||Researchers at the University
of Pennsylvania School of Medicine have found
that proteins known to promote cell death are also necessary
for the maturation and proliferation of immune cells.
||The Penn scientists discovered that in
the cells that lack the pro-death proteins Bax and Bak, calcium
signaling is disrupted and energy production is reduced.
Restoration of Bax corrects the signaling problems, increases
energy production, and stimulates cell division.
||The findings bolster the team’s
hypothesis that metabolic cell activity directly controls
life and death decisions in cells.
||The results were published online in
the journal Immunity.
(PHILADELPHIA) – Researchers at the University
of Pennsylvania School of Medicine have found that proteins known to promote cell
death are also necessary for the maturation and proliferation of
immune cells. Activation of T-cell receptors on the surface of
lymphocytes by foreign antigens initiate a calcium-mediated signaling
pathway that ends in cell differentiation and growth. The Penn
scientists discovered that in the cells that lack the pro-death
proteins Bax and Bak, calcium signaling is disrupted and energy
production is reduced. Restoration of Bax corrects the signaling
problems, increases energy production, and stimulates cell
The results, published online in the journal Immunity, bolster the team’s
hypothesis that metabolic cell activity directly controls life and death
decisions in cells. This issue also includes a related commentary by
the study’s lead author, Russell Jones, PhD, and senior author
Craig B. Thompson, MD.
It is well known that cells that lack Bax (Bcl-2-associated X protein)
and Bak (Bcl-2-antagonist/killer) continue living under conditions that
would cause normal cells to undergo programmed cell death or apoptosis.
What is less well understood, is why lymphocytes missing these key proteins
are unable to trigger a strong immune
response and do not proliferate as normal in response to stimulation.
“We simply say they are the same thing,” says Thompson,
Director of the Abramson Cancer Center and Chairman and Professor of
Cancer Biology and Medicine. “The molecular basis of both findings
is based on how Bax and Bak work on intracellular membranes.”
Specifically, the team found that when the T-cell receptor was stimulated
on mutant cells lacking both proteins, proliferation was severely reduced
relative to normal cells. Closer investigation showed that the amount
and rate of calcium release from intracellular stores was altered in
the mutant cells.
The inadequate calcium signals were unable to stimulate the mitochondria,
which are the energy factories in the cell. Without mitochondrial activation,
a key by-product of energy production, called reactive
oxygen species or ROS, were not produced. And because ROS tell the cell to divide, cell
proliferation is compromised.
Although Thompson’s group investigated the function of Bax and
Bak in T cells, the team thinks their findings will likely apply to many
different cell types. When a cell receives signals to increase metabolism,
it increases mitochondrial activity and energy production. That leads
to the production of more energy than the cell can deal with, and consequently,
the release of ROS. “It is the release of reactive oxygen species
by the mitochondria that actually generate the proliferation. We think
that is the basis of all cell proliferation,” says Thompson.
The study was funded by the National
Institutes of Health and the Abramson
Family Cancer Research Institute. Russell Jones received
support from the Cancer
Research Institute and the Canadian
Institutes for Health Research. Co-author Connie
support from the Human
Frontiers Science Program.
Additional co-authors include Thi Bui, Carl White, Muniswamy Madesh,
Connie Krawczyk, Tullia Lindsten, Brian Hawkins, Sara Kubek, Hao Shen,
and J. Kevin Foskett from Penn; Kenneth
Frauwirth from the University
of Maryland; Y.
Lynn Wang from the Weill
Medical College of Cornell University;
Stuart J. Conway, H. Llewelyn Roderick, and Martin D. Bootman from The
The Abramson Cancer Center (ACC) of
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