The protein Ras plays an important role in cellular growth control. Researchers have focused on the protein because mutations in its gene are found in more than 30 percent of all cancers, making it the most prevalent human oncogene.
University of North Carolina Lineberger Comprehensive Cancer Center and Harvard researchers have discovered an alternative mechanism for activating Ras that does not require mutation or hormonal stimulus. In healthy cells, Ras transmits hormone signals into the cell that prompt responses such as cell growth and the development of organs and tissues. A mutation on the RAS gene can chronically activate those signals, leading to tumor initiation and progression.
In an article published on-line in a November issue of Nature Structural and Molecular Biology, the UNC and Harvard teams discovered that modification of Ras at a specific site with a small protein known as ubiquitin can also lock Ras into an active signaling state. Thus, modification of Ras with a single ubiquitin – a process known as monoubiquitination - switches Ras to an active signaling state by disrupting the action of another protein known as the GTPase activating protein, or GAP. Work by two of the papers co-authors, Atsuo Sasaki and Lewis Cantley of Harvard, had previously found evidence for Ras's potential to become activated and promote Ras-mediated tumorigenesis by monoubiquitination.
Because of the strong link between Ras and cancer, Ras should be an attractive target for drug discovery efforts. Despite considerable efforts at developing treatments targeting the protein, Ras itself is now considered to be 'undruggable', leading researchers to try new approaches to developing drugs that target activated Ras. This could lead to benefits beyond cancer therapies, as the RAS gene has also been linked to developmental disorders such as Noonan syndrome, Costello syndrome and autoimmune lymphoproliferative syndrome.
Lead researcher Rachael Baker, a PhD candidate doing joint work in the labs of Henrik Dohlman, PhD, professor of pharmacology and vice chair of biochemistry and biophysics and Sharon Campbell, PhD, professor of biochemistry and biophysics at UNC, developed a novel method to modify Ras with ubiquitin and then subsequently characterized how ubiquitin modification can lead to Ras activation.
The attachment of ubiquitin to Ras at a specific site leads to Ras activation, much like with an oncogenic mutation, leading to an increased potential for cancer formation. Baker notes that the reaction can be reversed by enzymes in the cell that remove ubiquitin, making these enzymes possible targets for future pharmaceutical research.
"Establishing how Ras is activated by ubiquitin is just the first step in understanding this novel mechanism of cellular regulation." said Campbell.
The researchers next step will be to obtain a more detailed understanding of its role in cancer progression, first in cells and in animals and eventually in cancer patients.
University of North Carolina Health Care: http://www.med.unc.edu
This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.
Pharmacology can get a bad rap in the press. Professors George Davey Smith and David Nutt fight the case for statins and SSRIs.
People who spend time watching fish swim in aquarium tanks could improve their physical and mental wellbeing, a study shows.
The chytrid fungus has wiped out populations of amphibians around the world. A type of the fungus infects only salamanders, and researchers have identified vulnerable areas in North America.
NPR's Melissa Block speaks with the AP's Brazil bureau chief Brad Brooks about the investigation, which found high levels of dangerous viruses in water venues for the 2016 Summer Olympics.
Unusual clinical trial in Guinea offers promise for stopping epidemic
Researchers say study suggests need to target black men for screening of prostate cancer, which is projected to become the UK’s most common cancer by 2030 Black men in England have twice the lifetime risk of both being diagnosed with – and dying from – prostate cancer compared with white men, according to a study by Public Health England and Prostate Cancer UK.
MERS causes only mild symptoms in monkeys, so although the vaccine seemed to reduce their symptoms, it's hard to know if this will apply to humans as well
The World Health Organisation is doing its final checks and could declare Nigeria officially free of polio by September. Somalia could be next
Researchers in Hong Kong have cured infected monkeys of MERS using existing drugs
European Medicines Agency recommends RTS,S, or Mosquirix, developed by GSK and backed by Gates Foundation, for use in young children in Africa