Cyclin A is required at two points in the human cell cycle.

Abstract

Cyclins play a fundamental role in regulating cell cycle events in all eukaryotic cells. The human cyclin A gene was identified as the site of integration of hepatitis B virus in a hepatocarcinoma cell line; in addition, cyclin A is associated with the E2F transcription factor in a complex which is dissociated by the ElA oncogene product. Such findings suggest that cyclin A is a target for oncogenic signals. We have now found that DNA synthesis and entry into mitosis are inhibited in human cells microinjected with anti-cyclin A antibodies at distinct times. Cyclin A binds both cdk2 and cdc2, giving two distinct cyclin A kinase activities, one appearing in S phase, the other in G2. These results suggest that cyclin A defines novel control points of the human cell cycle.

B-Myb function can be markedly enhanced by cyclin A-dependent kinase and protein truncation

“…Therefore, both the timing of B-Myb modi®cation during S-phase and its relative e cacy suggest that cyclin A/Cdk2 is the enzyme responsible in vivo. Previously it has been shown that cyclin A expression is mandatory for the onset and maintenance of DNA synthesis in mammalian cells (Girard et al, 1991;Pagano et al, 1992). As cyclin A was found to synergise with B-Myb to promote cells into S-phase (Figure 6), it will be of interest to explore further the possibility that the requirement for cyclin A for DNA synthesis re¯ects, at least in part, enhancement of B-Myb by direct phosphorylation.…”

BPV-4 E8 transforms NIH3T3 cells, up-regulates cyclin A and cyclin A-associated kinase activity and de-regulates expression of the cdk inhibitor p27Kip1

“…These are two experimental conditions in which it has been shown that levels of the cdk inhibitor p27 Kip1 are elevated (Pagano et al, 1992). Thus E8 may operate by impairing the ability of p27 Kip1 to block cdk activity and cell cycle progression either by inhibiting gene transcription, promoting protein degradation or by inhibiting p27 Kip1 function.…”

“…D-type cyclins are required for progression through early/mid G1 phase of the cell cycle and in the decision to embark on a new cell cycle or to enter a quiescent state (GO) after mitosis, linking cell exposure to external cues to entry into the cell cycle (Won et al, 1992;Baldin et al, 1993). Cyclin E is expressed in late G1 and is required for entry into Sphase in mammalian ®broblasts (Resnitzky et al, 1994;Ohtsubo et al, 1995), while Cyclin A is ®rst expressed at the G1/S transition (Henglein et al, 1994) and is required, in complex with cdk2, for the completion of S-phase and, in complex with cdc2, for passage through G2 and mitosis (Girard et al, 1991;Pagano et al, 1992).…”

K-ras modulates the cell cycle via both positive and negative regulatory pathways

“…Although cyclin A, initially characterized as a`mitotic cyclin ' (Walker and Maller, 1991), is considered to function as an S-phase cyclin (Zindy et al, 1992;Pagano et al, 1992), recent work (Carbonaro-Hall et al, 1993;Rosenberg et al, 1995) suggests that cyclin A activity may also be essential for G 1 /S progression. Therefore, the e ect of activated K-ras on expression of both cyclin A and cyclin E (a G 1 cyclin; Ohtsubo et al, 1995), was studied.…”