title: A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells.
abstract: 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.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. lars.anders.hms@gmail.com
authors.forename: Lars
authors.initials: L
authors.lastname: Anders
authors.forename: Nan
authors.initials: N
authors.lastname: Ke
authors.forename: Per
authors.initials: P
authors.lastname: Hydbring
authors.forename: Yoon J
authors.initials: YJ
authors.lastname: Choi
authors.forename: Hans R
authors.initials: HR
authors.lastname: Widlund
authors.forename: Joel M
authors.initials: JM
authors.lastname: Chick
authors.forename: Huili
authors.initials: H
authors.lastname: Zhai
authors.forename: Marc
authors.initials: M
authors.lastname: Vidal
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Gygi
authors.forename: Pascal
authors.initials: P
authors.lastname: Braun
authors.forename: Piotr
authors.initials: P
authors.lastname: Sicinski
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D016922:Cellular Senescence / Q000235:genetics*; D019938:Cyclin D1 / Q000378:metabolism; D056743:Cyclin D3 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism* / Q000502:physiology; D016193:G1 Phase / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D020543:Proteome; D011725:Pyridines / Q000494:pharmacology; D016196:S Phase / Q000502:physiology; D015398:Signal Transduction; D013379:Substrate Specificity
chemical_list: D056743:Cyclin D3; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D010879:Piperazines; D020543:Proteome; D011725:Pyridines; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases; C500026:palbociclib
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