Phosphorylation-mediated stabilization of Bora in mitosis coordinates Plx1/Plk1 and Cdk1 oscillations

Cell Cycle. 2014;13(11):1727-36. doi: 10.4161/cc.28630. Epub 2014 Mar 26.

Abstract

Cdk1 and Plk1/Plx1 activation leads to their inactivation through negative feedback loops. Cdk1 deactivates itself by activating the APC/C, consequently generating embryonic cell cycle oscillations. APC/C inhibition by the mitotic checkpoint in somatic cells and the cytostatic factor (CSF) in oocytes sustain the mitotic state. Plk1/Plx1 targets its co-activator Bora for degradation, but it remains unclear how embryonic oscillations in Plx1 activity are generated, and how Plk1/Plx1 activity is sustained during mitosis. We show that Plx1-mediated degradation of Bora in interphase generates oscillations in Plx1 activity and is essential for development. In CSF extracts, phosphorylation of Bora on the Cdk consensus site T52 blocks Bora degradation. Upon fertilization, Calcineurin dephosphorylates T52, triggering Plx1 oscillations. Similarly, we find that GFP-Bora is degraded when Plk1 activity spreads to somatic cell cytoplasm before mitosis. Interestingly, GFP-Bora degradation stops upon mitotic entry when Cdk1 activity is high. We hypothesize that Cdk1 controls Bora through an incoherent feedforward loop synchronizing the activities of mitotic kinases.

Keywords: Bora; Cdk1; Plk1/Plx1; cell cycle; cleavage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CDC2 Protein Kinase
  • Cell Cycle Proteins / metabolism*
  • Cyclin-Dependent Kinases / metabolism*
  • Fluorescence Resonance Energy Transfer
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Mitosis / physiology*
  • Mutagenesis, Site-Directed
  • Phosphorylation
  • Protein Stability
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-mos / metabolism
  • Xenopus laevis

Substances

  • Cell Cycle Proteins
  • Proto-Oncogene Proteins
  • bora protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-mos
  • polo-like kinase 1
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • Cyclin-Dependent Kinases