title: Mad1 function in cell proliferation and transcriptional repression is antagonized by cyclin E/CDK2.
abstract: The transcription factors of the Myc/Max/Mad network play essential roles in the regulation of cellular behavior. Mad1 inhibits cell proliferation by recruiting an mSin3-corepressor complex that contains histone deacetylase activity. Here we demonstrate that Mad1 is a potent inhibitor of the G(1) to S phase transition, a function that requires Mad1 to heterodimerize with Max and to bind to the corepressor complex. Cyclin E/CDK2, but not cyclin D and cyclin A complexes, fully restored S phase progression. In addition inhibition of colony formation and gene repression by Mad1 were also efficiently antagonized by cyclin E/CDK2. This was the result of cyclin E/CDK2 interfering with the interaction of Mad1 with HDAC1 and reducing HDAC activity. Our findings define a novel interplay between the cell cycle regulator cyclin E/CDK2 and Mad1 and its associated repressor complex and suggests an additional mechanism how cyclin E/CDK2 affects the G(1) to S phase transition.
authors.affiliation: Abteilung Biochemie und Molekularbiologie, Institut für Biochemie, and Institut für Arbeitsmedizin, Klinikum der RWTH, 52057 Aachen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Rottmann
authors.forename: Annette R
authors.initials: AR
authors.lastname: Menkel
authors.forename: Caroline
authors.initials: C
authors.lastname: Bouchard
authors.forename: Jürgen
authors.initials: J
authors.lastname: Mertsching
authors.forename: Peter
authors.initials: P
authors.lastname: Loidl
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Martin
authors.initials: M
authors.lastname: Eilers
authors.forename: Juliane
authors.initials: J
authors.lastname: Lüscher-Firzlaff
authors.forename: Richard
authors.initials: R
authors.lastname: Lilischkis
authors.forename: Bernhard
authors.initials: B
authors.lastname: Lüscher
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D019927:Cyclin E / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000378:metabolism*; D016196:S Phase / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; D019927:Cyclin E; C501385:Mad1l1 protein, mouse; D009687:Nuclear Proteins; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2