Recent advances in our understanding of the cell division cycle are now tying the functions of Gl phase regulators to diverse processes involving signal transduction, differentiation, senescence, apoptosis, and malignant transformation. What determines the rate of Gl phase progression, and how do cells integrate mitogenic and antiproliferative signals with the cell cycle machinery?

Lessons From Budding Yeast In Saccharomyces cerevisiae, a single 34 kDa cyclindependent kinase (cdk)(p34cDCZB/cdc2, also known as cdkl) serves as a master controller of the cell cycle, assembling sequentially into active holoenzyme complexes with Gl, S phase, or mitotic cyclins temporally to direct distinct transitions (reviewed by Nasmyth, 1993; Reed, 1992). In the presence of appropriate nutrients, Gl cells that reach a critical size initiate DNA replication, form buds, and duplicate their spindle bodies in preparation for subsequent division. Gl cyclins (Clnl, Cln2, and Cln3) are required for these processes (Richardson et al., 1989)(see Figure I), and their overexpression contracts Gl phase and decreases cell size. Cln3-Cdc28 is present throughout Gl, and its kinase activity appears necessary for the subsequent transcriptional activation of the CLN7 and CLN2 genes (Tyers et al., 1993). In turn, the induced Clnl and Cln2 proteins associate with Cdc28, whose kinase activity further stimulates CLN7 and CLN2 transcription. CLN7 and CLN2 gene expression is controlled by a heterodimeric transcription factor composed of Swi4 and Swi6, and Cln-CdcP&mediated phosphorylation events likely affect their activity. Positive feedback leads to an abrupt rise in Cln-Cdc28 kinase activity late in Gl, which is associated with the commitment of cells to enter S phase (START)(Figure 1). Two B-type cyclins (Clb5 and Clb6), which are synthesized late in Gl and degraded as cells exit mitosis, are needed downstream for the actual onset of DNA replication (Epstein and Cross, 1992; Schwab and Nasmyth, 1993). The kinase activities of Clb-Cdc28 complexes are held in check by an inhibitory protein (p40sfc’)(Mendenhall, 1993) that accumulates early in Gl and is degraded shortly before S phase (Schwab et al., 1994). Phosphorylation of~ 40~‘~’by Clnl, Cln2-Cdc28 might trigger its ubiquitinmediated degradation, thereby enabling the Cln-regulated kinases to control S phase entry indirectly. Haploid Gl phase cells can also undergo cell cycle arrest and mate to form diploids. Conjugation is provoked by pheromones (a and a factors), secreted by cells of opposite mating types, that trigger a receptor-mediated signaling pathway (serpentine receptor-heterotrimeric G