16 P. Doerner
transcriptionally by CDK-dependent phosphorylation and proteolysis (Loy
et al. 1999; Reynolds et al. 2003), and Fkh2p is also phosphorylated in a CDK-
dependent manner. The expression targets of this ternary complex include the
mitotic cyclins required for chromosome segregation and cytokinesis.
At M/G1, another wave of gene expression occurs to mediate exit from mi-
tosis, and reset the cellular state such that the cell becomes responsive again
to the accumulation of mass by committing to a new round of cell division.
Expression of this suite of genes depends on the activity of two types of
transcription factors: Mcm1p; and the related and partially redundant Swi5p
and Ace2p proteins (Dohrmann et al. 1992). The latter two are themselves
transcriptionally regulated by the G2/M ternary complex factor, and post-
translationally regulated by CDK-dependent phosphorylation. In contrast,
two negatively acting homeodomain co-regulators that bind target promot-
ers in the vicinity of the Mcm1p binding sites act to restrict the autonomous,
M/G1-specific function of Mcm1p to this cell cycle transition. Their periodic
expression is mediated by SBF and later in the cycle presumably, by the G2/M
ternary complex factor.
The general principles of the budding yeast network of transcriptional reg-
ulators which periodically activate waves of cell cycle phase-specific gene ex-
pression are therefore: First,serial regulationsuch that transcription factors
functioning early in the cell cycle regulate subsequently acting transcription
factors, to form a fully connected regulatory cycle. Second,indirect coup-
lingbetween the factors responsible for sequential waves of transcription,
which is usually mediated by components of other oscillating mechanisms,
e.g. CDK-dependent phosphorylation or proteasome-mediated proteolysis,
that themselves are subject to prior transcriptional control. Indirect feedback
and feed-forward regulation are mechanisms to delay the initiation of the
next periodic wave of transcription. This is because activation of heteromeric
protein kinases such as cyclin–CDKs depends on the attainment of concen-
tration thresholds of the individual components and is furthermore subjected
to ultrasensitive control by series of activating kinases and counter-acting
protein phosphatases. A corollary is that the majority of the transcription fac-
tors comprising the cell cycle transcription network themselves need not be
transcriptionally regulated in a cell cycle phase-specific manner. Third, the
individual transcription factors that comprise the core regulatory network
themselves control series of dependent transcription factorsthat mediate the
expression of co-regulated sets of genes necessary for the successful comple-
tion of individual cell cycle phases (Horak et al. 2002).
Due to the paucity of data, it is currently not possible to gauge the relative
importance of the cell cycle transcriptional network vis à vis CDK-dependent
protein phosphorylation and ubiquitin-dependent proteolysis in controlling
cell cycle progression in different eukaryotic model systems. It is conceiv-
able that the relative contribution of transcriptional control compared to the
other canonical processes varies in different organisms, but due to the inher-