Researchers have discovered a key to the function of a specific protein that helps control the levels of other critical proteins within cells, including a protein that suppresses the spread of cancer. The new information about the mechanism of action of the protein, called gp78, may enable researchers to explore new types of therapies to prevent the spread of cancer. The study, by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, was published in the June 26, 2009, issue of Molecular Cell.

In all human cells, damaged or unnecessary proteins are destroyed through a complex process that involves their being tagged with chains of a small protein called ubiquitin. The ubiquitin-tagged proteins are then directed to a sophisticated cellular structure known as the proteasome, which degrades the proteins.

The addition of ubiquitin to targeted proteins, a process called ubiquitylation, takes place in a multistep process in which several types of proteins, or enzymes, function in a sequential, bucket brigade-like manner. First, ubiquitin is activated by an enzyme known as E1. The activated ubiquitin is then transferred to E2, another enzyme. The E2 binds in turn to another protein known as E3, or ubiquitin protein ligase, which is critical for the transfer of ubiquitin to the targeted protein. This process occurs in a highly regulated manner that allows the recognition and targeting of specific proteins. To achieve the necessary specificity, human cells have about 40 different types of E2 enzymes and more than 500 E3 proteins.

A majority of E3s have an internal structural component, or domain, known as a RING finger, which binds weakly to E2s and allows ubiquitylation to proceed. An earlier study by one of the lead authors of the current report, Allan M. Weissman, M.D., of NCI's Center for Cancer Research (CCR), discovered that a RING finger E3, known as gp78, has a unique region called G2BR that strongly binds to its E2. Weissman and other NCI scientists previously showed that higher levels of gp78 promote the spread of cancer by tagging a protein for degradation that suppresses metastasis and that the ubiquitin ligase activity of gp78 was required for this degradation. Other targets of gp78 include proteins that are involved in cystic fibrosis and in the regulation of lipid metabolism.

In this new work, a team of CCR researchers, led by R. Andrew Byrd, Ph.D., Xinhua Ji, Ph.D., and Weissman, used advanced structural techniques to study the structure of gp78 and its associated E2 enzyme to gain insight into how the complex functions in cells. The researchers determined the structural basis for the interaction between gp78 and its E2 and uncovered a previously unknown mechanism by which ubiquitylation can be regulated. They found that the gp78 G2BR binds its E2 in an area that is distinct from the sites where the gp78 RING finger domain binds to the E2. This binding causes subtle changes in the shape of the E2 that allow the gp78 RING finger domain and the E2 to join together 50 times more tightly than they otherwise would. Further research showed that this increased binding strength enhances ubiquitylation of target proteins by gp78.

This discovery may allow researchers to consider possible approaches to blocking the function of gp78 in cancer cells, leading to new types of treatment for cancer and other diseases. "Our study provides a previously unappreciated mechanism by which ubiquitylation can be regulated," said Weissman. "It is likely that other pairs of E2s and E3s interact through domains, which have yet to be characterized, that are similar to the gp78 G2BR and its corresponding binding site on its E2. This introduces the possibility of entirely new therapeutic avenues in cancer and other diseases."

This team is currently working to further define the interactions of E2s and RING finger domains. They also are collaborating with other NCI scientists to design and construct potential inhibitors of gp78, based on their discovery, for testing in animal models.

A shocking four out of every ten people who suffer from a skin disease in the UK have been bullied as a result of their condition, a new snapshot survey reveals.

23% said that they had suffered from an isolated incident of bullying, with a further 18% revealing that they suffered from regular bullying from their workplace or school. A staggering 92% had been on the receiving end of unwanted remarks and stares. The online survey, conducted by the skin disease research charity the British Skin Foundation, gives a thought provoking insight into the nine million people who live with a skin disease in the UK.

The survey was conducted to better understand how skin disease affects sufferers in the UK. 256 people were asked a series of questions relating to their skin disease and the impact it had on their life. The results show that the effects of skin disease go far beyond that of simply having to apply some cream. Four out of every ten people who took part said that their skin disease was a cause of high levels of stress and anxiety. One in ten participants said they had been hospitalized for their skin problems, 11% said they had taken time off work or education and 19% said they had regular loss of sleep as a direct result of their disease.

The results also highlighted the effects felt by those around the sufferer. When asked if they felt they were affected by someone else's skin disorder, 33% said they suffered from a lack of sleep and just under half of respondents stated they felt stressed or anxious by the other person's skin disease.

Worryingly, when asked about what forms of support they relied on for dealing with their skin disease, a quarter said they didn't rely on anyone or any service for help. Only 6 people out of the 256 relied on a patient support group, with the majority opting for friends and family (51%) and over a third relied on their GP for support.

The British Skin Foundation's Chief Executive, Matthew Patey, is determined to change the situation. He says: "It's about time people took skin disease seriously. We need to break down the misconception that skin disease is nothing to be concerned about. On the contrary, thousands of people will die this year alone from a skin disease. Although the survey offers only a tiny glimpse at what sufferers go through on a daily basis, we often forget that the effects are not limited to the symptomatic issues, but often branch out into discrimination and unfair treatment outside of the home."

Rates of death and hospital admissions for cardiovascular disease declined 30% over a 10-year period in Canada, according to a new study in CMAJ (Canadian Medical Association Journal), pointing to successful efforts to prevent heart disease, the leading cause of death globally. However, for the first time, more women than men are dying of cardiovascular causes.

The study, the first of its kind in Canada, looked at data from the Canadian Mortality Database, Statistics Canada's national death registry which contains information on the cause of all deaths in the country. It also looked at hospital admissions for heart attacks, heart failure and stroke.

A major finding was the rapid decline in death rates from heart attacks, with 4000 fewer Canadians dying from acute myocardial infarction in 2004 than in 1994. This could reflect declines in risk factors such as smoking and increased use of statins to control cholesterol.

However, the study showed high rates of death and hospital admission related to cardiovascular disease in elderly women. "This highlights the need for increased investment in education and research on cardiovascular health and disease in women," write Dr. Jack Tu from the Institute for Clinical Evaluative Sciences (ICES) and coauthors.

The authors caution that despite the 30% decrease, "these findings are not grounds for complacency. They suggest that previous efforts to prevent cardiovascular events have been successful, but in many cases they may have delayed the occurrence of such events until people are older and potentially more difficult to treat."

Rearrangements of all sizes in genomes, genes and exons can result from a glitch in DNA copying that occurs when the process stalls at a critical point and then shifts to a different genetic template, duplicating and even triplicating genes or just shuffling or deleting part of the code within them, said researchers from Baylor College of Medicine in a recent report in the journal Nature Genetics. The report further elucidated the effect of the fork stalling and template switching mechanism involved in some forms of copy number variation.

"I think this is going to make people think very hard about copy number variation with respect to genome evolution, gene evolution and exon shuffling," said Dr. James R. Lupski, vice chair of molecular and human genetics at BCM and senior author of the report.

The mechanism not only represents a newly discovered method by which the genome generates copy number variation among genes, but it also demonstrates that copy number variation can occur at a different time in the life of a cell. DNA replication takes place as the cell is dividing and becoming two - a process known as mitosis.

Copy number variation involves structural changes in the human genome that result in the deletion of genes or parts of them or extra copies of genes. Often, this process is associated with disease or with evolution of the genome itself.

DNA (deoxyribonucleic acid) exists as two complementary strands that remain together because of the attraction between nucleotides. A, or adenine, is always attracted to T, or thymine. C, or cytosine, is always attracted to G, or guanine.

When a cell divides, it must reproduce its DNA so that each cell that results from the division has the same genetic code. That means it must replicate its DNA. During this process, an enzyme called a helicase separates the two strands, breaking the hydrogen bonds between the A - T and G - C base pairs. The two separating strands become the replication fork. On one strand, an enzyme called DNA polymerase reads the genetic material in the strand as a template and makes a strand of complementary DNA to pair to it. Again, the code is A to T and C to G. This process is continuous. On the lagging strand, the complementary strand is made in short, separated segments by a process that involves RNA and a series of enzymes.

Until the 1990s, researchers studying reasons for genetic mutations or changes looked at molecular "typos" in this process, tiny changes in the As, Ts, Cs or Gs called single nucleotide polymorphism (SNPs). They changed the message of the gene. However, in the early 1990s, Lupski was one of the early champions of a newly discovered mechanism in which the structure of the DNA itself was grossly duplicated or deleted to change numbers of copies of a gene that occurred in the genetic material. This "copy number variation" wrote a new chapter in the understanding of human genetic variation.

In a previous report, Lupski and colleagues described how the process that copies DNA during cell division stalls when there is a problem with the genetic material. In some cases, the process seeks a different template, often copying another similar but significantly different stretch of DNA before it switches back to the appropriate area.

In this newer report, Lupski and colleagues describe how this process - called fork stalling and template switching (FoSTeS) in humans or microhomology-mediated break-induced replication (MMBIR) in simpler models - generated genomic rearrangements ranging in size from several megabases to a few hundred base pair during normal cell division, resulting in the duplication or even triplications of individual genes or the rearrangements of single exons (the coding region of genes).

"This phenomenon occurs throughout the genome," said Dr. Feng Zhang, a postdoctoral associate in Lupski's laboratory and the first author of the report.

In studies of subjects with abnormalities in the gene associated with Charcot-MarieTooth type 1A (PMP22), the researchers found that the fork stalling, template switching phenomenon explained the changes, from those that involved triplication of a gene to others that resulted from shuffling within an exon.

Studies of one family - two children and a mother - demonstrated that the event occurred during mitosis or cell division, a significant finding that further confirms the significance of the event.

The researchers noted that finding this mitotic rearrangement of the gene in the mother, who did not have the disorder, of two children with a neuropathy suggests that the mechanism might be considered in genetic counseling about the risk of having another child with the disorder.

The scientists wrote, "We propose that FoSTeS/MMBIR may be a key mechanism for generating structural variation, particularly nonrecurrent CNV (copy number variation), of the human genome. "

The observation of mosaicism for an apparent mitotically generated, FoSTeS/MMBIR-mediated complex PMP22 rearrangement in the unaffected mother of two children with neuropathy suggests this mechanism can have implications for genetic counseling regarding recurrence risk.

A London surgeon is pioneering a new way to remove abdominal organs through the belly button using an approach called single incision laparoscopic surgery (SILS) which requires only a 10 mm cut in the navel to allow entry of a camera and all the surgical instruments and through which organs like the appendix and gall bladder can be removed.

Imperial College Healthcare NHS Trust consultant surgeon Paraskevas Paraskeva, who also lectures at Imperial College London, is the first UK surgeon to use SILS to remove an appendix and a gall bladder.

Before SILS the organs were removed using three cuts in the torso, as well as the belly button, which leaves the patient with abdominal scars.

But SILS uses only one 10 mm "single access port" through which the surgical instruments and a camera are inserted, and through which the excised organ is removed and then the belly button is sewn up.

The procedure takes about 20 minutes for an appendix and an hour for a gall bladder, and the patient generally goes home on the same day. Paraskeva said in a statement last month that:

"This technique further minimises minimally invasive surgery."

"Having a single access port minimises the discomfort to the patient, reduces the risk of infection and because the incision is through the belly button, the surgery is scarless," he added.

SILS is the product of research carried out by Paraskeva and his team at the department of biosurgery and surgical technology at Imperial College London.

Aberdeen Royal Infirmary (ARI) in Scotland has also been using SILS to remove appendices and gall bladders. They started to use the procedure after learning about urologists at the Cleveland clinic in the USA using it to remove part of a kidney and also after hearing about Paraskeva's work at Imperial College London.

ARI's consultant surgeon Irfan Ahmed said that when he offered this method to his patients they were "excited by the idea and delighted with the cosmetic results after surgery".

He said:

"Single-incision laparoscopic surgery still needs to be studied in an academic setting before it becomes widely available."

Ahmed said he thinks SILS will replace traditional laparoscopic procedures performed by surgeons and gynaecologists in selected conditions.

"I see it happening routinely in the next two years," he said.

Consultant general surgeon Geoffrey Glazer, who is based at Wellington Hospital in London, told the BBC that as well as helping with the healing process, SILS was a "technological step forward" which might appeal to people who don't want scars on their abdomen.

He said other methods are also being developed to remove organs through existing orifices so that extra incisions don't have to be made.

One such method for example uses the rectum as the "access port", but this carries a higher risk of contamination.