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

CONTROL OF CELL DIVISION AND CELL GROWTH
1013
mitogen
mitogen receptor
Ras
MAP kinase
activation of transcription regulatory protein
CYTOSOL
NUCLEUS
immediate early
gene expression
Myc
transcription
regulatory
protein
Figure 17–61 Mitogen stimulation of cellcycle
entry. As discussed in Chapter 15,
mitogens bind to cell-surface receptors to
initiate intracellular signaling pathways. One
of the major pathways involves activation
of the small GTPase Ras, which activates a
MAP kinase cascade, leading to increased
expression of numerous immediate early
genes, including the gene encoding the
transcription regulatory protein Myc. Myc
increases the expression of many delayedresponse
genes, including some that lead
to increased G 1 -Cdk activity (cyclin D–
Cdk4), which triggers the phosphorylation
of members of the Rb family of proteins.
This inactivates the Rb proteins, freeing
the gene regulatory protein E2F to activate
the transcription of G 1 /S genes, including
the genes for a G 1 /S-cyclin (cyclin E) and
S-cyclin (cyclin A). The resulting G 1 /S-Cdk
and S-Cdk activities further enhance Rb
protein phosphorylation, forming a positive
feedback loop. E2F proteins also stimulate
the transcription of their own genes,
forming another positive feedback loop.
delayed-response gene expression
P
active Rb
protein
inactivated
E2F protein
active
G 1 -Cdk
positive feedback
active E2F
protein
S-phase gene
transcription
active
G 1 /S-Cdk
G 1 /S-cyclin
(cyclin E)
S-cyclin
(cyclin A)
active
S-Cdk
DNA
SYNTHESIS
P
P
positive
feedback
inactivated Rb
protein
G 1
S
cell cycle is complete and irreversible. The liberated E2F proteins, for example,
increase the transcription of their own genes. In addition, E2F-dependent transcription
of G 1 /S-cyclin (cyclin E) and S-cyclin (cyclin A) genes leads to increased
G 1 /S-Cdk and S-Cdk activities, which in turn increase Rb protein phosphorylation
and promote further E2F release MBoC6 (see m17.62/17.61
Figure 17–61).
The central member of the Rb family, the Rb protein itself, was identified originally
through studies of an inherited form of eye cancer in children, known as
retinoblastoma (discussed in Chapter 20). The loss of both copies of the Rb gene
leads to excessive proliferation of some cells in the developing retina, suggesting
that the Rb protein is particularly important for restraining cell division in this tissue.
The complete loss of Rb does not immediately cause increased proliferation
of retinal or other types of cells, in part because Cdh1 and CKIs also help inhibit
progression through G 1 and in part because other cell types contain Rb-related
proteins that provide backup support in the absence of Rb. It is also likely that
other proteins, unrelated to Rb, help to regulate the activity of E2F.