Scientists at the Francis Crick Institute in London have greatly
improved our understanding of how microtubules in the cell
cytoskeleton switch between phases of growth and shrinkage.
This has implications for cancer research because correct
switching frequency between growth and shrinkage is essential for
cell division - and cancer can result when cell division goes
awry.
Dr Christian Duellberg of the Crick, in Thomas Surrey's lab,
explained: "In analogy to the skeleton, cells have a cytoskeleton.
Microtubules form part of this cytoskeleton and are little tubes
that span throughout the space inside a cell.
"Unlike our static bones, microtubules change their length
constantly and switch between phases of growth and shrinkage. This
is important because cells need to be able to drastically change
their shape when they divide or move. However, exactly how this
switching occurs was unknown and has been a controversial topic in
the last decades."
Most scientists agree that there has to be some sort of
stabilising 'cap' at the end of microtubules. However,
how the size of this cap affects the stability of the
microtubules was unknown.
To investigate, the team measured the properties of the cap in
space (size) and time (duration of stability). They revealed for
the first time a clear link between the cap and microtubule
stability - the longer the cap, the more stable the
microtubule.
They showed that so-called End Binding (EB) proteins can bind to
the cap and make the microtuble unstable, which causes it to switch
from growing to shrinking more often. The scientists also showed
that these EB proteins, when labelled with dye, can be used to
measure the length of the cap by proxy and can therefore be used to
track microtubule stability directly and in real time using light
microscopy.
Dr Duellberg said: "Because the correct switching frequency
between growth and shrinkage of microtubules is essential for cell
division, drugs that affect this switching frequency have become
powerful tools in chemotherapy as they prevent cells from
dividing.
"An example of such a drug is Paclitaxel, which reduces the
switching frequency from growth to shrinkage. It is currently used
to treat forms of ovarian, breast, lung, pancreatic and other
cancers. However, resistance to the drug and side effects are a
problem. As our study provides more details into how microtubules
switch from growth to shrinkage, this might help to design better
drugs that affect microtubule properties more specifically."
As well as offering new insights into cancer, using dye-labelled
EB proteins to follow the stability of microtubules in real time
will help scientists find out more about diseases
caused by altered microtubule stability and incorrect switching
between growth and shrinkage. Examples include eye movement
disorders such as strabismus, where a patient's eyes don't align
correctly. The paper, The size of the EB cap determines
instantaneous microtubule stability, is published in the
journal eLife.