Division of labour between Myc and G1 cyclins in cell cycle commitment and pace control

Peng Dong; Manoj V Maddali; Jaydeep K Srimani; François Thélot; Joseph R Nevins; Bernard Mathey-Prevot; Lingchong You

doi:10.1038/ncomms5750

Division of labour between Myc and G1 cyclins in cell cycle commitment and pace control

Nat Commun. 2014 Sep 1:5:4750. doi: 10.1038/ncomms5750.

Authors

Peng Dong¹, Manoj V Maddali², Jaydeep K Srimani³, François Thélot⁴, Joseph R Nevins⁵, Bernard Mathey-Prevot⁶, Lingchong You⁷

Affiliations

¹ Computational Biology and Bioinformatics Program, Duke University, Durham, North Carolina 27708, USA.
² 1] Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA [2].
³ Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA.
⁴ Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27708, USA.
⁵ Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina 27708, USA.
⁶ 1] Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27708, USA [2] Department of Pediatrics, Duke University, Durham, North Carolina 27708, USA.
⁷ 1] Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA [2] Center for Genomic and Computational Biology, Duke University, Durham, North Carolina 27708, USA [3] Duke Center for Systems Biology, Duke University, Durham, North Carolina 27708, USA.

Abstract

A body of evidence has shown that the control of E2F transcription factor activity is critical for determining cell cycle entry and cell proliferation. However, an understanding of the precise determinants of this control, including the role of other cell-cycle regulatory activities, has not been clearly defined. Here, recognizing that the contributions of individual regulatory components could be masked by heterogeneity in populations of cells, we model the potential roles of individual components together with the use of an integrated system to follow E2F dynamics at the single-cell level and in real time. These analyses reveal that crossing a threshold amplitude of E2F accumulation determines cell cycle commitment. Importantly, we find that Myc is critical in modulating the amplitude, whereas cyclin D/E activities have little effect on amplitude but do contribute to the modulation of duration of E2F activation, thereby affecting the pace of cell cycle progression.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Bacterial Proteins / genetics
Bacterial Proteins / metabolism
Cell Cycle / drug effects
Cell Cycle / genetics*
Cell Line
Cyclin D / genetics*
Cyclin D / metabolism
Cyclin E / genetics*
Cyclin E / metabolism
E2F1 Transcription Factor / genetics*
E2F1 Transcription Factor / metabolism
Fibroblasts / cytology
Fibroblasts / drug effects
Fibroblasts / metabolism
Gene Expression Regulation
Genes, Reporter
Humans
Luminescent Proteins / genetics
Luminescent Proteins / metabolism
Mice
NIH 3T3 Cells
Piperazines / pharmacology
Promoter Regions, Genetic
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-myc / genetics*
Proto-Oncogene Proteins c-myc / metabolism
Purines / pharmacology
Pyridines / pharmacology
Rats
Signal Transduction
Single-Cell Analysis
Time-Lapse Imaging

Substances

Bacterial Proteins
Cyclin D
Cyclin E
E2F1 Transcription Factor
E2F1 protein, human
Luminescent Proteins
Piperazines
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-myc
Purines
Pyridines
yellow fluorescent protein, Bacteria
palbociclib
CVT 313

Abstract

Publication types

MeSH terms

Substances

Grants and funding