Molecule that Makes Life Possible
Heme, the iron-bearing,
oxygen-carrying core of hemoglobin, makes it possible for blood
to carry oxygen, but researchers from Penn's School of Medicine
have determined how free-floating heme can also make traumatic events
worse by damaging tissue. The researchers presented their findings
in the October 2 issue of the journal Nature. Fortunately,
the researchers also identified a chemical that can be targeted
by drug developers to impede the deleterious effects of free-floating
Following a traumatic
event--such as an accident, a stroke, a heart attack or even
surgery--heme floods the spaces between and inside cells and
exacerbates the damage. It does so by shutting down an important
cell membrane channel, an action that kills neurons and constricts
blood vessels. While investigating this process, the researchers
also determined that a chemical called NS1619 restores the function
of the cell membrane channel. NS1619 and its derivatives could be
the source for a new drug--one that prevents the secondary events
that worsen trauma damage.
can compensate and recycle loose heme. But when larger concentrations
are released, heme can gum up the works, specifically the Maxi-K
ion channel, a cell membrane protein important for blood vessel
relaxation and neuron excitability," said Dr. Xiang Dong Tang,
staff scientist in the department of physiology.
Maxi-K is a channel
that moves potassium ions out of cells. In the Nature paper,
Dr. Tang and his colleagues prove that the Maxi-K protein possesses
sites that bind heme. If these sites were removed or altered, heme
could not effect Maxi-K proteins.
The chemical heme
is essential for most forms of life. It exists in hemoglobin for
oxygen transport, in cytochromes for cellular energy production,
and in guanylate cyclase for blood pressure regulation. The molecule
itself is tiny, a flat snowflake of a carbon framework surrounding
a single atom of iron, but it is crucial for the cellular process
of respiration and the action of nitroglycerine.
Studying the heme
recycling system might prove useful in developing treatments for
preventing the secondary damage set off by heme. Certain cells,
such as neurons, do have ways of transporting heme. If the "heme
transport" is identified and the specific blocker is found,
it could help prevent symptoms resulting from trauma and bleeding.
to Dr. Tang and his colleagues, there is already a known agent that
can relieve Maxi-K from heme inhibition. NS1619 is known as the
"Maxi-K opener," and, as the researchers have shown, readily
reverses the heme-mediated inhibition.
Breast Cancer Susceptibility
Genes and DNA Repair
A study led by scientists
at The Wistar Institute defines a functional role for the tumor
suppressor proteins BRCA1 and BRCA2 in breast cancer. The findings,
presented in the November issue of the journal Molecular Cell,
also identify a number of novel proteins that work alongside BRCA1
and BRCA2 and might also play a part in breast cancer. These proteins
offer an important set of new targets for possible anti-cancer drugs.
The link between
the BRCA1 and BRCA2 genes and hereditary breast cancer was first
identified in the early 1990s, but the biological function of the
BRCA1 and BRCA2 proteins had remained elusive. The Wistar researchers
demonstrated how the two proteins combine with others to form a
complex called BRCC (BRCA1-and BRCA2-containing complex) and defined
the role of the complex in regulating DNA repair. The researchers
also discovered two new proteins that are part of BRCC and linked
one of them, BRCC36, to sporadic breast cancers.
an associate professor at the Wistar Institute and senior author
on the study, and his colleagues determined that the BRCC protein
complex acts as one large regulatory enzyme. They discovered that
one target of BRCC is a protein familiar to cancer researchers called
p53, a potential cancer-promoter if left unregulated. BRCC attaches
a chemical tag, a ubiquitin group, p53. The ubiquitin tag signals
the cell's digestive machinery to destroy the marked protein.
of cells with DNA-damaging radiation, BRCC interacted with p53 and,
to a lesser degree, a known DNA repair enzyme. According to the
Wistar researchers, this suggests that BRCC does not directly repair
DNA. Instead, BRCC appears to regulate the proteins that cause the
cell to divide and influence the proteins that repair DNA.
To study how BRCA1
functioned in the cell, Dr. Shiekhattar and his colleagues created
a line of cells that produce a specially tagged version of BARD1--a
protein known to interact with BRCA1. The tag allowed Dr. Shiekhattar
to isolate BARD1 and any protein found with it. When they found
the tag attached to a large complex of proteins, mass spectrometric
sequencing allowed them to determine and isolate the individual
parts of the complex.
Among the proteins
caught in this molecular dragnet, were BRCA2--indicating that
BRCA2 worked directly with BRCA1 in cells--and two new BRCC
subunits. Dr. Shiekhattar and his colleagues learned that disrupting
the function of the new subunits, named BRCC36 and BRCC45, made
cells more susceptible to DNA damage from ionizing radiation and
interfered with the ability of BRCC to halt the cell cycle at the
checkpoint before cell division.
Sirtuins in Metabolism, Aging, Gene Expression
In recent years,
scientists have learned that members of a family of enzymes known
as sirtuins play critical roles in a wide array of vital life processes,
including metabolism, aging, and gene expression. Some studies have
shown that low-calorie diets that extend life also boost sirtuin
activity dramatically, suggesting an intriguing link between metabolism
and aging through sirtuins. And in September, a team of investigators
found that a sirtuin-activating compound found in red wine increased
the life span of yeast cells by more than two-thirds.
Humans have at least
seven different sirtuins performing different tasks, and given the
evident importance of the work they do, researchers have been trying
to better understand how they function. Insights into their mode
of action could represent early steps toward developing a novel
class of drugs that might promote health in various ways.
Now, structural biologists
at The Wistar Institute studying the role of sirtuins in gene expression--specifically
in turning genes off--report new findings that significantly
illuminate how sirtuins work. The results point to a mechanism of
action likely to be general for the entire sirtuin enzyme family
and may offer the beginnings of an explanation for how metabolism
and aging may be linked through the mechanisms that control gene
expression. The research is featured on the cover of the November
issue of the journal Structure.
Using X-ray crystallography
and other techniques of structural biology, Dr. Ronen Marmorstein,
a professor in the Gene Expression and Regulation Program and senior
author on the Structure study and his group detailed the
structure of a sirtuin from yeast while bound to two molecules associated
with its biological function. One part of the sirtuin was bound
to a derivative of a molecule called NAD, which has a pivotal responsibility
in metabolism--it's needed to break down glucose. The other
part of the sirtuin was bound to a specific site on a histone protein.
Histones are primary players in controlling genes, and in this case
the sirtuin Sir2 is the site of action for silencing gene expression.
Vaccines to Protect Newborns in Developing World
In a new research
study, two prototype oral vaccines have both been shown capable
of inducing protection against a dangerous virus in newborn mice.
If the new vaccines are able to do the same for human newborns,
they might be able to address an important window of immunological
vulnerability in the lives of infant children. Particularly in the
developing world, where the threat of infectious diseases is generally
greater than in the developed world, many lives might be saved with
vaccines of this type.
The vaccines are
based on human and chimpanzee adenoviruses that have been altered
in the laboratory so that they are unable to replicate. In the current
proof-of-principle study the viruses were engineered to incorporate
a gene from the rabies virus. Following oral administration of the
vaccine, newborn mice developed antibodies that protected them from
subsequent exposure to the rabies virus. By extension, the researchers
say, the same vaccine strategy might also prove effective against
other viral diseases, such as measles, viral respiratory infections,
and viral diarrhea. A report on the study findings appeared in the
October 15 issue of the Journal of Immunology.
The potential significance
of the new study lies in the effectiveness of the prototype vaccines
in newborns. Although newborns are protected from most common viral
infections immediately after birth by antibodies received from their
mothers, these antibodies decline in the first weeks and months
of life as the fledgling immune system grows in its capacity to
generate its own antibody protections against viruses. Between the
waning of maternal-antibody protection and the development of a
fully functional immune system in the infant, a period of relatively
poor defense against disease for infants is frequently seen. This
is partly because the infant immune system is not yet sufficiently
developed, but also because the maternal antibodies, while protecting
the infant from infections, can interfere with the efficacy of traditional
"These new vaccines
we've developed trigger the production of protective antibodies
in newborn mice during a time in their lives when traditional vaccines
are commonly less than effective," said Dr. Hildegund C. J.
Ertl, professor and head of the Immunology Program at Wistar and
senior author of the study. "This had potentially important
public-health implications, especially in the developing world.
In addition, there are oral vaccines, which could make them easier
to distribute and administer in those same areas."
Almanac, Vol. 50, No. 14,
November 25, 2003