Publication: Cell proliferation and cancer
Authors
Lopez-Saez, J.F. ; De la Torre, C. ; Pincheira, J. ; Gimenez-Martin, G.
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
The discovery that phosphorylation of
selected proteins by cyclin-dependent kinases is the
engine which makes the cycle run provides a new image
of the control of proliferation and of its deregulation.
The high conservation of this machinery in the different
eukaryotic organisms emphasizes its early origin and its
importance for life. It also makes the extrapolation of
findings between different species feasible. The control
of proliferation relies basically on accelerating and
braking mechanisms which act on the engine driving the
cycle. This review particularly stresses the importance of
checkpoint or tumor suppressor pathways as transduction
systems of negative signals which may induce a
cycle braking operation. They prevent any important
cycle transition, as the initiation of proliferation, that of
replication, mitosis, etc., until the DNA and other
cellular conditions make such a progression safe. These
checkpoint pathways are able to recognize and transduce
signals about the adequacy of initiating or continuing
proliferation for a cell at a particular time, under a
particular set of external and internal conditions. Crucial
components of these pathways are proteins encoded by
some of the checkpoint genes that evaluate the final
balance of mitogenic and antimitogenic pathways
reaching them and, if the balance is negative, they
prevent temporarily cycle inititation or its progression by
inhibiting the corresponding cyclin-dependent kinases.
On the other hand, when the balance becomes positive,
they allow the activation of the cyclin-dependent
kinases. Uncontrolled cell proliferation associated with
cancer always depends on the functional abrogation of at
least one of the checkpoint pathways. The checkpoint or
tumor suppressor protein p53 is one of the proteins in
them, and mutations in the gene encoding it are present
in more than half of all human tumours. The review
touches new pharmacological strategies which have been
opened by the discovery of portions of some of the
Offprint requests to: Prof. Dr. Jorge F. Lopez-Saez, Departamento de
Biologia, Universidad Autonoma de Madrid, Canto Blanco, E-28049
Madrid, Spain
*This review is dedicated to Jesljs Vazquez, a great teacher, a great
histopathologist and, overall, a great man who left us prematurely.
signal transduction cascades involved in the transient
brake of cell proliferation. Restoration of checkpoint
pathways either prevents further proliferation of cells
with damaged genome until repair is over or,
alternatively, the dismantling of these checkpoints
induce those cells to commit suicide (apoptosis). The
fact that both restoration and dismantling of checkpoint
pathways sensitive to DNA damage have not disturbing
effects on any other proliferating cell with undamaged
DNA makes these selective strategies promissing.
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