D-type cycline

Eehner In mammalian cells there is more genetic redundancy. We are not sure to what extent the other D-type cyclins compensate when we are looking at cyclin D1 or D2 knockouts. The same is true for Cdk4 knockouts Cdk6 may compensate. There are many different mutant combinations that have not yet been analysed. 

Eehner We just can t detect it. Even if we overexpress cyclin D/Cdk4 we cannot detect the association of Dacapo with these complexes. This is negative evidence and should be interpreted cautiously. However, it is clear that the p27 association with mammalian D-type cyclin/Cdk complexes is readily detectable. Thus, there seems to be a difference between flies and mammals. 

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. 

Cyclins D and E in mammals are short-hved proteins with a lifetime of only ca. 20 min. Their instability is due to the occurrence of certain sequences in the C-terminal region deletion of these sequences is associated with stabilization of the cyclins (see 13.3.1). These sequence elements are known as PEST sequences, based on their composition. Due to the short half-life, the D type cyclins require a constant stimulus at the transcription level to achieve the concentration in Gi phase necessary for activation of CDK4/6 and to initiate crossing of the restriction point. 

Binding partners of the D type cyclins include CDK4 and CDK6 in particular, and CDK4 activation is attributed a key role. For full activation of CDK4, activating phos-... 

Negative regulation of the cell cycle in Gi phase is performed in particular by the inhibitors p21 p27 and pl5 , which are activated by external signals (see above, Fig. 13.10). The inhibitor pl6 also regulates by binding free D type cyclin, which leads to destabilization of cyclin D. 

Sherr, C.J. G1 phase progression cychng on cue (1994) Cell 79, 551-559 Sherr, C.J. D-type cyclins (1995) Trends Bioch. Sd. 20,187-190 Sherr, C.J. Cancer cell cycles (1996) Sdence 274,1672-1677... 

Several studies have implicated a role for cytokinins in the regulation of both the Gj—S cycle418,463 and the G2— M phase transition417,464 of the cell cycle. Cytokinin activates Arabidopsis cell division through induction of D-type cyclin, CycD3, at the Gi—S cell cycle phase transition.463,465 A sharp increase in the levels of cytokinins was reported in tobacco cell cultures at the G2—M phase.417 Roots of multiple mutants of cytokinin receptor genes show delay of the transition in G -M phase.466... 

H. Matsushime, D. E. Quelle, S. A. Shurtleff, M Shibuya, C. J. Sherr, and J. Y. Kato. D-type cyclin-dependent kinase activity in mammalian cells. Mol Cell Bid, 14 (3), 2066-2076, 1994. 

The growth factor-dependent synthesis of D-type cyclins occurs during the Go/Gi transition and peak in concentration in late Gi phase (13). These proteins have a very short half-life and are degraded rapidly after removal of mitogenic stimulation. The INK family of CKIs primarily inhibits cyclin D/CDK4/6 complexes. Only when the concentration of cyclin D exceeds that of the INK proteins can these cyclin D/CDK4/6 complexes overcome their inhibition (14, 15). 

MAPK proteins, which in turn are activated by different MAP kinase pathways (see Fig. 10.4). Much of the mitogenic effects of ERK signals can be explained by the observation that ERK-induced expression of transcription factors stimulates the transcription of D-type cyclins, which promotes the Gl/S-phase transition in the cell cycle (see Section 13.4.1). Furthermore, phosphorylation of the CTD of RNA polymerase II (see Section 1.4.3.4) has also been reported to be mediated by the ERK1/2 proteins. 

Fig. 13.14 A) Regulation of cyclin D. On the example of cyclin Dl, the figure illustrates the activating and inactivating influences on D-type cyclins. For explanation see text.

Inactivation of the repressing function of pRb can be achieved by an uncontrolled increase of D-type cyclins and CDK2/4, leading to inappropriate phosphorylation of pRb and subsequent crossing of the restriction point. Overexpression of cyclin... 

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