Growth Control of Myeloid Cells 
approach to identify sites within CSF-IR that, 
when mutated, can endow the receptor with on- 
cogenic activity. By randomly mutagenizing seg- 
ments of FMS and screening "libraries" of mu- 
tated genes for their ability to induce cell 
transformation, we identified several sites in the 
receptor where "activating mutations" occur. 
-With such information in hand, it is now possible 
to search for the presence of similar genetic le- 
sions in the FMS genes of myeloid leukemia cells 
and so determine whether FMS mutations play an 
etiologic role in such diseases. 
Role of CSF-1 in Cell Cycle Progression 
After proliferating macrophages complete cell 
division (mitosis, or M phase), they enter an 8- to 
10-hour gap phase (Gi), during which they pre- 
pare to replicate their chromosomal DNA. The 
ensuing period of DNA synthesis (S phase) lasts 
for seven hours, and once DNA replication is 
complete, the cells enter a second, shorter gap 
phase (G2) before dividing again and redistribut- 
ing copies of duplicated chromosomes to each 
daughter cell. CSF-1 is only required throughout 
Gi for cells to enter S phase, and once DNA syn- 
thesis begins, macrophages can complete cell di- 
vision in the absence of the growth factor. On the 
other hand, the requirement for persistent CSF- 
IR-mediated signals throughout the entire Gj 
interval implies that the expression of growth 
factor-responsive genes must be temporally regu- 
lated over an 8- to 10-hour period. 
Genetic data accumulated through studies of 
yeasts indicate that cell division-cycle genes 
called Gi cyclins act to prepare cells for DNA syn- 
thesis. We recently isolated a novel class of "D- 
type" cyclins from mammalian cells, at least two 
of which are differentially regulated by CSF-1 
during the Gj interval of the macrophage cell cy- 
cle. Related genes are expressed in other cell lin- 
eages, where their expression is governed by dif- 
ferent growth factors. Our idea is that these 
cyclins control progression through the Gj inter- 
val in mammalian cells by mechanistically link- 
ing early steps in growth factor-mediated signal 
transduction with the timing of the cell cycle 
clock. As might be expected, perturbations in the 
regulation of these cyclins occur in specific types 
of tumor cells and thus appear to contribute to 
malignancy. 
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