Essential Cell Biology 5th edition

584 CHAPTER 17 Cytoskeleton
(A)
GROWING MICROTUBULE
GTP-tubulin dimers add to
growing end of microtubule
tubulin dimer
with bound GTP
(GTP-tubulin)
Figure 17–16 GTP hydrolysis controls the dynamic instability of
microtubules. (A) Tubulin dimers carrying GTP (red ) bind more tightly
to one another than do tubulin dimers carrying GDP (dark green). The
rapidly growing plus ends of microtubules, capped by newly added
GTP-tubulin, therefore tend to keep growing. (B) From time to time,
however, especially if microtubule growth is slow, the dimers in this
GTP cap will hydrolyze their GTP to GDP before fresh dimers loaded
with GTP have time to bind. The GTP cap is thereby lost. Because
the GDP-carrying dimers are less tightly bound in the polymer, the
protofilaments peel away from the plus end, and the dimers are
released, causing the microtubule to shrink (Movie 17.3).
(B)
addition proceeds faster
than GTP hydrolysis by the dimers
GTP hydrolysis is faster
than addition of new
GTP-tubulin dimers
protofilaments containing GDPtubulin
peel away from the
microtubule wall
GDP-tubulin is released
to the cytosol
GTP cap
SHRINKING MICROTUBULE
GTP cap lost
GDP-tubulin
while the remainder is free in the cytosol, where it is available for microtubule
growth. Tubulin dimers joining this cytosolic pool rapidly exchange
their bound GDP for GTP, thereby becoming competent to add to another
growing microtubule.
Microtubule Dynamics Can Be Modified by Drugs
Drugs that prevent the polymerization or depolymerization of tubulin
dimers can have a rapid and profound effect on the organization of microtubules—and
thereby on the behavior of the cell. Consider the mitotic
spindle, the microtubule-based apparatus that guides the chromosomes
during mitosis (see Figure 17–11C). If a cell in mitosis is exposed to the
drug colchicine, which binds tightly to free tubulin dimers and prevents
their polymerization into microtubules, the mitotic spindle rapidly disappears,
and the cell stalls in the middle of mitosis, unable to partition the
chromosomes into two groups. This observation, and others like it, demonstrates
that the mitotic spindle is normally maintained by a balanced
addition and loss of tubulin subunits: when tubulin addition is blocked by
colchicine, tubulin loss continues until the spindle disappears.
The drug Taxol has the opposite effect on microtubule growth. It binds
tightly to microtubules and prevents them from losing subunits. Because
new subunits can still be added, the microtubules can grow but cannot
shrink. Despite this difference in the mechanism of action, Taxol has
the same overall effect as colchicine—arresting dividing cells in mitosis.
These experiments show that for the mitotic spindle to function, microtubules
must be able to assemble and disassemble. We discuss the behavior
of the spindle in more detail in Chapter 18, when we consider mitosis.
The inactivation or destruction of the mitotic spindle eventually kills
dividing cells. Because cancer cells divide in a less controlled way than
do normal cells of the body, they can sometimes be destroyed preferentially
by drugs that either stabilize or destabilize microtubules. Such
antimitotic drugs, which include colchicine and Taxol, are used to treat
human cancers (Table 17−1). As we discuss shortly, there are also drugs
that affect the polymerization of actin filaments.
QUESTION 17–2
Microtubules Organize the Cell Interior
Cells are able to modify the dynamic instability of their microtubules for
particular purposes. As cells enter mitosis, for example, microtubules
TABLE 17–1 DRUGS THAT AFFECT MICROTUBULES
Why do you suppose it is much
easier to add tubulin to existing
microtubules ECB5 e17.15-17.16
than to start a new
microtubule from scratch? Explain
how γ-tubulin in the centrosome
helps to overcome this hurdle.
Microtubule-specific
Drugs
Taxol
Colchicine, colcemid
Vinblastine, vincristine
Action
Binds and stabilizes microtubules
Binds tubulin dimers and prevents their polymerization
Binds tubulin dimers and prevents their polymerization