CARM1 (coactivator-associated arginine methyltransferase 1) belongs to a family of enzymes known as PRMTs (protein arginine methyltransferases), which can introduce arginine methylation. CARM1 is also referred to as PRMT4. Protein methylation, the addition of a methyl group to target proteins, is one type of post-translational modification that can change the function of the target proteins.
CARM1 has been reported to be overexpressed in breast cancer, and its overexpression is associated with high-grade tumors and poorer prognosis. So CARM1-specific inhibitors are considered a promising breast cancer therapy. However, until now only few targets of CARM1 have been identified, and how it recognizes these targets remains unclear.
Now, a team of researchers from the University of Wisconsin – Madison has mapped out the profile of CARM1 targets in breast cancer, by using the quantitative mass spectrometry. This may aid in the development of CARM1-spcific inhibitors for breast cancer treatment.
Study leader Prof. Wei Xu previously found two targets of CARM1: BAF155 and MED12. Additionally, CARM1-mediated BAF155 methylation correlates with breast cancer progression and metastasis. Other researchers include Evgenia Shishkova, Hao Zeng, Fabao Liu, Nicholas Kwiecien, Alexander Hebert, and Joshua Coon.
In this work, Xu's team employed multiple techniques including high-resolution mass spectrometry to globally profile CARM1 targets in two human breast cancer cell lines. They identified more than 300 CARM1-dependent arginine methylation events, and verified about 130 new CARM1 protein targets, many of which have cancer-related functions. Further, they also found that the N-terminus of CARM1 is necessary for target recognition and methylation. The researchers hypothesized that the design of CARM1-specific inhibitors should focus on the N-terminus of CARM1.
Overall, the study extends our knowledge of CARM1, provides insights into the working mechanism of other PRMTs, and opens up an avenue of drug discovery for breast cancer. Since CARM1 is also overexpressed in many other cancer types, the findings would have profound implications. (Cusabio offers CARM1, BAF155, MED12, and Recombinant Itgb7 proteins.)
The paper, "Global mapping of CARM1 substrates defines enzyme specificity and substrate recognition," appears in Nature Communications.

[PR]
# by whbio | 2017-05-27 00:59 | Comments(0)

A study in the Proceedings of the National Academy of Sciences (GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant-driven pancreatic tumorigenesis in mice) shows that inhibiting a specific protein may be a way to combat the deadly pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC), which accounts for 95% of all cases of pancreatic cancer, remains an aggressive type of malignant tumor in need of more effective therapies. The five-year survival rate is only about 5%, though surgery offers the only opportunity for a cure. In the United States alone, PDAC killed 39,590 people in 2014.

Mutations in the KRAS oncogene are present in 90% of PDACs. Previous studies have shown that KRAS mutations drive pancreatic tumorigenesis and is required for tumor maintenance, suggesting KRAS as a promising therapeutic target. However, the effect of drugs directly targeting KRAS turned out to be disappointing, highlighting the need to identify new therapeutic targets.

PDAC is very difficult to treat due to its excessive local invasion and early systemic dissemination. The glucose-regulated protein (GRP) is over-expressed in a variety of cancers including pancreatic cancer and associated with invasion and metastasis. Elevated GRP78 expression promotes the proliferation, migration, and invasion of pancreatic cancer cells and may predict poor prognosis in PDAC.

The new study describes an approach to stop the development of pancreatic cancer. In the work, the researchers demonstrated in a genetically engineered mouse model that expressing only 50% of the amount of GRP78 (a mechanism called haploinsufficiency ) stopped KRAS-driven pancreatic tumorigenesis. Further investigation showed that GRP78 haploinsufficiency in the pancreata led to reduction of epidermal growth factor receptor (EGFR), a protein that plays essential roles in both normal physiological conditions and cancerous conditions.

The researchers drew the conclusion that GRP78 is involved in PDAC development. Pharmacological inhibition of GRP78 could be a promising approach to improve the management of PDAC. (Cusabio offers Recombinant FGFR2, KRAS, GRP78, and EGFR proteins.)

[PR]
# by whbio | 2017-05-26 03:20 | Comments(0)

The flu, or called influenza, is quite prevalent worldwide, putting a burden on the health care system. Children, the elderly, diabetics, obese people, and those with compromised immune systems are at higher risk of having influenza, in comparison with the general population. The symptoms of influenza are similar to that of the common cold, but tend to be more severe. There are three types of influenza viruses, dubbed A, B, and C. Most case of influenza are caused by the influenza A virus (IAV).
In humans, the primary targets for influenza viruses are epithelial cells in the respiratory tract. When you get the flu, the virus turns infected lung cells into tiny factories that produce large numbers of new viral particles to spread the disease. How flu infection alters the metabolism of lung epithelial cells remains to be answered. In addition, there are no host targeted therapies, and viral resistance to the current frontline drugs is rising.
Now a study (Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention) appearing in Cell Reports offers a new approach to fight against influenza. The study, led by researchers from the University of Tennessee Health Science Center, St. Jude Children’s Research Hospital, and Pacific Northwest National Laboratory, showed increased glucose metabolism in pediatric patients with respiratory infection and identified metabolic changes induced by influenza. The researchers also found metabolic drugs that rescued mice from a lethal influenza infection.
An analysis of PET scans from 20 pediatric cancer patients with respiratory viral infections showed elevated glucose untake in their lungs. The researchers wondered whether this alteration was associated with viral infection. To answer the question, they used the means of quantitative proteomics to examine infected normal primary human bronchial epithelial (NHBE) cells, and found virus-associated increases in c-Myc, glycolysis, and glutaminolysis. These changes were important for viral replication.
Next, the researchers screened 80 metabolic drugs, and found that one drug called BEZ235 could reduce viral titers in flu-infected cells and improve the survival of flu-infected mice. BEZ235, which is a PI3K/mTOR dual inhibitor, is being tested as a cancer drug. This drug inhibits the PI3K and mTOR metabolic pathways that are critical for rapid cell division. In the future research, the team will investigate “how late into the course of influenza infection treatment with BEZ235 remains effective.” (Cusabio offers PI3K,mTOR, and other proteins like Recombinant AGTR1.)

[PR]
# by whbio | 2017-05-25 02:23 | Comments(0)

Alzheimer's disease (AD) was firstly described and named after a psychiatrist and pathologist Dr. Alois Alzheimer in 1906. It is an irreversible, progressive brain disorder that affects cognitive functions. Symptoms usually starts in patients’ mid-60s, but can also occur earlier. According to estimated, 5 million people in the USA have the disease, for which currently there are no treatments to stop or reverse the progression. Exiting therapies only temporarily improve symptoms. Its incidence is rising in line with the aging population. Mechanisms of AD have yet completely understood.

Published 26 April 2017 in Alzheimer’s Research and Therapy, a new study, carried out by Doris Lambracht-Washington, Min Fu, Pat Frost and Roger Rosenberg at UT Southwestern Medical Center, now reports a DNA vaccine that could protect against toxic proteins associated with AD. The researchers demonstrated that a DNA Aβ42 trimer vaccine led to high levels of antibody responses in rhesus macaques.

The accumulation of amyloid plaques between neurons in the brain is one of the markers of AD. This study showed that a vaccine that contains DNA of the toxic beta-amyloid (Aβ) protein can elicit a protective immune response. In the study, 6 rhesus monkeys received two different doses of the DNA Aβ42 trimer vaccine. The researchers monitored the humoral and cellular immune response in the animals. Results showed that the vaccine triggered high titer antibody responses (anti-Aβ42 IgG and IgA antibodies) in the monkeys. Moreover, these antibodies were able to detect amyloid plaques in the brain of an AD mouse model. Importantly, the vaccine did not accompany inflammatory interferon (IFN)-γ- and interleukin (IL)-17-producing T-cell responses. The researchers hope that their vaccine has protective effects in patients with early AD. (Cusabio produces and offers Biotin conjugated antibody.)

[PR]
# by whbio | 2017-05-24 11:02 | Comments(0)

Published in Nature Communications, a study sheds light on why mutations in KIAA1202 contribute to epilepsy and intellectual disability. The study is led by the Institute of Neuroscience of the National Research Council, the Università di Milano, Istituto Scientifico Ospedale San Raffaele, and the University of Modena and Reggio Emilia in the Italy, the University College London in the UK, University of Pittsburgh in the USA, Max Planck Institute for Molecular Genetics in the Germany, University of Basel in the Switzerland.

Intellectual disability (ID), once called mental retardation, is a generalized neurodevelopmental disorder characterized by limitations in intellectual functioning and in adaptive behavior. ID is estimated to affect 2-3% of the general population. This disability often has their onset before the age of 18, and patients typically have problems with everyday functions such as cognitive, language, motor, and social activities.

Epilepsy, a neurological disorder that causes people to have seizures, occurs more frequently in people with ID than in the general population. Previous studies have shown that some cases of epilepsy and intellectual disability are associated with mutations in a gene called KIAA1202. But the underlying mechanism remains unclear.

The KIAA1202 gene provides instructions for making a protein called Shrm4, which is only found in polarized tissues. The function of Shrm4 in the brain is unclear. The researchers demonstrated that Shrm4 plays a role in synaptogenesis and in maintaining GABABR-mediated inhibition. Without Shrm4, GABABR (GABAB receptors) are unable to reach synapses and exert their function.

GABAB receptors are metabotropic transmembrane receptors for GABA, the chief inhibitory neurotransmitter in the mammalian central nervous system. GABABR-mediated inhibition is crucial for synaptic plasticity, and dysfunction of these receptors is found in different neurological diseases.

The Shroom(Shrm) protein family has a key role in cytoskeletal organization. There are four types of Shrms proteins (Shrm1-4), which are localized to polarized tissues, such as neurons. In mice and humans, the Shrm family of proteins consists of Shrm2, Shrm3, and Shrm4. Previous studies have demonstrated that disruptions in Shrm4, which is encoded by the KIAA1202 gene (Xp11.2), is associated with mild-to-severe intellectual disability (ID) and increased susceptibility to seizures among humans. Now this study provide clear evidence that “disrupting Shrm4 expression are severe and manifest by increased anxiety, social behaviours impairments and a predisposition towards epilepsy.”

The study involves various analytical methods such as Western blots, GST pull-down and immunoprecipitation, Immunofluorescence and surface staining, Immunohistochemistry, and Immuno-Electron Microscopy. In these methods, various antibodies are used. By the way, CusAb is a manufacturer of bioproducts, including Shroom proteins, and Recombinant CLDN6.

[PR]
# by whbio | 2017-05-22 23:42 | Comments(0)