"A biologist, a physicist, and a nanotechnologist walk into a..."
sounds like the start of a joke. Instead, it was the start of a collaboration
that has helped to decipher a critical, but so far largely unstudied, phase
of how cells divide. Errors in cell division can cause mutations that lead to
cancer, and this study could shed light on the role of chromosome abnormalities
in uncontrolled cell replication.
 | | This is a montage of a fission yeast cell undergoing mitosis. The microtubule structures, including the spindle, are shown in red. The motor protein klp9p is shown in green. The motor binds to the spindle specifically at anaphase B onset, where it helps elongate the spindle. Credit: Phong Tran, PhD, University of Pennsylvania School of Medicine; Developmental Cell |
The biologist in question is University
of Pennsylvania School of Medicine Associate Professor of Cell and Developmental
Biology, Phong Tran, PhD. With physicist Francois Nedelec of the European Molecular
Biology Laboratory in Heidelberg, Germany, and Guilhem Velve-Casquillas, PhD,
a postdoc in Tran's lab who helped develop a device requiring nano-scale technology
used in the study, Tran uncovered the molecular players and mechanism underlying
a little-studied stage of cellular division called Anaphase B.
Anaphase B is just one part of the complex molecular choreography that is cell
division. The process is akin to two children dividing up their Halloween candy:
collect your candy, pile it in the middle, and divide it into two equal portions.
In cell division - the creation of two daughter cells from one -- it is the
doubled chromosomes that are piled in the middle to be sorted. The cell condenses
the chromosomes, arranges them at the midpoint of the dividing cell, sends half
to either end of the cell, and then forms a new cell membrane around each pool.
Anaphase is the step in cellular division during which the chromosomes physically
separate and are dragged to either end of the cell. And it's during this coming
together and pulling apart of the chromosomes that such mistakes as breakages
and uneven sorting can lead to cancerous mutations.
The physical structure that both organizes and facilitates the steps of Anaphase
is the spindle, and it is comprised of molecular struts called microtubules,
as well as microtubule-associated proteins, or MAPs, and molecular motors, which
provide the required physical force to move chromosomes. From fixed points called
spindle poles, at either end of the cell, microtubules extend towards the midline
of the cell, some capturing and positioning chromosomes at the midline, others
reaching further to overlap with microtubules originating from the other side
of the cell. What happens next - Anaphase -- is actually two discrete processes.
During Anaphase A, the chromosome-associated microtubules drag the chromosomes
towards either spindle pole; Anaphase B occurs as the overlapping microtubules
at the midzone move past one another to physically push the spindle poles apart.
In the August 14 issue of Developmental Cell, the team reports that a molecular
motor protein called Klp9p and the microtubule-associated protein Ase1p form
a complex and bind to the midzone of the spindle - a sort of molecular scaffold
that ensures a critical step: equal division of genetic material between two
daughter cells of cell division. They also found that this interaction is regulated
by a molecular switch, which is coordinated by two other proteins Cdc2p and
Clp1p.
"We now have a mechanism to describe Anaphase B, which was not well described
up to now," Tran says.
Anaphase A, Tran notes, has been extensively studied. He wanted to understand
what happens during Anaphase B. So his team, led by postdoctoral fellow Chuanhai
Fu, PhD, began systematically mutating molecular motors in the fission yeast,
Schizosaccharomyces pombe and then clocking each mutant's cell division. Only
in cells containing mutant Klp9p was Anaphase B significantly slower. The team
then showed that Klp9p and Ase1p come together at the midzone during Anaphase
B and that this interaction is required for proper spindle architecture and
function. What's more, this necessary Klp9p-Ase1p complex is blocked by Cdc2p.
But, taking away phosphates from Klp9p and Ase1p by the other protein Clp1p
just prior to Anaphase B releases the block, enabling the two proteins to form
their complex so cellular division can continue.
"Many molecules have been implicated with the spindle midzone, but no
details have been brought up in terms of molecular motors, microtubule-associated
proteins, and their binding and regulation by the phosphate switch," Tran
says. Now, however, "we have a very detailed and complete description of
four molecules" -- Klp9p, Ase1p, Cdc2p, and Clp1p - each playing a role
in one aspect of cellular division, Anaphase B."
The molecular machinery, Tran concludes, "is mechanically very beautiful."
According to Tran, the findings have potential implications for cancer biology,
in that inappropriate chromosomal segregation can lead to aneuploidies (cells
lacking the proper number of chromosomes), which is a hallmark of many cancers.
Posted August 18th, 2009
|
