Regulation Of The Cell Cycle By The Mapk And Pi3k Pathways

Normal cell proliferation thus often involves the coordinate activation of MAPK and PI3K pathways. Together, these pathways elicit a panoply of changes, such as increased metabolism, enhanced protein synthesis, reorganization of the cytoskeleton, inhibition of proapoptotic signals, and, of course, stimulation of cell cycle progression from G1/G0 into S-phase (cf. 5.2). Several mechanisms synergize to achieve this last effect (Figure 6.6).

Following their translocation into the nucleus as a consequence of MAPK activation, activated ERK protein kinases phosphorylate several transcriptional activators involved in cell cycle progression. In addition, ERK kinases

Figure 6.6 Cell cycle activation by coordinated action of the MAPK and PI3K pathways Following activation by mitogenic signals (top left corner), the pathways interact to stimulate cell cycle progression towards S phase. Negative regulators of the cell cycle are shaded.

phosphorylate the pp90RSK kinases which then as well translocate to the nucleus to phosphorylate a further set of transcriptional activators. Among the more important targets are the SRF, ETS1, ELK1 and MYC factors, which are all stimulated by this type of phosphorylation, and, of course, the API components FOS and JUN (^4.3), which are also induced at the transcriptional level.

In many cells, an important consequence of these events is a stimulation of Cyclin D transcription7. Accumulation of Cyclin D drives cell cycle progression during most of the G1 period. It is counteracted by degradation of the protein which is increased if Cyclin D is phosphorylated by GSK3. This inhibitory phosphorylation is blocked by phosphorylation of GSK3 by AKT. The coordinate activation of Cyclin D is thus an important point of synergy between the MAPK and PI3K pathways.

Further genes activated as a consequence of MAPK pathway stimulation are CDC25A and - to a lesser extent - CDK4. Induction of the CDC25A phosphatase synergizes with Cyclin D accumulation to increase CDK4 activity, since the phosphatase removes the inhibitory threonine phosphate from CDK4, as well as from CDK2.

As the CDK4/Cyclin D holoenzyme accumulates, it binds more and more p27KIP1, diverting it from CDK2. Since Cyclin E begins to accumulate at this stage of the cell cycle, the activity of the CDK2/Cyclin E enzyme increases

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