Cell cycle pathways also linked to cognitive
deficits in Down syndrome
Dana-Farber Cancer Institute
scientists have discovered new details of how cancer cells escape from tumor
suppression mechanisms that normally prevent these damaged cells from multiplying.
They also demonstrated a potential link between this cell proliferation control
mechanism and the cognitive deficits caused by Down syndrome.
The findings add to a still-sparse
understanding of how normal and cancerous cell growth is regulated and have
potential implications for improved treatments, say the authors of a pair of
articles in Genes & Development.
James A. DeCaprio, MD, of Dana-Farber said the results may provide new targets both for blocking
the progress of cancer and perhaps for facilitating the growth of neurons in
the developing brains of infants with Down syndrome.
DeCaprio is the
senior author and Larisa Litovchick, PhD, also of Dana-Farber, is the first
author of one of the papers.
They also are co-authors
on the second article, whose senior author is Nicholas Dyson, PhD, at Massachusetts General Hospital Cancer
In that report,
the researchers revealed a previously unrecognized link between two
cell-signaling pathways -- called Rb and Hippo in scientific shorthand -- that help
regulate the formation of cells and organs during early development.
Both pathways are
frequently disrupted in cancer.
The life of a cell
is defined by phases in which it grows, creates a duplicate set of chromosomes,
and divides into two daughter cells – all governed by external signals such as
growth-stimulating factors and internal “checkpoints.”
Cells can also
exit the growth cycle in two ways. They can become quiescent, or inactive,
(which most of our cells are most of the time) until they re-enter the growth
cycle. They can also become senescent: Cells entering senescence are damaged or
nearing the end of their lives, and ultimately die.
survive, in part, by ignoring signals to become senescent and continuing to
make copies of themselves at will, or by entering a quiescent state from which
they can be re-activated.
have a good understanding of how cells negotiate the molecular checkpoints that
control these transitions.
identifies a molecular switch required for entry into quiescence and
senescence,” said DeCaprio, whose laboratory group focuses on cell cycle
The gatekeeper to
cell senescence and quiescence is a group of eight proteins that assemble
themselves into the so-called DREAM complex, which helps cells exit the active
cycle by turning off more than 800 growth-related genes.
A key player that
triggers the assembly of the DREAM team is p130, a member of the Rb family of
DeCaprio said the
new research highlights p130’s underappreciated role in DREAM action.
“We have for the
first time linked p130 itself to quiescence and senescence” – the latter
contributing to cancer formation, said DeCaprio, who is also an associate
professor of medicine at Harvard
The report also for the first time reveals
that a molecular switch, an enzyme called DYRK1A, performs a crucial step in
assembling the p130-DREAM complex, and thus is novel control point for
quiescence and senescence.
When DYRK1A is
turned on, it acts through p130 to set in motion the assembly of DREAM, which
turns off the growth genes and allows cells to depart the growth cycle and
become quiescent or senescent.
to turn off cell growth genes may also be involved in the lower-than-normal
development of brain neurons in Down syndrome, say the scientists, who are
investigating possible new avenues to treating the disorder.
While they tend to
have cognitive losses, people with Down syndrome have a markedly lower risk of
most types of cancer. DYRK1A is made by a gene on chromosome 21, which is
present in three copies (instead of the normal two) in people with Down
syndrome, causing the enzyme to be overproduced.
DeCaprio said this
abnormal activity could explain both outcomes: DYRKIA-triggered DREAM formation
could help suppress cancers by driving them into senescence, and also reduce
the generation of brain cells during development.
The second paper
in Genes & Development describes
a functional connection between the Hippo signaling pathway and the Rb pathway
that contains DYRK1A. The researchers showed that a component of the Hippo
pathway, a protein called LATS2, can activate DYRK1A.
The authors said
that LATS2 gene is located in an area frequently missing in cancer cells,
suggesting that LATS2 might be a new control point for suppressing cancer cell
Co-authors on the
first paper, along with Litovchick and DeCaprio, are Laurence Florens, PhD,
Selene Swanson, PhD, and Michael Washburn, PhD, of the Stowers Institute for
Biomedical Research, Kansas City, Mo. The research was funded by grants from the U.S. Public Health Service
and the Department of Defense.
Authors on the
second paper, in addition to Dyson, are first author Katrin Tschop, PhD, MGH
Andrew Conery and Ed Harlow, PhD, Harvard
Litovchick and DeCaprio, Dana-Farber; and Jeffrey Settleman, PhD, MGH Cancer
Center. The research was funded by the National Institutes of Health.