Cell Cycle Control 
David H. Beach, Ph.D. — Investigator 
Dr. Beach is also Senior Staff Scientist at Cold Spring Harbor Laboratory and Adjunct Associate Professor 
in the Department of Microbiology at the State University of New York at Stony Brook. He received 
his undergraduate degree at the University of Cambridge, followed by a Ph.D. degree at the University of 
Miami, where he worked with Marcus Jacobson. His postdoctoral studies were done with Sydney Shall 
at the University of Susex and with Amar Klar at Cold Spring Harbor Laboratory. 
THE cell division cycle interests an increasing 
number of scientists and continues to be the 
central focus of our research. The two most criti- 
cal events of the cycle are the replication of DNA 
that occurs during the S (synthetic) phase and the 
segregation of chromosomes into daughter cells 
that occurs in the M (mitotic) phase. DNA replica- 
tion and mitosis are profoundly different cellular 
events, both molecularly and in terms of cellular 
mechanics, but both are regulated by closely re- 
lated enzymes, members of a family known as the 
cyclin kinases. 
Each of these kinases has a catalytic subunit, of 
which cdc2 is the prototype, and a regulatory sub- 
unit that is a cyclin. Cyclins derive their name 
simply from the property by which they were first 
recognized. Their abundance oscillates in the di- 
vision cycle, with the same periodicity as the cy- 
cle itself. Many cyclins have been discovered, all 
related in their amino acid sequence. In humans 
there are at least five groups of such proteins, 
called cyclins A, B, C, D, and E. Within each 
group there may be further members, such as Dl , 
D2, D3 or Bl, B2. Cyclins of different classes ap- 
pear to act at different stages of the cell cycle — 
B-type cyclins at mitosis, A type at S phase, and 
so on. 
Also, in the case of the D-type cyclins, each 
member of the family displays a specific tissue 
distribution. D-type cyclins have attracted partic- 
ular interest because they appear to act early in 
the cell division pathway and can also mutate to 
give rise to oncogenic forms. With cyclin Dl , the 
gene is amplified or rearranged in a wide range of 
human tumors, including cancers of the breast, 
esophagus, bladder, and lymphatic system. It is 
not yet known how overexpression or activation 
of cyclin Dl contributes to the pathology of 
cancer, but a clear connection has been 
established. 
A major activity in the Beach laboratory has 
centered on identification of the regulatory mole- 
cules controlling cyclin kinases, particularly the 
cyclin B/cdc2 enzyme that functions in mitosis. 
This enzyme is influenced by at least three phos- 
phorylation events, some activating and others in- 
hibiting. Tyrosine phosphorylation of cdc2 is the 
best-characterized inhibitory mechanism, and 
the relevant tyrosine kinases and phosphatases 
have been identified both in yeast and human 
cells. 
The tyrosine kinases are encoded by the mikl'^ 
and weel^ genes of yeast, and the tyrosine phos- 
phatases by the cdc25^ gene. Kinases and phos- 
phatases act antagonistically. Thus, in the ab- 
sence of the tyrosine kinase, cells enter mitosis 
prematurely before the completion of DNA repli- 
cation. Lack of the tyrosine phosphatase causes 
arrest in the G2 phase of the division cycle. 
A further class of negative regulators of mitosis 
has recently been discovered. The piml^ (pre- 
mature initiation of mitosis) gene of yeast en- 
codes a homologue of a human protein called 
RCCl. In the absence of piml/^CCl function, 
cells also enter mitosis before the completion of 
DNA replication. The gene product pirn 1 /RCCl 
is an integral nucleosomal protein (present at 
one copy per nucleosome) and is responsible for 
signaling the state of the chromatin to the cdc2/ 
cyclin B enzyme. Only when the chromatin is 
fully replicated can the cell proceed to division 
by activation of the cyclin B/cdc2 enzyme. The 
mechanism by which the pirn 1 /RCCl nucleoso- 
mal protein communicates with the cyclin ki- 
nases is an area of major current interest. 
Many substrates of the cyclin kinases have been 
discovered. They include major structural pro- 
teins such as lamins and vimentin, which play a 
vital role in the structural reorganization of the 
cell that occurs during mitosis. Other substrates 
include transcription factors and also negative 
growth regulators such as the p53 and rb 
proteins. 
It is unclear why such different cellular activi- 
ties as DNA replication and cell division are regu- 
lated by a family of cyclin kinases that are clearly 
related evolutionarily. The evolutionary similar- 
ity implies that there was once only one cyclin 
kinase and thus that this enzyme regulated only 
one cell cycle event in a primitive cell. Was that 
event DNA replication or cell division? It is very 
difficult to imagine the primitive cell, because all 
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