scholarly journals The MUC1 Cytoplasmic Tail and Tandem Repeat Domains Contribute to Mammary Oncogenesis in FVB Mice

2008 ◽  
Vol 1 ◽  
pp. BCBCR.S655
Author(s):  
Christine L. Hattrup ◽  
Judy M. Bradley ◽  
Kari L. Kotlarczyk ◽  
Cathy S. Madsen ◽  
Joseph G. Hentz ◽  
...  
Keyword(s):  
Mouse Models ◽  
Tandem Repeat ◽  
Late Onset ◽  
Cytoplasmic Tail ◽  
Mammary Carcinogenesis ◽  
Tumor Formation ◽  
Full Length ◽  
Relative Importance ◽  
Cancer Model ◽  
Repeat Domain

Background Though the importance of the transmembrane mucin MUC1 in mammary oncogenesis has long been recognized, the relative contributions of the cytoplasmic tail and tandem repeat domains are poorly understood. Methods To address this, mouse models of mammary carcinogenesis were created expressing full-length cytoplasmic tail-deleted, or tandem repeat-deleted MUC1 constructs. Results Overexpression of full-length MUC1 resulted in tumor formation in young mice (≤ 12 months); however, loss of either the cytoplasmic tail or the tandem repeat domain abrogated this oncogenic capacity. Aged mice in all strains developed late-onset mammary tumors similar to those previously described for the FVB background. Conclusions This study is the first spontaneous cancer model to address the relative importance of the cytoplasmic tail and tandem repeat domains to MUC1-driven mammary oncogenesis, and suggests that both of these domains are essential for tumor formation.

scholarly journals Development of a Novel Orthotopic Gastric Cancer Mouse Model

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Wonyoung Kang ◽  
Leigh Maher ◽  
Michael Michaud ◽  
Seong-Woo Bae ◽  
Seongyeong Kim ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Mouse Models ◽  
Cancer Metastasis ◽  
Soft Tissues ◽  
Tumor Formation ◽  
Cancer Model ◽  
Orthotopic Model ◽  
Cancer Models ◽  
Organotropic Metastasis ◽  
Nsg Mouse

Abstract Background Gastric cancer metastasis is a highly fatal disease with a five-year survival rate of less than 5%. One major obstacle in studying gastric cancer metastasis is the lack of faithful models available. The cancer xenograft mouse models are widely used to elucidate the mechanisms of cancer development and progression. Current procedures for creating cancer xenografts include both heterotopic (i.e., subcutaneous) and orthotopic transplantation methods. Compared to the heterotopic model, the orthotopic model has been shown to be the more clinically relevant design as it enables the development of cancer metastasis. Although there are several methods in use to develop the orthotopic gastric cancer model, there is not a model which uses various types of tumor materials, such as soft tissues, semi-liquid tissues, or culture derivatives, due to the technical challenges. Thus, developing the applicable orthotopic model which can utilize various tumor materials is essential. Results To overcome the known limitations of the current orthotopic gastric cancer models, such as exposure of tumor fragments to the neighboring organs or only using firm tissues for the orthotopic implantation, we have developed a new method allowing for the complete insertion of soft tissue fragments or homogeneously minced tissues into the stomach submucosa layer of the immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. With this completely-closed transplantation method, tumors with various types of tissue may be used to establish orthotopic gastric cancer models without the risks of exposure to nearby organs or cell leakage. This surgical procedure was highly reproducible in generating forty-eight mouse models with a surgery success rate of 96% and tumor formation of 93%. Among four orthotopic patient-derived xenograft (PDX) models that we generated in this study, we verified that the occurrence of organotropic metastasis in either the liver or peritoneal cavity was the same as that of the donor patients. Conclusion Here we describe a new protocol, step by step, for the establishment of orthotopic xenograft of gastric cancer. This novel technique will be able to increase the use of orthotopic models in broader applications for not only gastric cancer research but also any research related to the stomach microenvironment.

scholarly journals More than One Tandem Repeat Domain of the Extracellular Adherence Protein of Staphylococcus aureus Is Required for Aggregation, Adherence, and Host Cell Invasion but Not for Leukocyte Activation

2008 ◽  
Vol 76 (12) ◽  
pp. 5615-5623 ◽  
Author(s):  
Muzaffar Hussain ◽  
Axana Haggar ◽  
Georg Peters ◽  
Gursharan S. Chhatwal ◽  
Mathias Herrmann ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Host Cell ◽  
Tandem Repeat ◽  
Plasmon Resonance ◽  
Mononuclear Cells ◽  
Full Length ◽  
Host Cells ◽  
Repeat Domain ◽  
Thrombospondin 1 ◽  
Stimulation Of

ABSTRACT The extracellular adherence protein (Eap) is a multifunctional Staphylococcus aureus protein and broad-spectrum adhesin for several host matrix and plasma proteins. We investigated the interactions of full-length Eap and five recombinant tandem repeat domains with host proteins by use of surface plasmon resonance (BIAcore) and ligand overlay assays. In addition, agglutination and host cell interaction, namely, adherence, invasion, and stimulation of proliferation, were determined. With plasmon resonance, the interaction of full-length Eap isoforms (from strains Newman and Wood 46) with fibrinogen, fibronectin, vitronectin, and thrombospondin-1 was found to be specific but with different affinities for the ligands tested. In the ligand overlay assay, the interactions of five single tandem repeat domains (D1 to D5) of Eap-7 (from strain CI-7) with fibronectin, fibrinogen, vitronectin, thrombospondin-1, and collagen I differed substantially. Most prominently, D3 bound most strongly to fibronectin and fibrinogen. Full-length Eap, but none of the single tandem repeat domains, agglutinated S. aureus and enhanced adherence to and invasion of host cells by S. aureus. Constructs D3-4 and D1-3 (in cis) increased adherence and invasiveness compared to what was seen for single Eap tandem repeat domains. By contrast, single Eap tandem repeat domains and full-length Eap similarly modulated the proliferation of peripheral blood mononuclear cells (PBMCs): low concentrations stimulated, whereas high concentrations inhibited, proliferation. Taken together, the data indicate that Eap tandem repeat domains appear to have distinct characteristics for the binding of soluble ligands, despite a high degree of sequence similarity. In addition, more than one Eap tandem repeat domain is required for S. aureus agglutination, adherence, and cellular invasion but not for the stimulation of PBMC proliferation.

Telomere Length and Arsenic: Improving Animal Models of Toxicity by Choosing Mice With Shorter Telomeres

2021 ◽  
Vol 40 (3) ◽  
pp. 211-217
Author(s):  
Brayden Whitlock
Keyword(s):  
Animal Models ◽  
Telomere Length ◽  
Mouse Models ◽  
Arsenic Exposure ◽  
Tumor Formation ◽  
The Body ◽  
Cancer Resistance ◽  
Selective Pressures ◽  
Toxicity Monitoring ◽  
In Captivity

Arsenic is both a chemotherapeutic drug and an environmental toxicant that affects hundreds of millions of people each year. Arsenic exposure in drinking water has been called the worst poisoning in human history. How arsenic is handled in the body is frequently studied using rodent models to investigate how arsenic both causes and treats disease. These models, used in a variety of arsenic-related testing, from tumor formation to drug toxicity monitoring, have virtually always been developed from animals with telomeres that are unnaturally long, likely because of accidental artificial selective pressures. Mice that have been bred in captivity in laboratory conditions, often for over 100 years, are the standard in creating animal models for this research. Using these mice introduces challenges to any work that can be affected by the length of telomeres and the related capacities for tissue repair and cancer resistance. However, arsenic research is particularly susceptible to the misuse of such animal models due to the multiple and various interactions between arsenic and telomeres. Researchers in the field commonly find mouse models and humans behaving very differently upon exposure to acute and chronic arsenic, including drug therapies which seem safe in mice but are toxic in humans. Here, some complexities and apparent contradictions of the arsenic carcinogenicity and toxicity research are reconciled by an explanatory model that involves telomere length explained by the evolutionary pressures in laboratory mice. A low-risk hypothesis is proposed which has the power to determine whether researchers can easily develop more powerful and accurate mouse models by simply avoiding mouse lineages that are very old and have strangely long telomeres. Swapping in newer mouse lineages for the older, long-telomere mice may vastly improve our ability to research arsenic toxicity with virtually no increase in cost or difficulty of research.

scholarly journals The Cytoplasmic Tail of FPC Antagonizes the Full-Length Protein in the Regulation of mTOR Pathway

PLoS ONE ◽  
2014 ◽  
Vol 9 (5) ◽  
pp. e95630 ◽  
Author(s):  
Shixuan Wang ◽  
Maoqing Wu ◽  
Gang Yao ◽  
Jingjing Zhang ◽  
Jing Zhou
Keyword(s):  
Cytoplasmic Tail ◽  
Mtor Pathway ◽  
Full Length

scholarly journals Ehrlichia chaffeensis TRP120 nucleomodulin binds DNA with disordered tandem repeat domain

PLoS ONE ◽  
2018 ◽  
Vol 13 (4) ◽  
pp. e0194891 ◽  
Author(s):  
Valerie J. Klema ◽  
Krishna Mohan Sepuru ◽  
Nadia Füllbrunn ◽  
Tierra R. Farris ◽  
Paige S. Dunphy ◽  
...  
Keyword(s):  
Tandem Repeat ◽  
Ehrlichia Chaffeensis ◽  
Repeat Domain

scholarly journals Cardiac pathologies in mouse loss of imprinting models are due to misexpression of H19 long noncoding RNA

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Ki-Sun Park ◽  
Beenish Rahat ◽  
Hyung Chul Lee ◽  
Zu-Xi Yu ◽  
Jacob Noeker ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ventricular Function ◽  
Mouse Models ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Relative Importance ◽  
Maternal Loss ◽  
Loss Of Imprinting

Maternal loss of imprinting (LOI) at the H19/IGF2 locus results in biallelic IGF2 and reduced H19 expression and is associated with Beckwith-Wiedemann syndrome (BWS). We use mouse models for LOI to understand the relative importance of Igf2 and H19 mis-expression in BWS phenotypes. Here we focus on cardiovascular phenotypes and show that neonatal cardiomegaly is exclusively dependent on increased Igf2. Circulating IGF2 binds cardiomyocyte receptors to hyperactivate mTOR signaling, resulting in cellular hyperplasia and hypertrophy. These Igf2-dependent phenotypes are transient: cardiac size returns to normal once Igf2 expression is suppressed postnatally. However, reduced H19 expression is sufficient to cause progressive heart pathologies including fibrosis and reduced ventricular function. In the heart, H19 expression is primarily in endothelial cells (ECs) and regulates EC differentiation both, in vivo and in vitro. Finally, we establish novel mouse models to show that cardiac phenotypes depend on H19 lncRNA interactions with Mirlet7 microRNAs.

scholarly journals The Oncogenic Potential of a Mutant TP53 Gene Explored in Two Spontaneous Lung Cancer Mice Models

2020 ◽  
Author(s):  
Julian Ramelow ◽  
Christopher Brooks ◽  
Li GaO ◽  
Abeer A Almiman ◽  
Terence M Williams ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Mouse Models ◽  
Human Lung ◽  
Lung Tumor ◽  
Mutant Gene ◽  
Genetic Mutation ◽  
Tumor Formation ◽  
Human Lung Cancer ◽  
Oncogenic Potential ◽  
Age Related

Abstract BackgroundLung cancer is the number one cancer killer worldwide. A major impediment to progress in the lung cancer treatment field is the lack of realistic mouse models that replicate the complexity of human malignancy and immune contexture within the tumor microenvironment. Such models are urgently needed. Mutations of the tumor suppressor gene TP53 are among the most common alterations in human lung cancers.MethodsPreviously, we developed a line of lung cancer mouse model where mutant human TP53-273H is expressed in a lung specific manner in FVB/N background. To investigate whether the human TP53 mutant has a similar oncogenic potential when it is expressed in another strain of mouse, we crossed the FVB/N-SPC-TP53-273H mice to A/J strain and created A/J-SPC-TP53-273H transgenic mice. We then compared lung tumor formation between A/J-SPC-TP53-273H and FVB/N-SPC-TP53-273H.ResultsWe found the TP53-273H mutant gene has a similar oncogenic potential in lung tumor formation in both mice strains, although A/J strain mice have been found to be a highly susceptible strain in terms of carcinogen-induced lung cancer. Both transgenic lines survived more than 18 months and developed age related lung adenocarcinomas. With micro CT imaging, we found the FVB-SPC-TP53-273H mice survived more than 8 weeks after initial detection of lung cancer, providing a sufficient window for evaluating new anti-cancer agents.ConclusionsOncogenic potential of the most common genetic mutation, TP53-273H, in human lung cancer is unique when it is expressed in different strains of mice. Our mouse models are useful tools for testing novel immune check point inhibitors or other therapeutic strategies in treatment of lung cancer.

scholarly journals Similarities and differences between native HIV-1 envelope glycoprotein trimers and stabilized soluble trimer mimetics

2018 ◽  
Author(s):  
Alba Torrents de la Peña ◽  
Kimmo Rantalainen ◽  
Christopher A. Cottrell ◽  
Joel D. Allen ◽  
Marit J. van Gils ◽  
...  
Keyword(s):  
Envelope Glycoprotein ◽  
Neutralizing Antibodies ◽  
Transmembrane Domain ◽  
Cytoplasmic Tail ◽  
Full Length ◽  
Broadly Neutralizing Antibodies ◽  
Vaccine Research ◽  
Similarities And Differences ◽  
Membrane Tether ◽  
Hiv 1

AbstractThe HIV-1 envelope glycoprotein (Env) trimer is located on the surface of the virus and is the target of broadly neutralizing antibodies (bNAbs). Recombinant native-like soluble Env trimer mimetics, such as SOSIP trimers, have taken a central role in HIV-1 vaccine research aimed at inducing bNAbs. We therefore performed a direct and thorough comparison of a full-length native Env trimer containing the transmembrane domain and the cytoplasmic tail, with the sequence matched soluble SOSIP trimer, both based on an early Env sequence (AMC011) from an HIV+ individual that developed bNAbs. The structures of the full-length AMC011 trimer bound to either bNAb PGT145 or PGT151 were very similar to the structures of SOSIP trimers. Antigenically, the full-length and SOSIP trimers were comparable, but in contrast to the full-length trimer, the SOSIP trimer did not bind at all to non-neutralizing antibodies, most likely as a consequence of the intrinsic stabilization of the SOSIP trimer. Furthermore, the glycan composition of full-length and SOSIP trimers was similar overall, but the SOSIP trimer possessed slightly less complex and less extensively processed glycans, which may relate to the intrinsic stabilization as well as the absence of the membrane tether. These data provide insights into how to best use and improve membrane-associated full-length and soluble SOSIP HIV-1 Env trimers as immunogens.

PTEN PDZ-binding domain suppresses mammary carcinogenesis in the MMTV-PyMT breast cancer model

2018 ◽  
Vol 430 ◽  
pp. 67-78 ◽  
Author(s):  
Mingfei Yan ◽  
Yubing Wang ◽  
Chi Wai Wong ◽  
Penelope Mei-Yu Or ◽  
Kin Lok Wong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mammary Carcinogenesis ◽  
Binding Domain ◽  
Cancer Model ◽  
Breast Cancer Model
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