Cell Cycle Control 
Reentry of Quiescent Cells Into 
the Cell Cycle 
A vast fraction of the body's cells do not ac- 
tively participate in the cell cycle. Instead, they 
are in a quiescent state awaiting a signal to 
reenter the cycle. This signal is often in the form 
of a small protein termed a growth factor. Some 
forms of cancer appear to arise because cells 
reenter the cycle in the absence of a growth fac- 
tor, leading to uncontrolled cell growth. Some 
cells enter quiescence in the G2 phase. However, 
most quiescent cells waiting for proliferative sig- 
nals are in a specialized state of the Gj phase of 
the cell cycle known as Gq. Many normal cells 
often enter this state when deprived of growth 
factors. It is evident that the transition into and 
out of the Go state is related to the general ques- 
tion of how a cell decides it is time to prepare for 
DNA replication. Available evidence suggests that 
once a cell is committed to replicate its DNA, it 
almost invariably progresses on through the cell 
cycle until the G2 M checkpoint controls be- 
come activated. 
Many of the growth factors stimulate quiescent 
cells to reenter the cell cycle by binding to spe- 
cific receptors on the cell surface. These recep- 
tors are actually enzymes expressing a protein ki- 
nase activity that transfers phosphate groups to 
tyrosine residues on substrate proteins. Many on- 
cogenes that cause cancer turn out to be mutant 
versions of these growth factor tyrosine kinases 
that signal the cell to reenter the cycle in an un- 
controlled fashion. We have undertaken an analy- 
sis of the steps in signaling by tyrosine kinases, 
termed the signal transduction pathway, in order 
to gain a better understanding of how to control 
inappropriate signaling. Our approach has been 
to characterize biochemically an event rapidly 
stimulated by activated tyrosine kinase receptors 
and then work backward up the signaling path- 
way to define the signal transduction mechanism. 
Over the past five years we have identified in 
ribosomes a protein called S6 that is phosphory- 
lated on serine residues very rapidly after activa- 
tion of tyrosine kinase receptors. This means the 
signal transduction pathway involves receptor ty- 
rosine kinase activation of a serine kinase. We 
have shown that the activation does not occur by 
direct phosphorylation of the S6 kinase on tyro- 
sine residues, indicating that there are interme- 
diary molecules that participate in the signaling 
mechanism. Instead, the S6 kinase is activated by 
direct phosphorylation on serine and threonine 
residues by another serine/threonine protein ki- 
nase called microtubule-associated protein 2 ki- 
nase or MAP kinase. Xenopus MAP kinase has 
been purified this year and found to be itself 
phosphorylated on both threonine and tyrosine 
residues by additional upstream protein kinases. 
This means we are getting very close to the direct 
tyrosine phosphorylation events stimulated by a 
tyrosine kinase receptor. 
In both G, phase after the Gq transition and in 
G2-arrested cells, cdc2 kinase becomes activated 
after reentry into the cell cycle and may also expe- 
rience an increase in its rate of synthesis, indicat- 
ing that it works at both checkpoints in the cycle. 
In the Gi phase, cdc2 kinase is complexed with a 
different group of proteins, known as Gj cyclins, 
whose synthesis increases in late Gj. AfuU under- 
standing of cell cycle control will come when the 
entire sequence of events from tyrosine kinase 
activation to cdc2 and Gj cyclin synthesis is 
elucidated. 
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