M phase cyclin

Seueert, W., Butcher, B., and Jentsch, S. Role of a ubiquitin-conjugating enzyme in degradation of S- and M-phase cyclins. Nature 1995, 373, 78-81. 

APC is active from mid-M phase (anaphase) to the end of G1 phase and required for disconnecting sister chromatids and exit from M-Phase to Gl. The complex mediates the ubiquitination of Securin and Cyclin B. Degradation of these proteins, which block mitotic progression, promotes anaphase onset and exit from mitosis. 

Swenson, K. I., Farrell, K. M., and Ruderman, J. V. (1986). The clam embryo protein cyclin A induces entry into M phase and the resumption of meiosis in Xenopus oocytes. Cell 47 861-870. 

Subsequent experiments addressed the possibility that the target of MAPK responsible for these effects is p90Rsk. Upon injection of the constitutively active form of Rsk described above, oocytes undergoing the MI/MII transition in the presence of U126 remained in M phase with an elevated cyclin B level, a shift in Cdc27 and metaphase-arrested spindles. These results indicate that these actions of the MAPK pathway on the APC, like those involved in CSF arrest at metaphase, are mediated solely by p90Rsk. 

FIG. 4. Hypothetical action of the cyclin A2-dependent mechanism retarding exit from the first embryonic M phase in the mouse. 

This suggests that cyclin A2 is not essential for the early embryonic cell cycles. Also D-type cyclins seem to be dispensable for the early mouse embryo cell cycle progression since embryonic stem (ES) cells do not express them at all before differentiation (Savatier et al 1996). We do not know, however, whether the D-type cyclins are also absent in the early embryo. These observations suggest that not only could the first cell cycles of the mouse embryo have specific modifications, but also further embryonic cell cycles are specifically modified as well. Mammalian embryonic cell cycles are probably modified often during development. Such studies could allow us to determine a profile of a minimal cell cycle in mammals which must, however, be much more complex than a simple S M phase embryonic cell cycle of amphibians or insects. 

In a recent study, the antiproliferative effect of different carotenoids, including (3-carotene, lycopene and lutein, on PCNA and cyclin Dl expression in human KB cells have been studied. The results indicate that carotenoids suppressed cell growth by acting as inhibitors of the expressions of PCNA and cyclin Dl, although in a different extent (Cheng et al., 2007). On the other hand, (3-carotene was able to induce a cell cycle delay in G2/M phase by decreasing the expression of cyclin A in human colon adenocarcinoma cells (Palozza et al., 2002a). 

Entry of animal cells into mitosis is based on the mitosis-promoting factor (MPF). MPF consists of CDK1 (cdc2) and cyclin B. The intracellular concentration of cyclin B increases constantly until mitosis starts, and then declines again rapidly (top left). MPF is initially inactive, because CDKl is phosphorylated and cyclin B is dephosphorylated (top center). The M phase is triggered when a protein phosphatase [1] dephosphorylates the CDK while cyclin B is phosphorylated by a kinase [2]. in its active form, MPF phosphorylates various proteins that have functions in mitosis—e.g., histone HI (see p. 238), components of the cytoskeleton such as the laminins in the nuclear membrane, transcription factors, mitotic spindle proteins, and various enzymes. 

The G]/S cyclins include the D and E type cyclins the M phase specific cyclins include the B type cyclins. Cyclins of type A are active in S, G2 and M phases. 

In M phase, new phosphorylation of many proteins is observed that starts, in particular, from the CDC2-cyclin B complex. The phosphorylation mostly affects proteins involved in the reorganization of the cytoskeleton, the nuclear membrane and the formation of the spindle apparatus. As a consequence of phosphorylation events, inhibition of vesicular transport and general inhibition of transcription occur. 

During cell division, a replication-competent state is established at the replication start sites, the pre-RC. This contains the ORC, the MCM proteins and the cdc6 protein. Formation of the pre-RC in late M phase and in G1 phase licenses the chromatin for DNA replication. With entry into S phase, the MCM proteins and the Cdc6 protein dissociate from the start site. Their phosphorylation by an active S phase cyclin-CDK complex is responsible for the dissociation. 

The activity of the S phase cyclin-CDK complex is, in turn, controlled by an inhibitor, the Sicl protein. At the start of G1 phase, the S phase cyclin-CDK complex is inactivated by the Sic-1 protein. Only when the inhibitor is degraded by ubiquitin-media-ted proteolysis when the start point is crossed is an active S phase cyclin-CDK complex available. This removes the MCM proteins and Cdc6 protein from the origin by phos-phorylating them and thus enables replication. A second protein kinase, Cdc7/Dbf4p complex, is also involved in this phosphorylation. Once replication has taken place, the renewed formation of a pre-RC is hindered by the activity of the G2/M cyclin-CDK complex. 

Entry into and the course of mitosis are primarily determined by the activity of the CDC2 kinase. The CDC2 kinase in the active form exists as a complex with cychn B and, together with the cyclin, forms the mitosis promoting factor, MPF. The activity of MPF oscillates in the cell cycle and is the triggering factor for entry of the cell into M phase. 

FIGURE 12-43 Variations in the activities of specific CDKs during the cell cycle in animals. Cyclin E-CDK2 activity peaks near the G1 phase-S phase boundary, when the active enzyme triggers synthesis of enzymes required for DNA synthesis (see Fig. 12-46). Cyclin A-CDK2 activity rises during the S and G2 phases, then drops sharply in the M phase, as cyclin B-CDK1 peaks. 

FIGURE 12-44 Regulation of CDK by phosphorylation and proteolysis. (a) The cyclin-dependent protein kinase activated at the time of mitosis (the M phase CDK) has a "T loop" that can fold into the substrate-binding site. When Thr150 in the T loop is phosphorylated, the loop moves out of the substrate-binding site, activating the CDK... 

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