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RESEARCHERS UNCOVER KEY CANCER-PROMOTING GENE

Thu, 08 Jan 2015 13:39:43 GMT

One of the mysteries in cancer biology is how one protein, TGF-beta, can both stop cancer from forming and encourage its aggressive growth.

Now, researchers at the University of Michigan Comprehensive Cancer Center have uncovered a key gene that may explain this paradox and provide a potential target for treatment.

TGF-beta is known as a tumor suppressor, meaning it’s necessary to keep cells in check and growing normally. But at some point, its function flips and it becomes a tumor promoter, fostering aggressive growth and spread of cancer. The researchers identified Bub1 as a key gene involved in regulating TGF-beta receptor.

The study is published in Science Signaling.

“Our data that Bub1 is involved at the receptor level is completely unexpected,” says study director Alnawaz Rehemtulla, Ph.D., Ruth Tuttle Freeman Research Professor of radiation oncology and radiology and co-director of the Center for Molecular Imaging at the University of Michigan Medical School.

“Bub1 is well-known for its role in cell division. But this is the first study that links it to TGF-beta. We think this may explain the paradox of TGF-beta as a tumor promoter and a tumor suppressor,” he adds.

The team of researchers at the University of Michigan, including Shyam Nyati, Ph.D., and Brian D. Ross, Ph.D., developed a way to screen for genes that regulate the TGF-beta receptor. When 720 genes from the human genome were screened against lung cancer and breast cancer cells, Bub1 emerged as playing a strong role in TGF-beta signaling.

Bub1 was shown to bind to the TGF-beta receptor and allows it to turn on aggressive cell growth. When the researchers blocked Bub1, it shut down the TGF-beta pathway completely. TGF-beta is known to play a role in cells developing characteristics of aggressive cancer cells. Researchers also have known that Bub1 is highly expressed in many different types of cancer.

Because Bub1 is found in many types of cancer, developing a drug to target it could potentially impact multiple cancers. A compound to target Bub1 has been developed but is not ready for testing in patients. Initial lab testing suggests that a Bub1 inhibitor can very specifically target Bub1 without causing damage to other parts of the cell.

“When you look at gene expression in cancer, Bub1 is in the top five. In addition, Bub1 expression levels correlate with outcome in patients with lung and breast cancer. But we never knew why. Now that we have that link, we’re a step closer to shutting down this cycle,” Rehemtulla says.

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The above story is based on materials provided by University of Michigan Health System . Note: Materials may be edited for content and length .

PROTEIN ONE FIRST IN PROTEIN INNOVATION

Wed, 07 Jan 2015 17:01:04 GMT

Protein One is a development stage biotechnology company. The primary aim of the company is to deliver high quality purified, biologically active proteins to research labs, medical institutions and pharmaceutical companies via a Universal Protein Array (UPA) under development by the company to help companies with their drug discovery program.

In an effort to advance systems biology research, Protein One offers protein mutation or modification services which may very well enhance understanding of these protein alterations in mediating biological activities.

The purified proteins will be sold in two different formats: through the patent pending UPA system, or Individually by request. The company’s aim is to include over 300 purified active proteins in our inventory within two years, and to successfully transfer from a prototype to an operationally complete model of the UPA.

Protein One's expertise in active protein production allows us to provide customers with functionally active and highly purified recombinant proteins as well as native protein fractions from mammalian cells. Our product lines include general transcription factors, transcriptional activators and coactivators, pre-mRNA processing factors, tumor suppressors and other cancer related proteins.

Strategy & Focus

It is Protein One’s intent to maintain a leadership position in the proteomics industry by producing protein based Life Science Bioreagents. The purification of unique recombinant proteins, the creation of various protein array platforms and assay kits will enable scientists to further understand protein function and subsequently create new science applications and novel protein based drug discovery.

The scientific team continues to work towards the short term purification of a 500 recombinant protein catalog to include some complex, high market utility and very difficult to purify proteins many of which will only be available from Protein One. These diverse protein products associated with transcription, nuclear receptors, cancer and other diseases will form a basis for research use tools which will evolve into GMP products for clinical therapeutic and diagnostic utility in the near future.

TBP (TATA BOX BINDING PROTEIN)

Wed, 07 Jan 2015 16:56:34 GMT

The Cellular TATA Binding Protein is Required for Rep-Dependent Replication of a Minimal Adeno-Associated Virus Type 2 p5 Element.

The p5 promoter region of adeno-associated virus type 2 (AAV-2) is a multifunctional element involved in rep gene expression, Rep-dependent replication, and site-specific integration. We initially characterized a 350-bp p5 region by its ability to behave like a cis-acting replication element in the presence of Rep proteins and adenoviral factors. The objective of this study was to define the minimal elements within the p5 region required for Rep-dependent replication. Assays performed in transfected cells (in vivo) indicated that the minimal p5 element was composed by a 55-bp sequence (nucleotides 250 to 304 of wild-type AAV-2) containing the TATA box, the Rep binding site, the terminal resolution site present at the transcription initiation site (trs+1), and a downstream 17-bp region that could potentially form a hairpin structure localizing the trs+1 at the top of the loop. Interestingly, the TATA box was absolutely required for in vivo but dispensable for in vitro, i.e., cell-free, replication. We also demonstrated that Rep binding and nicking at the trs+1 was enhanced in the presence of the cellular TATA binding protein, and that overexpression of this cellular factor increased in vivo replication of the minimal p5 element. Together, these studies identified the minimal replication origin present within the AAV-2 p5 promoter region and demonstrated for the first time the involvement of the TATA box, in cis, and of the TATA binding protein, in trans, for Rep-dependent replication of this viral element.

What is the official name of the TBP gene?

The official name of this gene is “TATA box binding protein.”

TBP is the gene's official symbol. The TBP gene is also known by other names.

What is the normal function of the TBP gene?

The TBP gene provides instructions for making a protein called the TATA box binding protein. This protein is active in cells and tissues throughout the body, where it plays an essential role in regulating the activity of most genes.

The TATA box binding protein attaches (binds) to a particular sequence of DNA known as the TATA box. This sequence occurs in a regulatory region of DNA near the beginning of many genes. Once the protein is attached to the TATA box near a gene, it acts as a landmark to indicate where other enzymes should start reading the gene. The process of reading a gene's DNA and transferring the information to a similar molecule called mRNA is known as transcription.

One region of the TBP gene contains a particular DNA segment known as a CAG/CAA trinucleotide repeat. This segment is made up of a series of three DNA building blocks (nucleotides) that appear multiple times in a row. Normally, the CAG/CAA segment is repeated 25 to 42 times within the gene.

How are changes in the TBP gene related to health conditions?

Huntington disease-like syndrome - caused by mutations in the TBP gene

A particular type of mutation in the TBP gene has been found to cause a progressive brain disorder known as Huntington disease-like 4 (HDL4) or spinocerebellar ataxia type 17 (SCA17). The features of this disorder vary widely among affected individuals. The condition was first described as HDL4 in people whose signs and symptoms closely resembled those of Huntington disease, including uncontrolled movements, emotional problems, and loss of thinking ability.

The disorder is now more commonly known as SCA17 because difficulty coordinating movements (ataxia) and other movement problems are the most frequent signs and symptoms. It is unknown why some people with TBP mutations have a disorder resembling Huntington disease, while others have more prominent ataxia.

The mutation associated with HDL4/SCA17 increases the size of the CAG/CAA trinucleotide repeat in the TBP gene. People with this condition have 43 to 66 CAG/CAA repeats. People with 43 to 48 CAG/CAA repeats may or may not have signs and symptoms, while people with 49 or more repeats almost always develop the disorder.

An increased number of CAG/CAA repeats in the TBP gene leads to the production of an abnormally long version of the TATA box binding protein. The abnormal protein builds up in nerve cells (neurons) in the brain and disrupts the normal functions of these cells. The dysfunction and eventual death of neurons in certain areas of the brain underlie the signs and symptoms of HDL4/SCA17. Because the TBP gene is active throughout the body, it is unclear why the effects of a mutation in this gene are limited to the brain.

Where is the TBP gene located?

Cytogenetic Location: 6q27

Molecular Location on chromosome 6: base pairs 170,554,332 to 170,572,869

TRANSCRIPTION FACTOR II B

Wed, 07 Jan 2015 16:50:55 GMT

Tubon et al., "Nonconserved Surface of the TFIIB Zinc Ribbon Domain Plays a Direct Role in RNA Polymerase II Recruitment", Molecular and Cellular Biology, 24:2863-2874, April 2004

Transcription factor IIB (TFIIB) is one of several general transcription factors that make up the RNA polymerase II preinitiation complex. It is encoded by the TFIIB gene. Transcription factor IIB localizes to the nucleus where it forms a complex (the DAB complex) with transcription factors IID and IIA. The protein serves as a bridge between transcription factor IID, which initially recognizes the promoter sequence, and RNA polymerase II. It is involved in the selection of the transcription start site; mutations in TFIIB cause a shift in the transcription start site.

Interactions

Transcription factor IIB makes protein-protein interactions with the TATA-binding protein (TBP) subunit of transcription factor IID, and the RPB1 subunit of RNA polymerase II.

Transcription Factor IIB makes sequence-specific protein-DNA interactions with the B recognition element (BRE), a promoter element flanking the TATA element. The role of TFIIB in the vast number of human promoters lacking TATA and BRE elements remains unclear.

Recent study shows that TFIIB links transcription inhibition with the p53-dependent DNA damage response.

NOVARTIS TAPS INTO GENE EDITING FOR NEXT GENERATION DRUGS

Wed, 07 Jan 2015 16:39:11 GMT

Novartis is diving deeper into the world of gene-based medicine by signing deals with two U.S. biotech companies, giving it access to a powerful new genome editing technology.

The tie-ups with unlisted Intellia Therapeutics and Caribou Biosciences show the Swiss drugmaker's confidence in the potential of so-called CRISPR technology, both for making new medicines and as a research tool.

CRISPR, which stands for clustered regularly interspaced short palindromic repeats, allows scientists to edit the genes of selected cells accurately and efficiently. It has created great excitement since emerging two years ago and is being tipped for a Nobel Prize.

While current gene therapy approaches involve adding genes to affected cells, CRISPR opens up the possibility of correcting those cells' faulty genes in the lab before returning them to the patient.

Translating that promise into new treatments will take many years but Novartis' decision to apply the technology in its research labs is an important endorsement, since the company is the world's largest drugmaker by sales.

It is also a sign the Swiss group intends to be at the forefront of the nascent field, after recently establishing a new cell and gene therapies unit within the company.

Mark Fishman, head of the Novartis Institutes for BioMedical Research (NIBR), said genome editing could open a new branch of medicine, leading to cures for diseases caused by faulty genes.

"We have glimpsed the power of CRISPR tools in our scientific programmes in NIBR and it is now time to explore how to safely extend this powerful technology to the clinic," he said.

The deal with Intellia gives Novartis exclusive rights to develop programmes focused on engineered chimeric antigen receptor T-cells (CARTs) and the right to develop a certain number of targets for editing hematopoietic stem cells.

Novartis is in the vanguard of developing CARTs, which modify patients' immune cells to recognise and destroy cancerous ones, although rivals such as Pfizer are moving in and several biotech companies, including stock market newcomer Juno, are competing hard.

The Caribou collaboration is non-exclusive and focused on using CRISPR as a research tool for drug discovery.

Novartis said it was taking a stake in Caribou and increasing its equity investment in Intellia as part of the deals. Novartis initially invested in Intellia after its launch by Atlas Venture and Caribou three months ago. Financial details were not disclosed by the companies on Wednesday.

Source : Reuters | Fox News Health

GENOME WIDE EXPRESSION CHANGES IN VASCULAR TISSUE IDENTIFIED DUE TO INFECTION DIET

Wed, 07 Jan 2015 16:27:32 GMT

Although it has been shown that a diet high in fat and exposure to certain bacteria can cause atherosclerosis (the buildup of fats, cholesterol and other substances on artery walls which can restrict blood flow), researchers have for the first time identified distinct gene pathways that are altered by these different stimuli. These findings, which currently appear in BMC Genomics, suggest that future therapies for this disease may need to be individualized.

Atherosclerosis is a common human disease associated with heart attack and stroke. Certain bacteria as well as high fat diet are associated with an increased risk for atherosclerosis. One of these bacteria, Porphyromonas gingivalis, is found in the mouth of humans with periodontal disease; another, Chlamydia pneumoniae, causes pneumonia.

In this study, the researchers used four experimental groups to compare genome-wide expression changes in vascular tissue. The first group was subjected to Porphyromonas gingivalis while the second group received Chlamydia pneumoniae. The third group was placed on a high-fat diet while the fourth group was the control. In collaboration with the Clinical and Translational Science Institute (CTSI) at Boston University, the researchers performed genome-wide microarray profiling and analysis of vascular tissue from all groups to reveal gene pathways altered in the atherosclerotic plaque by each treatment group.

"Given the prevalence of diet-induced obesity and infection with Porphyromonas gingivalis and Chlamydia pneumoniae in the general population and the likelihood of co-morbidity of obesity with chronic or recurring infection with these common pathogens, these findings suggest that the development of atherosclerosis in humans is likely more complex and multifactorial than previously appreciated," explained senior author Caroline Attardo Genco, PhD, professor of medicine and microbiology at BUSM. "These findings may explain how specific infections or a high-fat diet may cause atherosclerotic plaques to undergo changes which affect their size and stability and may ultimately lead to a heart attack," she added.

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The above story is based on materials provided by Boston University Medical Center . Note: Materials may be edited for content and length .