Mad1 function in cell proliferation and transcriptional repression is antagonized by cyclin E/CDK2.
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.
Rottmann
Sabine
S
Abteilung Biochemie und Molekularbiologie, Institut für Biochemie, and Institut für Arbeitsmedizin, Klinikum der RWTH, 52057 Aachen, Germany.
Menkel
Annette R
AR
Bouchard
Caroline
C
Mertsching
Jürgen
J
Loidl
Peter
P
Kremmer
Elisabeth
E
Eilers
Martin
M
Lüscher-Firzlaff
Juliane
J
Lilischkis
Richard
R
Lüscher
Bernhard
B
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
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