ARTD1 regulates cyclin E expression and consequently cell-cycle re-entry and G1/S progression in T24 bladder carcinoma cells.
ADP-ribosylation is involved in a variety of biological processes, many of which are chromatin-dependent and linked to important functions during the cell cycle. However, any study on ADP-ribosylation and the cell cycle faces the problem that synchronization with chemical agents or by serum starvation and subsequent growth factor addition already activates ADP-ribosylation by itself. Here, we investigated the functional contribution of ARTD1 in cell cycle re-entry and G1/S cell cycle progression using T24 urinary bladder carcinoma cells, which synchronously re-enter the cell cycle after splitting without any additional stimuli. In synchronized cells, ARTD1 knockdown, but not inhibition of its enzymatic activity, caused specific down-regulation of cyclin E during cell cycle re-entry and G1/S progression through alterations of the chromatin composition and histone acetylation, but not of other E2F-1 target genes. Although Cdk2 formed a functional complex with the residual cyclin E, p27(Kip 1) protein levels increased in G1 upon ARTD1 knockdown most likely due to inappropriate cyclin E-Cdk2-induced phosphorylation-dependent degradation, leading to decelerated G1/S progression. These results provide evidence that ARTD1 regulates cell cycle re-entry and G1/S progression via cyclin E expression and p27(Kip 1) stability independently of its enzymatic activity, uncovering a novel cell cycle regulatory mechanism.
a Department of Molecular Mechanisms of Disease , University of Zurich , Zurich , Switzerland.|b Life Science Zurich Graduate School, University of Zurich , Zurich, Switzerland.
Karolin
K
Léger
a Department of Molecular Mechanisms of Disease , University of Zurich , Zurich , Switzerland.|b Life Science Zurich Graduate School, University of Zurich , Zurich, Switzerland.
Ann-Katrin
AK
Hopp
a Department of Molecular Mechanisms of Disease , University of Zurich , Zurich , Switzerland.
Monika
M
Fey
a Department of Molecular Mechanisms of Disease , University of Zurich , Zurich , Switzerland.
Michael O
MO
Hottiger
D045744:Cell Line, Tumor; D019927:Cyclin E / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000378:metabolism; D016193:G1 Phase; D055785:Gene Knockdown Techniques; D006801:Humans; D015513:Oncogene Proteins / Q000378:metabolism*; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D016196:S Phase; D014158:Transcription, Genetic; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology*
C475820:CCNE1 protein, human; D019927:Cyclin E; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D015513:Oncogene Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2
E2F-1; PARP1; cell cycle regulation; cyclin E; gene expression; p27