Open AccessRepression of c-Myc responsive genes in cycling cells causes G1 arrest through reduction of cyclin E/CDK2 kinase activity
Author(s) -
Katrien Berns,
E. Marielle Hijmans,
René Bernards
Publication year - 1997
Publication title -
oncogene
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.395
H-Index - 342
eISSN - 1476-5594
pISSN - 0950-9232
DOI - 10.1038/sj.onc.1201280
Subject(s) - biology , cyclin a2 , cyclin d , cyclin dependent kinase 2 , cyclin e , cyclin a , cyclin b , cyclin d1 , cell cycle , microbiology and biotechnology , cyclin dependent kinase , cyclin d3 , cancer research , cyclin dependent kinase complex , g1 phase , cyclin dependent kinase 3 , cyclin , cell cycle checkpoint , cyclin dependent kinase 4 , kinase , protein kinase a , gene , genetics
The c-myc gene encodes a sequence-specific DNA binding protein involved in proliferation and oncogenesis. Activation of c-myc expression in quiescent cells is sufficient to mediate cell cycle entry, whereas inhibition of c-myc expression causes cycling cells to withdraw from the cell cycle. To search for components of the cell cycle machinery that are targets of c-Myc, we have made a mutant c-Myc protein, named MadMyc, that actively represses c-myc target genes. Expression of MadMyc in cycling NIH3T3 cells causes a significant accumulation of cells in G1. The MadMyc-induced G1 arrest is rescued by ectopic expression of cyclin E/CDK2 and cyclin D1/ CDK4, but not by Cdc25A, a known cell cycle target of c-Myc. The MadMyc G1 arrest does not require the presence of a functional retinoblastoma protein and is associated with a strong reduction in cyclin E/CDK2 kinase activity in arrested cells. MadMyc does not cause alterations in the expression levels of cyclin E, CDK2, p27kip1, cyclin D1 or CDK4 in G1-arrested cells. These data indicate that inhibition of c-Myc activity in exponentially growing cells leads to G1 arrest through loss of cyclin E-associated kinase activity.