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A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells.

Cyclin D-dependent kinases (CDK4 and CDK6) are positive regulators of cell cycle entry and they are overactive in the majority of human cancers. However, it is currently not completely understood by which cellular mechanisms CDK4/6 promote tumorigenesis, largely due to the limited number of identified substrates. Here we performed a systematic screen for substrates of cyclin D1-CDK4 and cyclin D3-CDK6. We identified the Forkhead Box M1 (FOXM1) transcription factor as a common critical phosphorylation target. CDK4/6 stabilize and activate FOXM1, thereby maintain expression of G1/S phase genes, suppress the levels of reactive oxygen species (ROS), and protect cancer cells from senescence. Melanoma cells, unlike melanocytes, are highly reliant on CDK4/6-mediated senescence suppression, which makes them particularly susceptible to CDK4/6 inhibition.

Pubmed ID: 22094256

Authors

  • Anders L
  • Ke N
  • Hydbring P
  • Choi YJ
  • Widlund HR
  • Chick JM
  • Zhai H
  • Vidal M
  • Gygi SP
  • Braun P
  • Sicinski P

Journal

Cancer cell

Publication Data

November 15, 2011

Associated Grants

  • Agency: NCI NIH HHS, Id: R01 CA083688
  • Agency: NCI NIH HHS, Id: R01 CA083688
  • Agency: NCI NIH HHS, Id: R01 CA083688-10
  • Agency: NIDCR NIH HHS, Id: RL1 DE019022
  • Agency: NIDCR NIH HHS, Id: RL1 DE019022
  • Agency: NIDCR NIH HHS, Id: RL1 DE019022-04

Mesh Terms

  • Cell Aging
  • Cell Transformation, Neoplastic
  • Cyclin D1
  • Cyclin D3
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinases
  • Forkhead Transcription Factors
  • G1 Phase
  • HEK293 Cells
  • Humans
  • Melanocytes
  • Melanoma
  • Molecular Sequence Data
  • Phosphorylation
  • Piperazines
  • Proteome
  • Pyridines
  • S Phase
  • Signal Transduction
  • Substrate Specificity