Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

522 Chapter 8: Analyzing Cells, Molecules, and Systems
SUDDEN
ACTIVATING
INPUT
A
inactive
fast gene
activation
A
A
A
R
slow gene
repression
rate of protein synthesis
sudden
activating
input
K A << K R
protein X output
A protein
R protein
rate of protein synthesis
sudden
activating
input
K A >> K R
protein X output
A protein
R protein
GENE X
time
(A) (B) (C)
X
time
An Incoherent Feed-forward Interaction Generates Pulses
Imagine that a sudden input signal immediately activates a transcription activator
A and that the same input signal induces the much slower synthesis of a transcription
repressor protein R that acts on the same gene X. If A and R control gene
expression by an AND NOT logic function like that described above, our intuition
tells us that this system should be able to generate a pulse of transcription: when
A is activated (and R is absent), the transcription of gene X will begin and cause
an increase in the concentration of protein X, but MBoC6 then n8.615/8.86 transcription will shut off
when the concentration of R increases to a sufficiently high value.
Arrangements of this type are common in the cell. In E. coli, for example, galactose
metabolic genes are positively regulated by the catabolite activator protein
(CAP), which is activated at high levels of cAMP. The same genes are repressed
by the GalS repressor protein, which is encoded by a gene whose transcription is
likewise activated by CAP. Thus, an increase in input (cAMP) activates A (CAP),
and transcription of the galactose genes begins. But activation of A also causes
a subsequent buildup of R (GalS), which causes the same genes to be repressed
after a delay. This results in an incoherent feed-forward motif (Figure 8–85A).
The response of the incoherent feed-forward motif will vary, depending on
the parameters of the system. Suppose, for example, that the transcription activator
protein A binds more weakly to the gene regulatory region than does the
transcription repressor protein R (K A < K R ). In this case, there will be a transient
burst of protein synthesized by the affected gene (gene X) in response to a sudden
activating input (Figure 8–85B). In contrast, the output will be more sustained if
K A is much larger than K R , because the repression will be too weak to overcome
the gene activation (Figure 8–85C). Other properties of this network, such as the
dependence of the amplitude of the pulse on the various rate constants in the system,
can be explored with the same computational tools. Thus, our intuitive guess
about how this system would behave was only partially correct; even the simplest
of networks depends on precise interaction strengths, demonstrating yet again
why mathematics is needed to complement cartoon drawings.
Figure 8–85 How an incoherent feedforward
motif can generate a brief
pulse of gene activation in response
to a sustained input. (A) Diagram of an
incoherent feed-forward motif in which the
transcription activator A and the repressor
R control the expression of gene X using
the AND NOT logic of Figure 8–83A.
(B) When K A « K R , this motif generates a
pulse of protein X expression, such that the
output goes back down even if the input
remains high. (C) When K A » K R , the same
motif responds to a sustained input by
generating a sustained output.
A Coherent Feed-forward Interaction Detects Persistent Inputs
In the bacterium E. coli, the sugar arabinose is only consumed when the preferred
sugar, glucose, is scarce. The strategy that cells use to assess the presence of arabinose
and absence of glucose involves a feed-forward arrangement that is different
from the one just described. In this case, depletion of glucose causes an increase
of cAMP, which is sensed by the CAP transcription activator protein, as described
previously. In this case, however, CAP also induces the synthesis of a second transcription
activator, AraC. Both activator proteins are necessary to activate arabinose
metabolic genes (the AND logic function in Figure 8–83B).