and exit in all eukaryotic cells, Gj cyclins are pre- 
sumed to function as regulatory subunits of other 
cyclin-dependent kinases that instead govern Gj pro- 
gression and entry into S phase. In mammalian cells, 
such genes might also control differentiative deci- 
sions made during the Gj interval that are accompa- 
nied by transient cell cycle arrest. 
Cloning of murine and human D-type cyclins has 
now revealed the presence of three highly con- 
served genes that map to different chromosomes, 
have similar intron-exon organizations, and are inde- 
pendently regulated by growth factors in most, if 
not all, mammalian cells. For example, following 
restimulation of growth factor-deprived macro- 
phages with CSF-1, cyclin Dl induction precedes 
that of cyclin D2, whereas cyclin D3 is not ex- 
pressed. Cyclin Dl mRNAand protein levels remain 
elevated in the proliferating cells as long as CSF-1 is 
present, but the expression of cyclin D2 is periodic 
and is maximal at the Gj/S transition. In contrast, in 
peripheral blood T lymphocytes stimulated with 
mitogens to enter the cell cycle, cyclins D2 and D3 
are expressed, but cyclin Dl is not, and expression 
of cyclin D2 temporally precedes that of cyclin D3. 
All of the cyclin D proteins have short half-lives, and 
premature withdrawal of CSF-1 during the G, inter- 
val leads to their rapid degradation, correlating with 
the subsequent failure of cells to enter S phase. 
During Gj the cyclin D proteins associate with 
p34cdc2 jjj^g polypeptides and are themselves phos- 
phorylated. A future challenge will be to identify 
these cyclin-dependent kinases and their key physio- 
logic substrates. Possible substrates for complexes 
between D-type cyclins and their catalytic subunits 
include the retinoblastoma gene (Rb-1) product, 
whose phosphorylation in late Gj appears to be re- 
quired for S-phase entry. The different D-type cy- 
clins possibly interact with more than one such ki- 
nase, further suggesting that their functions are 
unlikely to be redundant. Perturbations of either cy- 
clin Dl or D2 gene expression have now been dem- 
onstrated to result from chromosomal transloca- 
tions, inversions, retroviral insertions, and gene 
amplification in lymphomas, thymomas, parathy- 
roid adenomas, squamous cell carcinomas, and in 
primary adenocarcinomas of the breast, implying 
that their deregulation can contribute to neoplasia. 
Dr. Sherr is also a member of the Department of 
Tumor Cell Biology at St. Jude Children's Re- 
search Hospital and Adjunct Professor of Biochem- 
istry at the University of Tennessee College of Med- 
icine, Memphis. 
Articles 
Inaba, T., Matsushime, H., Valentine, M., Roussel, 
M.F., Sherr, C.J., and Look, A.T. 1992. Genomic 
organization, chromosomal localization, and inde- 
pendent expression of human cyclin D genes. Ge- 
nomics 13-565-574. 
Matsushime, H., Roussel, M.F., Matsushima, K., 
Hishinuma, A. , and Sherr, C.J. 1991. Cloning and 
expression of murine interleukin-1 receptor an- 
tagonist in macrophages stimulated by colony- 
stimulating factor 1. 78:616-623- 
Matsushime, H., Roussel, M.F., and Sherr, C.J. 
1991. Novel mammalian cyclins (CYL genes ) ex- 
pressed during Gl. Cold Spring Harb Symp 
Quant Biol 56:69-74. 
Roussel, M.F., Cleveland, J. L., Shurtleflf, S.A., and 
Sherr, C.J. 1991. Myc rescue of a mutant CSF-1 
receptor impaired in mitogenic signalling. Na- 
ture 353:361-363. 
Sherr, C.J. 1991. Mitogenic response to colony- 
stimulating factor 1. Trends Genet 7:398-402. 
van Daalen Wetters, T., Hawkins, S.A., Roussel, 
M.F., and Sherr, C.J. 1992. Random mutagenesis 
of CSF- 1 receptor {FMS) reveals multiple sites for 
activating mutations within the extracellular do- 
main. EMBO / 11:551-557. 
DEVELOPMENTAL CHANGES IN THE DROSOPHILA GENOME DURING OOGENESIS 
AixanC. Spradling, Ph.D., Investigator 
The genetic information for development is 
stored within the DNA backbone making up each 
chromosome, primarily as encoded RNA and protein 
sequences. Other DNA regions mediate expression 
of only the appropriate genes in each cell of the 
developing organism. At least occasionally this in- 
formation involves changes in the relative copy 
number (gene amplification) or structure (gene re- 
arrangement) of the DNA sequences themselves 
within specific developing cells, as part of their pro- 
gram of differentiation. Dr. Spradling's laboratory is 
interested in the molecular mechanisms controlling 
CELL BIOLOGY AND REGULATION 
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