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CDK11 inhibition induces cytoplasmic p21WAF1 splice variant by p53 stabilisation and SF3B1 inactivation

Radovan Krejcir1, Lukasz Arcimowicz1, Lucia Martinkova1

  • 1RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic.

Molecular Oncology
|October 17, 2025
PubMed

Insights

Blocking cyclin-dependent kinase 11 (CDK11) stabilizes p53, leading to the production of a novel CDKN1A (p21WAF1) isoform, p21L. This isoform exhibits reduced proliferation control, revealing a new link between RNA splicing and cell cycle regulation.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Cycle Regulation

Background:

  • Cyclin-dependent kinase 11 (CDK11) plays roles in transcription and RNA splicing.
  • CDK11 is a potential therapeutic target in cancer treatment.
  • CDKN1A (p21WAF1) is a key cell cycle inhibitor, with canonical (p21C) and novel (p21L) isoforms.

Purpose of the Study:

  • To investigate the effects of CDK11 inhibition on p53 and CDKN1A isoforms.
  • To compare the proliferation inhibitory potential of p21C and p21L.
  • To elucidate the mechanism regulating p21L induction and its evolutionary conservation.

Main Methods:

  • Inhibition of CDK11 using the OTS964 inhibitor.
  • Analysis of p53 stabilization and MDM2 downregulation.
  • Assessment of CDKN1A (p21WAF1) isoform expression and proliferation.
  • Phage display to identify antibody epitopes for isoform specificity.
  • Investigation of SF3B1 inhibition and its effect on p21L induction.

Main Results:

  • CDK11 inhibition stabilizes p53 via MDM2 downregulation, inducing both p21C and p21L.
  • The p21L isoform shows reduced proliferation inhibition due to altered motifs and cytoplasmic localization.
  • p21L induction is triggered by inhibition of the spliceosomal protein SF3B1, which is phosphorylated by CDK11.
  • An analogous p21L isoform was found in murine cells, indicating evolutionary conservation.

Conclusions:

  • CDK11 inhibition impacts cell proliferation through differential regulation of p21WAF1 isoforms.
  • The novel p21L isoform has diminished antiproliferative activity.
  • A link exists between RNA splicing regulation (via SF3B1) and cell cycle control mediated by CDK11 and p21WAF1 alternative splicing.
Keywords:
MDM2SF3B1cyclin‐dependent kinase 11p21Lp21WAF1p53

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