34.7:
M-Cdk Drives Transition Into Mitosis
A cell’s transition into mitosis is characterized by the activation of M-Cdk complexes, consisting of the protein kinase Cdk1—or cyclin-dependent kinase 1—bound to M cyclin.
M-Cdk complexes form when M cyclin accumulates. In most cells, M cyclin levels peak during G2—the gap phase following the chromosomal duplication of S phase—and early mitosis.
The M-Cdk complex is phosphorylated at an active site by CDK-activating kinase, or CAK. However, the complex remains inactive, because it is also phosphorylated at two inhibitory sites by the protein kinase Wee1.
M-Cdk is activated largely by the protein phosphatase Cdc25. Cdc25 removes the phosphates that inhibit M-Cdk and suppresses the inhibitory activity of Wee1.
M-Cdk drives the transition into mitosis by activating factors necessary for early mitotic processes.
In prophase, M-Cdk activity spurs the shortening and compaction of chromosomes, known as chromosome condensation. During prophase, M-Cdk also initiates the formation of the mitotic spindle—which separates chromosomes into two daughter cells.
During prometaphase in animal cells, M-Cdk helps degrade the nuclear envelope, allowing the nucleus to break apart.
In metaphase, M-Cdk mediates the attachment of sister chromatids to opposite poles of the spindle.
M-Cdk promotes the multiphase reorganization of the Golgi apparatus, which is important for correct spindle formation and segregation of the organelle. In addition, throughout mitosis, M-Cdk is involved in the reorganization of the actin cytoskeleton, which helps determine spindle orientation and the axis of cell division, among other functions.
34.7:
M-Cdk Drives Transition Into Mitosis
Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin promotes M phase events—such as mitotic spindle formation, sister chromatid attachment to opposite spindle poles, chromosome condensation, nuclear envelope breakdown, and the actin cytoskeleton and Golgi apparatus rearrangement. By promoting these processes, M cyclin drives the transition into the M phase.
Like other cyclins, M cyclin levels fluctuate during the cell cycle. Cdk levels, however, remain relatively stable. In most cells (embryonic cells are an exception), M cyclin gene transcription increases, and M cyclin accumulates as the cell approaches the G2/M transition. The accumulated M cyclin binds to Cdk, forming M-Cdk complexes. The M-Cdks are primed to trigger M phase events upon activation, largely by Cdc25.
Active M-Cdk enables the transition into mitosis by phosphorylating proteins that enable several early mitotic processes. However, M-Cdk is not the only protein kinase that regulates this transition. Polo-like kinases and Aurora kinases, for example, also contribute to early mitotic processes.
Plk1 is a polo-like kinase necessary for the normal bipolar formation of the mitotic spindle. Plk1 phosphorylates proteins that help separate the spindle poles. Aurora-A also regulates proteins involved in forming and stabilizing the mitotic spindle, while Aurora-B allows sister chromatids to attach to the spindle. Together, M-Cdk and other protein kinases help regulate the transition between the G2 and M phases of the cell cycle.
Suggested Reading
- Asghar, Uzma, Agnieszka K. Witkiewicz, Nicholas C. Turner, and Erik S. Knudsen. 2015. “The History and Future of Targeting Cyclin-Dependent Kinases in Cancer Therapy.” Nature Reviews Drug Discovery 14 (2): 130–46. https://doi.org/10.1038/nrd4504.
- “CDK.” 2014. Nature News. Nature Publishing Group. 2014. https://www.nature.com/scitable/topicpage/cdk-14046166/.