scholarly journals SAMHD1 in cancer: curse or cure?

2021 ◽  
Author(s):  
Kerstin Schott ◽  
Catharina Majer ◽  
Alla Bulashevska ◽  
Liam Childs ◽  
Mirko H. H. Schmidt ◽  
...  
Keyword(s):  
Tumor Development ◽  
Negative Regulator ◽  
Driver Gene ◽  
Cellular Functions ◽  
Dntp Pool ◽  
Dna Replication And Repair ◽  
Cancer Types ◽  
Dna End Resection ◽  
Underlying Mechanisms ◽  
Deoxyribonucleoside Triphosphate

AbstractHuman sterile α motif and HD domain-containing protein 1 (SAMHD1), originally described as the major cellular deoxyribonucleoside triphosphate triphosphohydrolase (dNTPase) balancing the intracellular deoxynucleotide (dNTP) pool, has come recently into focus of cancer research. As outlined in this review, SAMHD1 has been reported to be mutated in a variety of cancer types and the expression of SAMHD1 is dysregulated in many cancers. Therefore, SAMHD1 is regarded as a tumor suppressor in certain tumors. Moreover, it has been proposed that SAMHD1 might fulfill the requirements of a driver gene in tumor development or might promote a so-called mutator phenotype. Besides its role as a dNTPase, several novel cellular functions of SAMHD1 have come to light only recently, including a role as negative regulator of innate immune responses and as facilitator of DNA end resection during DNA replication and repair. Therefore, SAMHD1 can be placed at the crossroads of various cellular processes. The present review summarizes the negative role of SAMHD1 in chemotherapy sensitivity, highlights reported SAMHD1 mutations found in various cancer types, and aims to discuss functional consequences as well as underlying mechanisms of SAMHD1 dysregulation potentially involved in cancer development.

scholarly journals Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

2017 ◽  
Vol 114 (20) ◽  
pp. E4010-E4019 ◽  
Author(s):  
Eric Q. Wei ◽  
Daniel S. Sinden ◽  
Lan Mao ◽  
Hailin Zhang ◽  
Chuan Wang ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Pressure Overload ◽  
Negative Regulator ◽  
Relative Distribution ◽  
Coat Proteins ◽  
Structural Protein ◽  
Cellular Functions ◽  
Hypertrophic Response ◽  
Channel Current ◽  
Underlying Mechanisms

The fibroblast growth factor (FGF) homologous factor FGF13, a noncanonical FGF, has been best characterized as a voltage-gated Na+ channel auxiliary subunit. Other cellular functions have been suggested, but not explored. In inducible, cardiac-specific Fgf13 knockout mice, we found—even in the context of the expected reduction in Na+ channel current—an unanticipated protection from the maladaptive hypertrophic response to pressure overload. To uncover the underlying mechanisms, we searched for components of the FGF13 interactome in cardiomyocytes and discovered the complete set of the cavin family of caveolar coat proteins. Detailed biochemical investigations showed that FGF13 acts as a negative regulator of caveolae abundance in cardiomyocytes by controlling the relative distribution of cavin 1 between the sarcolemma and cytosol. In cardiac-specific Fgf13 knockout mice, cavin 1 redistribution to the sarcolemma stabilized the caveolar structural protein caveolin 3. The consequent increase in caveolae density afforded protection against pressure overload-induced cardiac dysfunction by two mechanisms: (i) enhancing cardioprotective signaling pathways enriched in caveolae, and (ii) increasing the caveolar membrane reserve available to buffer membrane tension. Thus, our results uncover unexpected roles for a FGF homologous factor and establish FGF13 as a regulator of caveolae-mediated mechanoprotection and adaptive hypertrophic signaling.

scholarly journals Characterization of the Survival Influential Genes in Carcinogenesis

2021 ◽  
Vol 22 (9) ◽  
pp. 4384
Author(s):  
Divya Sahu ◽  
Yu-Lin Chang ◽  
Yin-Chen Lin ◽  
Chen-Ching Lin
Keyword(s):  
Cell Cycle ◽  
Cox Regression ◽  
Monte Carlo Algorithm ◽  
Functional Modules ◽  
Protective Genes ◽  
Cancer Types ◽  
Underlying Mechanisms ◽  
Patient Prognosis ◽  
Pan Cancer

The genes influencing cancer patient mortality have been studied by survival analysis for many years. However, most studies utilized them only to support their findings associated with patient prognosis: their roles in carcinogenesis have not yet been revealed. Herein, we applied an in silico approach, integrating the Cox regression model with effect size estimated by the Monte Carlo algorithm, to screen survival-influential genes in more than 6000 tumor samples across 16 cancer types. We observed that the survival-influential genes had cancer-dependent properties. Moreover, the functional modules formed by the harmful genes were consistently associated with cell cycle in 12 out of the 16 cancer types and pan-cancer, showing that dysregulation of the cell cycle could harm patient prognosis in cancer. The functional modules formed by the protective genes are more diverse in cancers; the most prevalent functions are relevant for immune response, implying that patients with different cancer types might develop different mechanisms against carcinogenesis. We also identified a harmful set of 10 genes, with potential as prognostic biomarkers in pan-cancer. Briefly, our results demonstrated that the survival-influential genes could reveal underlying mechanisms in carcinogenesis and might provide clues for developing therapeutic targets for cancers.

scholarly journals Genetic background-dependent abnormalities of the enteric nervous system and intestinal function in Kif26a-deficient mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yukiko Ohara ◽  
Lisa Fujimura ◽  
Akemi Sakamoto ◽  
Youichi Teratake ◽  
Shuichi Hiraoka ◽  
...  
Keyword(s):  
Genetic Background ◽  
Survival Rates ◽  
Gastrointestinal Diseases ◽  
Negative Regulator ◽  
Enteric Neurons ◽  
Enteric Neuron ◽  
Protein Coding ◽  
Underlying Mechanisms ◽  
Functional Gastrointestinal Diseases ◽  
Deficient Mice

AbstractThe Kif26a protein-coding gene has been identified as a negative regulator of the GDNF-Ret signaling pathway in enteric neurons. The aim of this study was to investigate the influence of genetic background on the phenotype of Kif26a-deficient (KO, −/−) mice. KO mice with both C57BL/6 and BALB/c genetic backgrounds were established. Survival rates and megacolon development were compared between these two strains of KO mice. Functional bowel assessments and enteric neuron histopathology were performed in the deficient mice. KO mice with the BALB/c genetic background survived more than 400 days without evidence of megacolon, while all C57BL/6 KO mice developed megacolon and died within 30 days. Local enteric neuron hyperplasia in the colon and functional bowel abnormalities were observed in BALB/c KO mice. These results indicated that megacolon and enteric neuron hyperplasia in KO mice are influenced by the genetic background. BALB/c KO mice may represent a viable model for functional gastrointestinal diseases such as chronic constipation, facilitating studies on the underlying mechanisms and providing a foundation for the development of treatments.

scholarly journals miRNA Mediated Noise Making of 3′UTR Mutations in Cancer

Genes ◽  
2018 ◽  
Vol 9 (11) ◽  
pp. 545 ◽  
Author(s):  
Wei Wu ◽  
Lingxiang Wu ◽  
Mengyan Zhu ◽  
Ziyu Wang ◽  
Min Wu ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Target Genes ◽  
Expression Profiles ◽  
Tumor Development ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Messenger Rnas ◽  
Cellular Functions ◽  
Mrna Binding

Somatic mutations in 3′-untranslated regions (3′UTR) do not alter amino acids and are considered to be silent in cancers. We found that such mutations can promote tumor progression by altering microRNA (miRNA) targeting efficiency and consequently affecting miRNA–mRNA interactions. We identified 67,159 somatic mutations located in the 3′UTRs of messenger RNAs (mRNAs) which can alter miRNA–mRNA interactions (functional somatic mutations, funcMutations), and 69.3% of these funcMutations (the degree of energy change > 12 kcal/mol) were identified to significantly promote loss of miRNA-mRNA binding. By integrating mRNA expression profiles of 21 cancer types, we found that the expression of target genes was positively correlated with the loss of absolute affinity level and negatively correlated with the gain of absolute affinity level. Functional enrichment analysis revealed that genes carrying funcMutations were significantly enriched in the MAPK and WNT signaling pathways, and analysis of regulatory modules identified eighteen miRNA modules involved with similar cellular functions. Our findings elucidate a complex relationship between miRNA, mRNA, and mutations, and suggest that 3′UTR mutations may play an important role in tumor development.

scholarly journals Clinical Impact of Sphingosine-1-Phosphate in Breast Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Junko Tsuchida ◽  
Masayuki Nagahashi ◽  
Kazuaki Takabe ◽  
Toshifumi Wakai
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Cancer Metastasis ◽  
Clinical Importance ◽  
Breast Cancer Metastasis ◽  
Lipid Mediator ◽  
Breast Cancer Patients ◽  
Cellular Functions ◽  
Sphingosine 1 Phosphate ◽  
Underlying Mechanisms

Breast cancer metastasizes to lymph nodes or other organs, which determine the prognosis of patients. It is difficult to cure the breast cancer patients with distant metastasis due to resistance to drug therapies. Elucidating the underlying mechanisms of breast cancer metastasis and drug resistance is expected to provide new therapeutic targets. Sphingosine-1-phosphate (S1P) is a pleiotropic, bioactive lipid mediator that regulates many cellular functions, including proliferation, migration, survival, angiogenesis/lymphangiogenesis, and immune responses. S1P is formed in cells by sphingosine kinases and released from them, which acts in an autocrine, paracrine, and/or endocrine manner. S1P in extracellular space, such as interstitial fluid, interacts with components in the tumor microenvironment, which may be important for metastasis. Importantly, recent translational research has demonstrated an association between S1P levels in breast cancer patients and clinical outcomes, highlighting the clinical importance of S1P in breast cancer. We suggest that S1P is one of the key molecules to overcome the resistance to the drug therapies, such as hormonal therapy, anti-HER2 therapy, or chemotherapy, all of which are crucial aspects of a breast cancer treatment.

scholarly journals Toll-Interacting Protein, Tollip, Inhibits IL-13-Mediated Pulmonary Eosinophilic Inflammation in Mice

2018 ◽  
Vol 10 (2) ◽  
pp. 106-118 ◽  
Author(s):  
Yoko Ito ◽  
Niccolette Schaefer ◽  
Amelia Sanchez ◽  
David Francisco ◽  
Rafeul Alam ◽  
...  
Keyword(s):  
Lung Inflammation ◽  
Negative Regulator ◽  
Airflow Limitation ◽  
Eosinophilic Inflammation ◽  
Interacting Protein ◽  
Proinflammatory Responses ◽  
Cytokine Milieu ◽  
Underlying Mechanisms

Toll-interacting protein (Tollip) is a key negative regulator of innate immunity by preventing excessive proinflammatory responses. Tollip genetic variation has been associated with airflow limitation in asthma subjects and Tollip expression. Whether Tollip regulates lung inflammation in a type 2 cytokine milieu (e.g., IL-13) is unclear. Our goal was to determine the in vivo role of Tollip in IL-13-mediated lung eosinophilic inflammation and the underlying mechanisms. Tollip-knockout (KO) and wild-type (WT) mice were inoculated intranasally with recombinant mouse IL-13 protein to examine lung inflammation. To determine how Tollip regulates inflammation, alveolar macrophages and bone marrow-derived macrophages from Tollip KO and WT mice were cultured with or without IL-13 and/or IL-33. IL-13-treated Tollip KO mice significantly increased lung eosinophilic inflammation and eotaxin-2 (CCL24) levels compared with the WT mice. IL-13- treated Tollip KO (vs. WT) macrophages, in the absence and particularly in the presence of IL-33, increased expression of the IL-33 receptor ST2L and CCL24, which was in part dependent on enhanced activation of interleukin (IL)-1 receptor-associated kinase 1 (IRAK1) and signal transducer and activator of transcription 6 (STAT6). Our results suggest that Tollip downregulates IL-13-mediated pulmonary eosinophilia in part through inhibiting the activity of the ST2L/IL-33/IRAK1 axis and STAT6.

scholarly journals Secondary Somatic Mutations in G-Protein-Related Pathways and Mutation Signatures in Uveal Melanoma

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1688 ◽  
Author(s):  
Francesca Piaggio ◽  
Veronica Tozzo ◽  
Cinzia Bernardi ◽  
Michela Croce ◽  
Roberto Puzone ◽  
...  
Keyword(s):  
G Protein ◽  
Uveal Melanoma ◽  
Tumor Development ◽  
Splicing Factor ◽  
Driver Mutations ◽  
Driver Gene ◽  
Protein Subunit ◽  
Mutational Signatures ◽  
Kegg Pathways ◽  
Tyrosine Kinase 2

Background: Uveal melanoma (UM), a rare cancer of the eye, is characterized by initiating mutations in the genes G-protein subunit alpha Q (GNAQ), G-protein subunit alpha 11 (GNA11), cysteinyl leukotriene receptor 2 (CYSLTR2), and phospholipase C beta 4 (PLCB4) and by metastasis-promoting mutations in the genes splicing factor 3B1 (SF3B1), serine and arginine rich splicing factor 2 (SRSF2), and BRCA1-associated protein 1 (BAP1). Here, we tested the hypothesis that additional mutations, though occurring in only a few cases (“secondary drivers”), might influence tumor development. Methods: We analyzed all the 4125 mutations detected in exome sequencing datasets, comprising a total of 139 Ums, and tested the enrichment of secondary drivers in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that also contained the initiating mutations. We searched for additional mutations in the putative secondary driver gene protein tyrosine kinase 2 beta (PTK2B) and we developed new mutational signatures that explain the mutational pattern observed in UM. Results: Secondary drivers were significantly enriched in KEGG pathways that also contained GNAQ and GNA11, such as the calcium-signaling pathway. Many of the secondary drivers were known cancer driver genes and were strongly associated with metastasis and survival. We identified additional mutations in PTK2B. Sparse dictionary learning allowed for the identification of mutational signatures specific for UM. Conclusions: A considerable part of rare mutations that occur in addition to known driver mutations are likely to affect tumor development and progression.

scholarly journals Emodin promotes apoptosis of human endometrial cancer through regulating the MAPK and PI3K/ AKT pathways

2019 ◽  
Vol 13 (1) ◽  
pp. 489-496 ◽  
Author(s):  
Jun Jiang ◽  
Nanyang Zhou ◽  
Pian Ying ◽  
Ting Zhang ◽  
Ruojia Liang ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Signaling Pathways ◽  
Tumor Development ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Western Blot Assay ◽  
Anti Oxidant ◽  
Underlying Mechanisms ◽  
Induced Apoptosis ◽  
Dose Dependent

AbstractEmodin, a major component of rhubarb, has anti-tumor effects in a variety of cancers, influencing multiple steps of tumor development through modulating several signaling pathways. The aim of this study is to examine the effect of emodin on cell apoptosis and explore the underlying mechanisms in human endometrial cancer cells. Here we report that emodin can inhibit KLE cell proliferation and induce apoptosis in a time- and dose-dependent manner. Western blot assay found that emodin was involved in MAPK and PI3K/Akt signaling pathways. Specifically, emodin significantly suppressed the phosphorylation of AKT, and enhanced the phosphorylation of MAPK pathways. Furthermore, the generation of reactive oxygen species (ROS) was up-regulated in KLE cells upon treatment with emodin, while the anti-oxidant agent N-acetyl cysteine (NAC) can inhibit emodin-induced apoptosis and promote the activation of AKT and Bcl-2. Taken together, we revealed that emodin may induce apoptosis in KLE cells through regulating the PI3K/AKT and MAPK signaling pathways, indicating the importance of emodin as an anti-tumor agent.

scholarly journals A Systematic Pan-Cancer Analysis of Genetic Heterogeneity Reveals Associations with Epigenetic Modifiers

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 391 ◽  
Author(s):  
Mafalda de Matos ◽  
Ioana Posa ◽  
Filipa Carvalho ◽  
Vanessa Morais ◽  
Ana Grosso ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Genetic Heterogeneity ◽  
Dna Methyltransferase ◽  
Tumor Development ◽  
Predictive Biomarkers ◽  
Cell Populations ◽  
Major Mechanism ◽  
Molecular Features ◽  
Genome Wide ◽  
Cancer Types

Intratumor genetic heterogeneity (ITH) is the main obstacle to effective cancer treatment and a major mechanism of drug resistance. It results from the continuous evolution of different clones of a tumor over time. However, the molecular features underlying the emergence of genetically-distinct subclonal cell populations remain elusive. Here, we conducted an exhaustive characterization of ITH across 2807 tumor samples from 16 cancer types. Integration of ITH scores and somatic variants detected in each tumor sample revealed that mutations in epigenetic modifier genes are associated with higher ITH levels. In particular, genes that regulate genome-wide histone and DNA methylation emerged as being determinant of high ITH. Indeed, the knockout of histone methyltransferase SETD2 or DNA methyltransferase DNMT3A using the CRISPR/Cas9 system on cancer cells led to significant expansion of genetically-distinct clones and culminated in highly heterogeneous cell populations. The ITH scores observed in knockout cells recapitulated the heterogeneity levels observed in patient tumor samples and correlated with a better mitochondrial bioenergetic performance under stress conditions. Our work provides new insights into tumor development, and discloses new drivers of ITH, which may be useful as either predictive biomarkers or therapeutic targets to improve cancer treatment.

Invited Review: Engineering approaches to cytoskeletal mechanics

2000 ◽  
Vol 89 (5) ◽  
pp. 2085-2090 ◽  
Author(s):  
Dimitrije Stamenović ◽  
Ning Wang
Keyword(s):  
Cell Biology ◽  
Theoretical Models ◽  
Force Balance ◽  
Mechanical Forces ◽  
Cellular Functions ◽  
Cellular Mechanics ◽  
Recent Developments ◽  
Biochemical Mechanisms ◽  
Underlying Mechanisms ◽  
Biochemical Signals

An outstanding problem in cell biology is how cells sense mechanical forces and how those forces affect cellular functions. Various biophysical and biochemical mechanisms have been invoked to answer this question. A growing body of evidence indicates that the deformable cytoskeleton (CSK), an intracellular network of interconnected filamentous biopolymers, provides a physical basis for transducing mechanical signals into biochemical signals. Therefore, to understand how mechanical forces regulate cellular functions, it is important to know how cells respond to changes in the CSK force balance and to identify the underlying mechanisms that control transmission of mechanical forces throughout the CSK and bring it to equilibrium. Recent developments of new experimental techniques for measuring cell mechanical properties and novel theoretical models of cellular mechanics make it now possible to identify and quantitate the contributions of various CSK structures to the overall balance of mechanical forces in the cell. This review focuses on engineering approaches that have been used in the past two decades in studies of the mechanics of the CSK.

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