Michael B. Kastan talks with
ScienceWatch.com and answers a few questions about
this month's Emerging Research Front Paper in the field of
Molecular Biology & Genetics.
Article: Cell-cycle checkpoints and
Journal: NATURE, 432 (7015): 316-323 NOV 18 2004
Addresses: St Jude Childrens Hosp, Dept Hematol Oncol, 332
N Lauderdale St, Memphis, TN 38105 USA.
St Jude Childrens Hosp, Dept Hematol Oncol, Memphis, TN
Danish Canc Soc, Inst Canc Biol, Dept Cell Cycle &
Canc, DK-2100 Copenhagen, Denmark.
Why do you think your paper is highly
The control of cell cycle progression after DNA damage and other cellular
stresses is an important determinant of cellular and organismal outcome
following stress exposure. DNA damage contributes to cancer development, is
a major mechanism by which we try to kill tumor cells, and contributes to
the side effects of cancer therapies on normal tissues. Thus, it is of
great interest in the cancer biology field.
"Since these pathways are also
important in many other disease processes, it
is not hard to envision that individuals with
diseases other than cancer could benefit from
such new drugs as well."
These signal transduction pathways that control cellular responses to DNA
damage and other stresses are also proving increasingly important in many
other fields of study, including neurosciences, metabolism, aging, and
environmental links to human disease. This paper was a review article in a
prominent journal. This visibility, in combination with the importance of
the field, probably both contributed to the paper's citation frequency.
How did you become involved in this research and were
any particular problems encountered along the way?
As a clinical oncologist, I have been interested in the molecular basis of
DNA damage responses from both cancer development and cancer therapeutic
perspectives. Since my initial report in 1991 that the p53 tumor suppressor
protein is a cell cycle checkpoint determinant after DNA damage, a
significant fraction of the efforts in my laboratory have focused on signal
transduction pathways that are initiated by DNA damage and other cellular
Work in my lab over the past decade has also contributed to the expanding
insights on the ATM protein kinase as a central mediator of cellular stress
responses. Dr. Jiri Bartek of the Danish Cancer Society Institute of Cancer
Biology in Copenhagen, Denmark, has an established history of important
contributions to the field of cell cycle control and has turned his
attention to DNA damage signaling in the past several years.
Where do you see your research leading in the
Both of us will continue to elucidate the molecular events involved in
stress signaling and DNA repair, always while keeping an eye towards the
potential opportunities for manipulating these pathways for patient
benefit. For example, modulators of these DNA damage responses could be
used to make tumors more sensitive to cytotoxic therapies, an approach
already being used by the recent development of Parp inhibitors. This is
certain to be only the first such examples of therapeutic benefits coming
from small-molecule manipulation of DNA damage response pathways.
Do you foresee any social or political implications for
Improving cancer cure rates or decreasing the toxicities of cancer
therapies would certainly qualify as a social implication of the work, and
we are already in the process of developing small molecules targeting these
pathways that we hope to use in these ways. Since these pathways are also
important in many other disease processes, it is not hard to envision that
individuals with diseases other than cancer could benefit from such new
drugs as well.
Michael B. Kastan, M.D., Ph.D.
Director, Comprehensive Cancer Center
St. Jude Children's Research Hospital
Memphis, TN, USA Web