Advertisement

Topics

Loss of atrx cooperates with p53-deficiency to promote the development of sarcomas and other malignancies.

08:00 EDT 10th April 2019 | BioPortfolio

Summary of "Loss of atrx cooperates with p53-deficiency to promote the development of sarcomas and other malignancies."

The SWI/SNF-family chromatin remodeling protein ATRX is a tumor suppressor in sarcomas, gliomas and other malignancies. Its loss of function facilitates the alternative lengthening of telomeres (ALT) pathway in tumor cells, while it also affects Polycomb repressive complex 2 (PRC2) silencing of its target genes. To further define the role of inactivating ATRX mutations in carcinogenesis, we knocked out atrx in our previously reported p53/nf1-deficient zebrafish line that develops malignant peripheral nerve sheath tumors and gliomas. Complete inactivation of atrx using CRISPR/Cas9 was lethal in developing fish and resulted in an alpha-thalassemia-like phenotype including reduced alpha-globin expression. In p53/nf1-deficient zebrafish neither peripheral nerve sheath tumors nor gliomas showed accelerated onset in atrx+/- fish, but these fish developed various tumors that were not observed in their atrx+/+ siblings, including epithelioid sarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma and rare types of carcinoma. These cancer types are included in the AACR Genie database of human tumors associated with mutant ATRX, indicating that our zebrafish model reliably mimics a role for ATRX-loss in the early pathogenesis of these human cancer types. RNA-seq of p53/nf1- and p53/nf1/atrx-deficient tumors revealed that down-regulation of telomerase accompanied ALT-mediated lengthening of the telomeres in atrx-mutant samples. Moreover, inactivating mutations in atrx disturbed PRC2-target gene silencing, indicating a connection between ATRX loss and PRC2 dysfunction in cancer development.

Affiliation

Journal Details

This article was published in the following journal.

Name: PLoS genetics
ISSN: 1553-7404
Pages: e1008039

Links

DeepDyve research library

PubMed Articles [17523 Associated PubMed Articles listed on BioPortfolio]

ATRX loss induces multiple hallmarks of the alternative lengthening of telomeres (ALT) phenotype in human glioma cell lines in a cell line-specific manner.

Cancers must maintain their telomeres at lengths sufficient for cell survival. In several cancer subtypes, a recombination-like mechanism termed alternative lengthening of telomeres (ALT), is frequent...

ATRX promotes maintenance of herpes simplex virus heterochromatin during chromatin stress.

The mechanisms by which mammalian cells recognize and epigenetically restrict viral DNA are not well defined. We used herpes simplex virus with bioorthogonally labeled genomes to detect host factors r...

Loss of ATRX/DAXX expression and alternative lengthening of telomeres in uterine leiomyomas.

Uterine leiomyomas (ULs) are the most common gynecologic tumors and affect 3 of every 4 women by the age of 50 years. The majority of ULs are classified as conventional tumors, whereas 10% represent v...

Serum Levels of Asymmetric and Symmetric Dimethylarginine in Women with Vitamin D Deficiency and History of Pregnancy Loss - A Pilot Study.

Vitamin D deficiency has been reported to be associated with pregnancy loss. Asymmetric dimethyl-L-arginine (ADMA) and symmetric dimethyl-L-arginine (SDMA) are arginine analogues that have direct and ...

RANK deletion in NPY neurons attenuates estrogen deficiency related bone loss.

The RANKL pathway is known to be an important aspect of the pathogenesis of estrogen-deficiency induced bone loss. RANK deletion specifically in NPY neurons has been shown to enhance the ability of th...

Clinical Trials [7314 Associated Clinical Trials listed on BioPortfolio]

Cognitive and Self-regulatory Mechanisms Of Obesity Study

This study will be the first clinical trial to examine the impact of two different weight loss interventions on novel mechanisms that promote obesity and impede its successful treatment, i...

Clinical Observational Study: IBD Patients With Restless-legs-syndrome and Iron Deficiency Syndrome

Patients with inflammatory bowel disease, such as Crohn´s disease or ulcerative colitis, have recurring episodes of abdominal pain, diarrhea and loss of weight. Besides this other clinica...

Cobalamin Status in Young Children With Developmental Delay

During fetal life and infancy, an adequate cobalamin status is important for normal growth and central nervous system development. During the last years we have detected cobalamin deficien...

Cobalamin Status in Young Children With Gastrointestinal Symptoms or Feeding Problems

During fetal life and infancy, an adequate cobalamin status is important for normal growth and central nervous system development. During the last years we have detected cobalamin deficien...

Iron Supplementation of Marginally Low Birth Weight Infants

Iron is essential for brain development and there is a well established association between iron deficiency in infants and poor neurological development. In Sweden, about 5% of newborns ha...

Medical and Biotech [MESH] Definitions

ATP-dependent DNA helicase that contains two N-terminal ZINC FINGERS and C-terminal ATP-binding and helicase domains. It functions in the regulation of gene transcription and CHROMATIN REMODELING. ATRX undergoes cell-cycle dependent phosphorylation, which causes it to translocate from the NUCLEAR MATRIX to CHROMATIN; thus, it may change its role from gene regulation during INTERPHASE to ensuring proper chromosome segregation at MITOSIS. Mutations in the ATRX gene are associated with cases of X-LINKED MENTAL RETARDATION co-morbid with ALPHA-THALASSEMIA (ATRX syndrome).

A condition produced by a deficiency of CHOLINE in animals. Choline is known as a lipotropic agent because it has been shown to promote the transport of excess fat from the liver under certain conditions in laboratory animals. Combined deficiency of choline (included in the B vitamin complex) and all other methyl group donors causes liver cirrhosis in some animals. Unlike compounds normally considered as vitamins, choline does not serve as a cofactor in enzymatic reactions. (From Saunders Dictionary & Encyclopedia of Laboratory Medicine and Technology, 1984)

Early pregnancy loss during the EMBRYO, MAMMALIAN stage of development. In the human, this period comprises the second through eighth week after fertilization.

A nutritional condition produced by a deficiency of proteins in the diet, characterized by adaptive enzyme changes in the liver, increase in amino acid synthetases, and diminution of urea formation, thus conserving nitrogen and reducing its loss in the urine. Growth, immune response, repair, and production of enzymes and hormones are all impaired in severe protein deficiency. Protein deficiency may also arise in the face of adequate protein intake if the protein is of poor quality (i.e., the content of one or more amino acids is inadequate and thus becomes the limiting factor in protein utilization). (From Merck Manual, 16th ed; Harrison's Principles of Internal Medicine, 12th ed, p406)

A nutritional condition produced by a deficiency of THIAMINE in the diet, characterized by anorexia, irritability, and weight loss. Later, patients experience weakness, peripheral neuropathy, headache, and tachycardia. In addition to being caused by a poor diet, thiamine deficiency in the United States most commonly occurs as a result of alcoholism, since ethanol interferes with thiamine absorption. In countries relying on polished rice as a dietary staple, BERIBERI prevalence is very high. (From Cecil Textbook of Medicine, 19th ed, p1171)

Advertisement
Quick Search
Advertisement
Advertisement

 


DeepDyve research library

Relevant Topics

Nutrition
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...

Brain Cancer
According to the American Brain Tumor Association, just over 24,000 patients will be diagnosed with a primary malignant brain tumour during 2012 in the US alone. Some 80% of primary malignant brain tumours are gliomas, a broad term which includes all tum...


Searches Linking to this Article