Direct induction of cyclin D2 by Myc contributes to cell cycle progression and sequestration of p27.
Ectopic expression of Myc induces Cdk2 kinase activity in quiescent cells and antagonizes association of p27(kip1) with Cdk2. The target gene(s) by which Myc mediates this effect is largely unknown. We now show that p27 is rapidly and transiently sequestered by cyclin D2-Cdk4 complexes upon activation of Myc and that cyclin D2 is a direct target gene of Myc. The cyclin D2 promoter is repressed by Mad-Max complexes and de-repressed by Myc via a single highly conserved E-box element. Addition of trichostatin A to quiescent cells mimics activation of Myc and induces cyclin D2 expression, suggesting that cyclin D2 is repressed in a histone deacetylase-dependent manner in quiescent cells. Inhibition of cyclin D2 function in established cell lines, either by ectopic expression of p16 or by antibody injection, inhibits Myc-dependent dissociation of p27 from Cdk2 and Myc-induced cell cycle entry. Primary mouse fibroblasts that are cyclin D2-deficient undergo accelerated senescence in culture and are not immortalized by Myc; induction of apoptosis by Myc is unimpaired in such cells. Our data identify a downstream effector pathway that links Myc directly to cell cycle progression.
Bouchard
C
C
Institute of Molecular Biology and Tumour Research, Phillips-Universität Marburg, Emil-Mannkopff-Strasse 2, 35033 Marburg.
Thieke
K
K
Maier
A
A
Saffrich
R
R
Hanley-Hyde
J
J
Ansorge
W
W
Reed
S
S
Sicinski
P
P
Bartek
J
J
Eilers
M
M
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins; D002460:Cell Line; D056742:Cyclin D2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000235:genetics*; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D051381:Rats; D012689:Sequence Homology, Nucleic Acid; D025521:Tumor Suppressor Proteins
C080336:CCND2 protein, human; C486196:Ccnd2 protein, mouse; C486197:Ccnd2 protein, rat; C493961:Cdkn1b protein, mouse; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D056742:Cyclin D2; D016213:Cyclins; D017931:DNA Primers; D008869:Microtubule-Associated Proteins; D016271:Proto-Oncogene Proteins c-myc; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27