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Updated: Jun 11, 2025

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Evolution of the Cdk4/6-Cdkn2 system in invertebrates

Shiori Yuki1, Shunsuke Sasaki2, Yuta Yamamoto2

  • 1Graduate School of Arts and Sciences, Iwate University, Morioka, Japan.

Genes to Cells : Devoted to Molecular & Cellular Mechanisms
|October 9, 2024
PubMed

Insights

Cyclin-dependent kinase 4/6 (Cdk4/6) and its inhibitor, cyclin-dependent kinase inhibitor 2 (Cdkn2), were analyzed in invertebrates. Their interaction is conserved, with Cdkn2 evolutionarily linked to Fas associated factor 1.

Area of Science:

  • Cell Biology
  • Evolutionary Biology
  • Biochemistry

Background:

  • The cell cycle progression is regulated by cyclin-dependent kinases (Cdks).
  • The G1 phase decision is controlled by Cdk4/6, inhibited by Cdkn2.
  • Mammalian studies primarily inform Cdk4/6 and Cdkn2 interactions.

Purpose of the Study:

  • To comprehensively analyze the evolutionary distribution and interaction of Cdk4/6 and Cdkn2 in invertebrates.
  • To investigate the conservation of key residues (D84 in Cdkn2, R24/31 in Cdk4/6) involved in their interaction.
  • To explore the evolutionary linkage between Cdkn2 and Fas associated factor 1 (Faf1).

Main Methods:

  • Comparative genomic analysis of Cdk4/6 and Cdkn2 across diverse invertebrate phyla.
  • Bioinformatic analysis to assess the conservation of amino acid residues crucial for protein-protein interaction.
  • Statistical correlation analysis to determine the relationship between Cdkn2 presence and residue conservation.
  • Phylogenetic analysis to investigate the co-evolution of Cdkn2 and Faf1.

Main Results:

  • Cdk4/6 is widely distributed in invertebrates, while Cdkn2 shows uneven distribution.
  • The positive charge at R24/31 in Cdk4/6 is conserved in species possessing Cdkn2.
  • A statistically significant correlation exists between the presence of Cdkn2 and the conservation of the positive charge at R24/31.
  • Cdkn2 exhibits a strong evolutionary linkage with Faf1, indicated by conserved microsynteny.

Conclusions:

  • The interaction between Cdk4/6 and Cdkn2 is evolutionarily conserved in invertebrates, suggesting functional importance.
  • The conservation of specific residues and the linkage with Faf1 highlight key evolutionary pressures shaping these cell cycle regulators.
  • Further research is warranted to elucidate the functional implications of the Cdkn2-Faf1 association and conserved microsynteny.
Keywords:
cell cycle regulationcomparative genomicscyclin‐dependent kinasecyclin‐dependent kinase inhibitorevolutioninvertebratessyntenytumor suppressor

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