation, acting as a sophisticated molecular code, which is interpreted by HPTM-specific effectors. Here, we review the role of histone lysine methylation changes in regulating the response to radiation-induced genotoxic damage in mammalian cells. We also discuss the role of histone methyltransferases (HMTs) and histone demethylases (HDMs) and the effects of the modulation of their expression and/or the pharmacological inhibition of their activity on the radio-sensitivity of different cell lines. Finally, we provide a bioinformatic analysis of published datasets showing how the mRNA levels of known HMTs and HDMs are modulated in different cell lines by exposure to different irradiation conditions.

scholarly journals Effects of Somatic Mutations in the C-Terminus of Insulin-Like Growth Factor 1 Receptor on Activity and Signaling

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Barbara P. Craddock ◽  
W. Todd Miller
Keyword(s):  
Growth Factor ◽  
Protein Interactions ◽  
Mammalian Cells ◽  
Somatic Mutations ◽  
Catalytic Domain ◽  
Human Cancer ◽  
Insulin Like Growth Factor ◽  
Tail Region ◽  
C Terminus

The insulin-like growth factor I receptor (IGF1R) is overexpressed in several forms of human cancer, and it has emerged as an important target for anticancer drug design. Cancer genome sequencing efforts have recently identified three somatic mutations in IGF1R: A1374V, a deletion of S1278 in the C-terminal tail region of the receptor, and M1255I in the C-terminal lobe of the kinase catalytic domain. The possible effects of these mutations on IGF1R activity and biological function have not previously been tested. Here, we tested the effects of the mutations on the in vitro biochemical activity of IGF1R and on major IGF1R signaling pathways in mammalian cells. While the mutations do not affect the intrinsic tyrosine kinase activity of the receptor, we demonstrate that the basal (unstimulated) levels of MAP kinase and Akt activation are increased in the mutants (relative to wild-type IGF1R). We hypothesize that the enhanced signaling potential of these mutants is due to changes in protein-protein interactions between the IGF1R C-terminus and cellular substrates or modulators.

Role of small nuclear RNAs in eukaryotic gene expression

2013 ◽  
Vol 54 ◽  
pp. 79-90 ◽  
Author(s):  
Saba Valadkhan ◽  
Lalith S. Gunawardane
Keyword(s):  
Gene Expression ◽  
Protein Interactions ◽  
Rna Stability ◽  
Splice Sites ◽  
Branch Site ◽  
Small Nuclear Rnas ◽  
Eukaryotic Gene Expression ◽  
Eukaryotic Gene ◽  
Rna Biogenesis

Eukaryotic cells contain small, highly abundant, nuclear-localized non-coding RNAs [snRNAs (small nuclear RNAs)] which play important roles in splicing of introns from primary genomic transcripts. Through a combination of RNA–RNA and RNA–protein interactions, two of the snRNPs, U1 and U2, recognize the splice sites and the branch site of introns. A complex remodelling of RNA–RNA and protein-based interactions follows, resulting in the assembly of catalytically competent spliceosomes, in which the snRNAs and their bound proteins play central roles. This process involves formation of extensive base-pairing interactions between U2 and U6, U6 and the 5′ splice site, and U5 and the exonic sequences immediately adjacent to the 5′ and 3′ splice sites. Thus RNA–RNA interactions involving U2, U5 and U6 help position the reacting groups of the first and second steps of splicing. In addition, U6 is also thought to participate in formation of the spliceosomal active site. Furthermore, emerging evidence suggests additional roles for snRNAs in regulation of various aspects of RNA biogenesis, from transcription to polyadenylation and RNA stability. These snRNP-mediated regulatory roles probably serve to ensure the co-ordination of the different processes involved in biogenesis of RNAs and point to the central importance of snRNAs in eukaryotic gene expression.

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