Worth a thousand words: Hopkins researchers paint picture of cancer-promoting culprit

They say that a picture can be worth a thousand words. This especially is true for describing the structures of molecules that function to promote cancer. Researchers at Johns Hopkins have built a three-dimensional picture of an enzyme often mutated in many types of cancers. The results, published Dec. 14 in Science, suggest how the most common mutations in this enzyme might lead to cancer progression.

“Now that we have a better picture of the protein and how it is altered in cancer, we can envision development of mutation-specific inhibitors for cancer therapy,” says Victor Velculescu, M.D., Ph.D., associate professor at the Johns Hopkins Kimmel Cancer Center.

The enzyme known as PIK3CA is mutated frequently in many cancers, including colon, brain, stomach, breast and lung. Moreover, most of the reported mutations occur in a few so-called hotspots in the protein. All known mutations make PIK3CA more active than normal, which causes cells to divide more frequently or faster than normal to give rise to cancer.

“We tried to guess how the enzyme’s activity was affected by the mutations based on their locations along the length of the protein,” says L. Mario Amzel, Ph.D., professor and director of biophysics and biophysical chemistry at Hopkins. “But without a 3-D structure, it’s hard to do. It’s like having a puzzle but missing critical pieces.”

The research team isolated purified PIK3CA and part of another protein it normally binds to, grew crystals of the purified enzyme bound to its partner and figured out its 3-D structure using techniques that shoot X-rays through the protein crystals. Using computers, they analyzed the X-ray pattern and assembled a 3-D model of the enzyme. Onto this model the researchers then mapped all the cancer-associated mutations.

According to Sandra Gabelli, Ph.D., an instructor of biophysics and biophysical chemistry at Hopkins, the researchers originally suspected that the mutations somehow interfered with the way PIK3CA interacted with other proteins and parts of the cell and therefore must be on the outside surface of the enzyme. However, their results show that nearly all the mutations map to regions within the enzyme. “Somehow, these internal mutations must cause the protein to subtly change how it works and interacts with itself,” says Amzel. “It’s an interesting problem to solve, trying to figure out what slight shape and structural changes can make an enzyme work better-usually we’re trying to figure out why things stop working.”

The team currently is unraveling the structure of mutated PIK3CA so that they can compare mutated to unmutated to better understand how the mutations lead to cancer. Another goal is to find drugs that can specifically interfere with PIK3CA and turn it down, to develop cancer-fighting therapies.


Source: Johns Hopkins Medical Institutions

Related stories:

The first autism disease genes
The autistic disorder was first described, more than sixty years ago, by Dr. Leo Kanner of the Johns Hopkins Hospital (USA), who created the new label 'early infantile autism'. At the same time an Austrian scientist, Dr. Hans Asperger, described a milder form of the disorder that became known as Asperger Syndrome, characterised by higher cognitive abilities and more normal language function. Today, both disorders are classified in the continuum of 'Pervasive Developmental Disorders' (PDD), more often referred to as Autism Spectrum Disorders (ASD).
Missing protein may be key to autism
A missing brain protein may be one of the culprits behind autism and other brain disorders, according to researchers at MIT's Picower Institute for Learning and Memory.
Studies spot numerous undiscovered gene alterations in pancreatic and brain cancers
HHMI investigators have detected a multitude of broken, missing, and overactive genes in pancreatic and brain tumors, in the most detailed genetic survey yet of any human tumor. Some of these genetic changes were previously unknown and could provide new leads for improved diagnosis and therapy for these devastating cancers.
Researchers piece together gene 'network' linked to schizophrenia
Reporting this week in the Archives of General Psychiatry, researchers at the Johns Hopkins University School of Medicine have uncovered for the first time molecular circuitry associated with schizophrenia that links three previously known, yet unrelated proteins.
Accumulated bits of a cell's own DNA can trigger autoimmune disease
A security system wired within every cell to detect the presence of rogue viral DNA can sometimes go awry, triggering an autoimmune response to single-stranded bits of the cell's own DNA, according to a report in the August 22nd issue of the journal Cell, a Cell Press publication. The source of that single-stranded DNA is so-called endogenous retroelements—genetic elements accounting for a substantial portion of the genome that can move to new locations using a "copy and paste" mechanism, according to the researchers.
Rifamycin antibiotics attack tuberculosis bacteria with walls, not signals
(PhysOrg.com) -- Amid concerns about the rising number of new tuberculosis cases worldwide, researchers led by Rockefeller University’s Seth A. Darst have reexamined and disproved a theory that describes how a potent class of antibiotics kills a deadly form of bacteria. The findings, which will appear in this week’s online issue of the Proceedings of the National Academy of Sciences, not only bring scientists closer to understanding how these antibiotics work but also how the bacteria become resistant to their effects.
A snooze button for the circadian clock
We may use the snooze button to fine-tune our sleep cycles, but our cells have a far more meticulous and refined system. Humans, and most other organisms, have 24-hour rhythms that are regulated by a precise molecular clock that ticks inside every cell. After decades of study, researchers are still identifying all the gears involved in running this “circadian” clock and are working to put each of the molecular cogs in its place.
Model for angelman syndrome developed
A model for studying the genetics of Angelman syndrome, a neurological disorder that causes mental retardation and other symptoms in one out of 15,000 births, has been developed by biologists at The University of Texas at Austin.

News discussion:

Medicine & Health news