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

Dong, Peng; Maddali, Manoj V; Srimani, Jaydeep K.; Thélot, François A.; Nevins, Joseph R.; Mathey-Prévôt, Bernard; Li, You

doi:10.1038/ncomms5750

Cited by 67 publications

(117 citation statements)

References 69 publications

Supporting

Mentioning

102

Contrasting

Order By: Relevance

“…MYC, however, does not only indirectly regulate the cell cycle through metabolism, it also directly triggers cell cycle progression, particularly during the G1 restriction point, by activating genes such as cyclin D and cyclin-dependent kinase 4 (CDK4) (183–186). In addition, MYC activates the expression of E2F transcription factors, creating a feed-forward loop that promotes progression into S phase (187). MYC and E2F together activate key DNA replication genes, such as the family of minichromosome maintenance complex (MCM) genes, to initiate and sustain DNA replication (140, 188).…”

Section: Myc Metabolism and Cell Cycle Progressionmentioning

confidence: 99%

MYC, Metabolism, and Cancer

et al. 2015

View full text Add to dashboard Cite

Summary The MYC oncogene encodes a transcription factor, MYC, whose broad effects make its precise oncogenic role enigmatically elusive. The evidence to date suggests that MYC triggers selective gene expression amplification to promote cell growth and proliferation. Through its targets, MYC coordinates nutrient acquisition to produce ATP and key cellular building blocks that increase cell mass and trigger DNA replication and cell division. In cancer, genetic and epigenetic derangements silence checkpoints and unleash MYC’s cell growth- and proliferation-promoting metabolic activities. Unbridled growth in response to deregulated MYC expression creates dependence on MYC-driven metabolic pathways, such that reliance on specific metabolic enzymes provides novel targets for cancer therapy.

show abstract

Section: Myc Metabolism and Cell Cycle Progressionmentioning

confidence: 99%

MYC, Metabolism, and Cancer

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Expression levels of endogenous E2F1 can exhibit significant cell-cell variability, which is even higher for exogenous transgenes delivered, for example, via adenoviral transduction. 20,21 Depending on the average E2F1 level and the extent of cell-cell variability, one can draw different conclusions from experiments on the same system as E2F1 may trigger opposing effects.…”

mentioning

confidence: 99%

Expression level is a key determinant of E2F1-mediated cell fate

et al. 2017

Self Cite

View full text Add to dashboard Cite

The Rb/E2F network has a critical role in regulating cell cycle progression and cell fate decisions. It is dysfunctional in virtually all human cancers, because of genetic lesions that cause overexpression of activators, inactivation of repressors, or both. Paradoxically, the downstream target of this network, E2F1, is rarely strongly overexpressed in cancer. E2F1 can induce both proliferation and apoptosis but the factors governing these critical cell fate decisions remain unclear. Previous studies have focused on qualitative mechanisms such as differential cofactors, posttranslational modification or state of other signaling pathways as modifiers of the cell fate decisions downstream of E2F1 activation. In contrast, the importance of the expression levels of E2F1 itself in dictating the downstream phenotypes has not been rigorously studied, partly due to the limited resolution of traditional population-level measurements. Here, through single-cell quantitative analysis, we demonstrate that E2F1 expression levels have a critical role in determining the fate of individual cells. Low levels of exogenous E2F1 promote proliferation, moderate levels induce G1, G2 and mitotic cell cycle arrest, and very high levels promote apoptosis. These multiple anti-proliferative mechanisms result in a strong selection pressure leading to rapid elimination of E2F1-overexpressing cells from the population. RNA-sequencing and RT-PCR revealed that low levels of E2F1 are sufficient to induce numerous cell cycle-promoting genes, intermediate levels induce growth arrest genes (i.e., p18, p19 and p27), whereas higher levels are necessary to induce key apoptotic E2F1 targets APAF1, PUMA, HRK and BIM. Finally, treatment of a lung cancer cell line with a proteasome inhibitor, MLN2238, resulted in an E2F1-dependent mitotic arrest and apoptosis, confirming the role of endogenous E2F1 levels in these phenotypes. The strong anti-proliferative activity of moderately overexpressed E2F1 in multiple cancer types suggests that targeting E2F1 for upregulation may represent an attractive therapeutic strategy in cancer.

show abstract

“…A normal fate specification without correct division timing may lead to catastrophes, for example, cancerous development (1). Therefore, metazoan development demonstrates stereotyped division timing (2,3).…”

mentioning

confidence: 99%

Timing of Tissue-specific Cell Division Requires a Differential Onset of Zygotic Transcription during Metazoan Embryogenesis

Wong

Guan

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Metazoan development demands not only precise cell fate differentiation but also accurate timing of cell division to ensure proper development. How cell divisions are temporally coordinated during development is poorly understood. Caenorhabditis elegans embryogenesis provides an excellent opportunity to study this coordination due to its invariant development and widespread division asynchronies. One of the most pronounced asynchronies is a significant delay of cell division in two endoderm progenitor cells, Ea and Ep, hereafter referred to as E2, relative to its cousins that mainly develop into mesoderm organs and tissues. To unravel the genetic control over the endodermspecific E2 division timing, a total of 822 essential and conserved genes were knocked down using RNAi followed by quantification of cell cycle lengths using in toto imaging of C. elegans embryogenesis and automated lineage. Intriguingly, knockdown of numerous genes encoding the components of general transcription pathway or its regulatory factors leads to a significant reduction in the E2 cell cycle length but an increase in cell cycle length of the remaining cells, indicating a differential requirement of transcription for division timing between the two. Analysis of lineage-specific RNA-seq data demonstrates an earlier onset of transcription in endoderm than in other germ layers, the timing of which coincides with the birth of E2, supporting the notion that the endoderm-specific delay in E2 division timing demands robust zygotic transcription. The reduction in E2 cell cycle length is frequently associated with cell migration defect and gastrulation failure. The results suggest that a tissue-specific transcriptional activation is required to coordinate fate differentiation, division timing, and cell migration to ensure proper development.Proper development of metazoans depends not only on precise differentiation of cell fate but also on tight control over division timing or division pace between cells, which we refer to as temporal coordination. A normal fate specification without correct division timing may lead to catastrophes, for example, cancerous development (1). Therefore, metazoan development demonstrates stereotyped division timing (2, 3). Despite intensive studies on the regulation of cell fate differentiation, genetic control over temporal coordination of cell division during metazoan development is poorly understood. Timing of cell division is particularly critical during early developmental stages such as embryogenesis when cells undergo rapid division and migration, which is concomitant with cell fate differentiation.Because of technical challenges in quantifying cell division timing especially when an embryo undergoes rapid cell division, most of the studies on cell division timing focus on the earliest stage of development (4). For example, the first embryonic division in Caenorhabditis elegans produces two daughters, namely AB and P1, with differential developmental potential. The two cells also divide asynchronously with the ...

show abstract

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

Cited by 67 publications

References 69 publications

MYC, Metabolism, and Cancer

MYC, Metabolism, and Cancer

Expression level is a key determinant of E2F1-mediated cell fate

Timing of Tissue-specific Cell Division Requires a Differential Onset of Zygotic Transcription during Metazoan Embryogenesis

Contact Info

Product

Resources

About