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Other Members of the Cell Cycle Family
The Cks proteins were originally discovered in yeast because
of their interaction with another protein family that Reed
has studied for over 15 years called the cyclin-dependent
kinases. These are one of the crucial regulatory enzymes controlling
cellular division and the cell cycle, a biological process
that Reed has been studying for more than 30 years—since
his days in graduate school.
The cyclin dependent kinases are binary proteins belonging
to a large family of eukaryotic kinases—enzymes that
exploit an abundant molecule in the cell known as ATP to attach
phosphate groups to other proteins in the cell. In mammals,
there are several different "cyclins" and a few different
kinases that can come together at various points in the cell
cycle to carry out specific phosphorylations.
In general, phosphorylation acts as a cellular "signal"
that can do everything from turning the proteins on or off,
controlling their transport, or even regulating survival of
the cell.
"This is one of the primary modes of biological regulation,"
says Reed. And in the case of the specific action of cyclin-dependent
kinases, he adds, "These phosphorylation events drive both
mitosis and meiosis."
Cyclin dependent kinase-mediated phosphorylation is that
event that gets the cell's transcription machinery running,
duplicating the cell's DNA at just the right moment late in
the cell cycle before a cell divides during mitosis. Naturally,
these proteins must themselves be highly regulated, accumulating
rapidly when they are needed to accomplish a specific task
and disappearing when they are not. One of the primary modes
of regulation is the degradation of the cyclin subunits when
they are not needed.
Reed discovered one of these cyclin subunits, cyclin E,
in the early 1990s and has since spent a considerable amount
of time studying it. The protein activates by binding to the
cyclin dependent kinase 2 protein and together the complex
is involved in the initiation of DNA replication.
One facet of Reed's work is concentrated on the cyclin dependent
kinases, their regulation, and their interactions with other
proteins in the cell—besides those that they phosphorylate.
The Cks proteins are a facet of this work. In meiosis, the
cell cycle is controlled by the Cdk–Cks complex, the
structure of which Reed and TSRI Professor John Tainer solved
a few years ago. Reed's research suggests that the Cks proteins
seem to serve as "adaptors" that allow the cyclin dependent
kinases to interact more efficiently with their molecular
targets.
Another facet of his work is how the cyclin dependent kinases
and their regulation are relevant to human cancer. He has
a multifaceted project that aims to understand protein turnover,
the role of Cyclin E in carcinogenesis, and how the deregulation
of the protein causes cell proliferation and cancer.
"Cancer is a disease of cell proliferation," he says. "And
one of the reasons we study [the normal machinery of] cell
proliferation is to understand how it works so that we can
figure out what goes wrong."
CDK and Cancer
In some malignant cancer cells, the levels of cyclin E do
not drop. When cyclin E is overexpressed, cells become genomically
and genetically unstable—gaining and losing chromosomes.
"This chromosome instability," says Reed, "is one of the hallmarks
of cancer."
Reflecting the complexity of the cell, the loss of control
is not necessarily related to problems with the cyclin E itself
but rather problems with one protein that is supposed to control
it.
Last year Reed published a study looking at another cellular
protein called "hCdc4" which is a specificity factor for the
cells' ubiquitin ligase machinery, which degrades proteins.
The cell uses hCdc4 to target cyclin E to help the cell turn
it over.
Reed discovered evidence suggesting that hCdc4 is a tumor
suppressor protein—its presence works to counter the
proliferation of cancer cells. He found that in certain types
of cancer, particularly endometrial cancer, the hCDC4
gene is often mutated. Reed's group is now analyzing breast
cancer samples for similar hCdc4 mutations. These mutations
create forms of the hCdc4 protein that fail to target cyclin
E, and this leads to the accumulation of cyclin E in the cell.
The accumulation of cyclin E leads to the chromosomal instability,
which is known to contribute to cancer.
Reed is trying to work out how and why cyclin E is turned
over in order to address some of the problems that it causes
with regard to cancer. Similarly, he is trying to figure out
the role of the Cks proteins in all of this. Gene expression
analysis studies of several different tumor cells have shown
that Cks2 (and to a lesser extent Cks1) is one of the most
frequently overexpressed proteins in cancer cells.
"Overexpression of this protein may be deleterious to cell
integrity and [may be] part of the process of malignant transformation,"
says Reed, adding that he would like to know why, and upon
finding out why would like to use that knowledge to formulate
a strategy to stop it.
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