Cyclin-Dependent Kinases Are Regulators and Effectors of Oscillations Driven by a Transcription Factor Network

Abstract

Summary During embryonic cell cycles, B-cyclin-CDKs function as the core component of an autonomous oscillator. Current models for the cell-cycle oscillator in non-embryonic cells are slightly more complex, incorporating multiple G1, S-phase, and mitotic cyclin-CDK complexes. However, periodic events persist in yeast cells lacking all S-phase and mitotic B-cyclin genes, challenging the assertion that cyclin-CDK complexes are essential for oscillations. These and other results led to the proposal that a network of sequentially activated transcription factors functions as an underlying cell-cycle oscillator. Here we examine the individual contributions of a transcription-factor network and cyclin-CDKs to the maintenance of cell-cycle oscillations. Our findings suggest that while cyclin-CDKs are not required for oscillations, they do contribute to oscillation robustness. A model emerges in which cyclin expression (thereby, CDK activity) is entrained to an autonomous transcriptional oscillator. CDKs then modulate oscillator function and serve as effectors of the oscillator.

Silencing of CDK2, but not CDK1, separates mitogenic from anti-apoptotic signaling, sensitizing p53 defective cells for synthetic lethality

“…Together, these data corroborate previous evidence that the CDK system is the regulator and effector of an oscillating transcription factor network. 9,10 Our data extend these findings at the protein/phosphoprotein level.…”

The CDK-APC/C Oscillator Predominantly Entrains Periodic Cell-Cycle Transcription

“…It is important to compare our results with experimental results supporting the GTO model [Orlando et al, 2008, Simmons Kovacs et al, 2012, Bristow et al, 2014]. …”

“…The absence of a second Start gene pulse argues against GTO models requiring no cyclin-Cdk activity at all [Lee et al., 2002, Simmons Kovacs et al, 2012]. However, some GTO models are hybrid models, which incorporate the Start cyclin CLN3 [Simon et al., 2001, Orlando et al, 2008], and CLN3 is not present in clnΔ* and clnΔ*clbΔ* cells.…”

“…2 D right) could drive the global cell cycle transcription program without CDK-APC/C regulation. Evidence for such a CDK-APC/C-independent global transcriptional oscillator (GTO) has been reported in yeast cells; hundreds of genes oscillate in mutant strains with crippled CDK-APC/C oscillations [Orlando et al, 2008, Simmons Kovacs et al, 2012, Bristow et al, 2014]. …”

The cell cycle rallies the transcription cycle

“…3 Such temporal regulation of gene expression has been well characterized during cell cycle progression. 4 In S. cerevisiae, the CDK Cdc28 (also known as Cdk1) is necessary and sufficient for cell cycle regulation by phosphorylating a large number of substrates to coordinate cell cycle events. 5 Specifically, Cdc28 phosphorylates Whi5 in late G1, leading to dissociation of Whi5 from the transcription factor complex SBF (Swi4/6-dependent cell-cycle box binding factor).…”