Research that blows our mind.
In one of the most highly cited papers from July 2014, researchers
from the departments of Cancer Biology and the Kimmel Cancer Center at Thomas
Jefferson University in Philadelphia describe a new function in a new location with a novel interaction for
the cell cycle protein cyclin D1.
Such a discovery can shake your world just a little
bit. It’s like seeing your supervisor,
the highly intelligent yet quiet and reserved enigma of a man, at your
favourite coffee shop. Wait, my boss
leaves his office? And he works here
too, just like me? Your mind is blown
and getting coffee there is never the same.
And so it is with cyclin D1.
Once thought of as a cell cycle protein, residing solely in the nucleus,
translating pro-growth signals into proliferative actions by allowing cells to
enter the cell cycle and divide, this new paper suggests cyclin D1 can leave
its workspace for an alternative workspace, the cytoplasm. Because of its pro-proliferative function, cyclin
D1 is considered oncogenic and studies have shown that its gene is commonly
overexpressed in cancer, including breast cancer. The current study focuses on cyclin d1 in estrogen-receptor
positive breast cancer and its role in the DNA damage response (DDR) pathway. The
estrogen receptor bound to its ligand, estrodial (a form estrogen, abbreviated
as E2), has important survival and proliferative effects that
mediate tumorigenesis. Approximately 75
percent of breast cancer patients are estrogen receptor (ERα)
positive and can be treated with anti-estrogen therapies such as tamoxifen.
Because DNA damage occurs regularly and randomly, cells
possess methods to repair these damages.
Sensing damage such as double-stranded DNA breaks (DSB), the DDR fixes
the error before a cell duplicates its DNA and divides. Phosphorylation, a
specific type of modification, of H2AX, a major sensor of this pathway,
recruits additional proteins responsible for performing the repair. Without the DDR, genetic instability ensues
and cancer can arise. Oncogenes,
including both of today’s players cyclin D1 and estrogen, often induce DSBs and
therefore the DDR, potentially potentiating tumor progression.
In this highly cited study, the authors connect ERα-mediated
DDR with cyclin D1-mediated DDR through a novel mechanism. A previous study demonstrated how estrogen
signaling prolonged the DNA damage response and delayed activation of H2AX in
response to irradiation and DNA damage.
To show that this effect occurs through cyclin D1, in the current study
the researchers generated breast cancer cells with and without cyclin D1
expression. When cyclin D1 expression is
reduced, this delayed induction of H2AX was abrogated and the DNA damage
response pathway was not activated.
But does this effect only happen in the nucleus, when in
contact with genome and its DNA breaks? The
answer is “no”. The estrogen receptor sits on the cell surface and relays
signals from outside the cell into the interior of the cell. Because it resides outside the nucleus, it is
not surprising that ERα can also function in the cytoplasm, in a nongenomic,
non-DNA-interacting manner. In fact, one
of the ways that ERα delays activation of the DNA damage response is through
activation of several cytoplasmic proteins.
Through a series of experiments, the authors show that cyclin D1 can
bind with cytoplasmic ERα and this interaction is responsible for activation of
specific signaling proteins and delayed induction of the DNA damage response
pathway. Cyclin D1 functions outside the
nucleus. Mind blown.
There’s a lot more complexity to this study. At its core, this cell biological paper informs
knowledge about how cells respond to specific stimuli and how this affects
additional proteins and their signaling patterns. The impact of this study, however, is quite
simple: cyclin D1 does more than we thought it could, in cellular regions that
we did not think it frequented.
Perhaps this shouldn’t surprise us. And it's not the first time that cyclin D1 has shown itself in the cytoplasm. I can list many other proteins that serve
more than one function, even contradictory functions. However, this paper reminds ourselves of two
things: one, the cellular system is incredibly complex and yet related; and we must
not limit our thinking and box proteins into single functions or
locations. Who knows what will blow our
minds when our minds are open.
References:
1. Li Z., Chen K.,
Jiao X., et al. Cyclin D1 Integrates
Estrogen-mediated DNA damage repair signaling.
2014. Cancer Research. DOI 10.1158/0008-5472.CAN-13-3137
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