Commitment to a Cellular Transition Precedes Genome-wide Transcriptional Change

Eser, Umut; Falleur-Fettig, Melody; Johnson, Amy L.; Skotheim, Jan M.

doi:10.1016/j.molcel.2011.06.024

Cited by 82 publications

(111 citation statements)

References 66 publications

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“…This structure clearly has many favourable dynamical features that we have documented in recent work in the yeast system: cell size control [16], positive feedback-driven coherent cell cycle entry [18,19] and irreversibility [20,44]. Many of these features have been attributed to the animal system as well [40,42].…”

Section: Were Rb E2f Kip1 Cyclins D and E Present In The Eukaryotimentioning

confidence: 65%

“…Prior to Start, a cell integrates various internal and external signals, such as those arising from cell size, nutrients and mating pheromone, to produce an all-or-none decision to enter the mitotic cell cycle. G1 regulation proceeds in two steps separated by a rapid positive feedback-driven transition: the first step, dependent on the upstream cyclin Cln3, yields cell size control and initial inactivation of Whi5, while the second, cell size-independent step pertains to the activation of the cell division machinery by the rapidly increasing CDK activity arising from a transcriptional positive feedback loop in which Cln1,2 complete Whi5 inactivation and yield full and coherent expression of the entire regulon activated by the SBF (Swi4-Swi6) and MBF (Mbp1-Swi6) transcription factors [16][17][18][19]. The transition point (i.e.…”

Section: The G1 -S Regulatory Network In Budding Yeast and Animals Hamentioning

confidence: 99%

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Evolution of networks and sequences in eukaryotic cell cycle control

Cross

Buchler

Skotheim

2011

Phil. Trans. R. Soc. B

128

114

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The molecular networks regulating the G1 -S transition in budding yeast and mammals are strikingly similar in network structure. However, many of the individual proteins performing similar network roles appear to have unrelated amino acid sequences, suggesting either extremely rapid sequence evolution, or true polyphyly of proteins carrying out identical network roles. A yeast/ mammal comparison suggests that network topology, and its associated dynamic properties, rather than regulatory proteins themselves may be the most important elements conserved through evolution. However, recent deep phylogenetic studies show that fungal and animal lineages are relatively closely related in the opisthokont branch of eukaryotes. The presence in plants of cell cycle regulators such as Rb, E2F and cyclins A and D, that appear lost in yeast, suggests cell cycle control in the last common ancestor of the eukaryotes was implemented with this set of regulatory proteins. Forward genetics in non-opisthokonts, such as plants or their green algal relatives, will provide direct information on cell cycle control in these organisms, and may elucidate the potentially more complex cell cycle control network of the last common eukaryotic ancestor.

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Section: Were Rb E2f Kip1 Cyclins D and E Present In The Eukaryotimentioning

confidence: 65%

Section: The G1 -S Regulatory Network In Budding Yeast and Animals Hamentioning

confidence: 99%

Evolution of networks and sequences in eukaryotic cell cycle control

Cross

Buchler

Skotheim

2011

Phil. Trans. R. Soc. B

128

114

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“…32 Cdk2 is unlikely to play a direct role in turning on the E2F program; a recent reexamination of microarray data from HeLa cell synchronization-andrelease experiments suggested that initial transcription of the genes responsible for positive feedback in the E2F transcription network, including cyclin E1 and cyclin E2, occurs concomitant with expression of E2F1 itself. 35 Instead, the role of Cdk2 might be analogous to that of a Cdk1/ Cln1,2-dependent positive-feedback loop that regulates the G 1 /S transcription program in budding yeast. 36 In Saccharomyces cerevisiae, two related transcription factors, SBF and MBF, function analogously to metazoan E2Fs and are negatively regulated by Whi5, the analog of RB.…”

Section: A Dose Of Reality: Targeting the Physiologic Cdk Network Witmentioning

confidence: 99%

Why minimal is not optimal: Driving the mammalian cell cycle—and drug discovery—with a physiologic CDK control network

Merrick

Fisher

2012

Cell Cycle

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P rogression through the eukaryotic cell division cycle is governed by the activity of cyclin-dependent kinases (CDKs).For a CDK to become active it must (1) bind a positive regulatory subunit (cyclin) and (2) be phosphorylated on its activation (T) loop. In metazoans, multiple CDK catalytic subunits, each with a distinct set of preferred cyclin partners, regulate the cell cycle, but it has been difficult to assign functions to individual CDKs in vivo. Biochemical analyses and experiments with dominant-negative alleles suggested that specific CDK/cyclin complexes regulate different events, but genetic loss of interphase CDKs (Cdk2, -4 and -6), alone or in combination, did not block proliferation of cells in culture. These knockout and knockdown studies suggested redundancy or plasticity built into the CDK network but did not address whether there was true redundancy in normal cells with a full complement of CDKs. Here, we discuss recent work that took a chemicalgenetic approach to reveal that the activity of a genetically non-essential CDK, Cdk2, is required for cell proliferation when normal cyclin pairing is maintained. These results have implications for the systemslevel organization of the cell cycle, for regulation of the restriction point and G 1 /S transition and for efforts to target Cdk2 therapeutically in human cancers.

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“…Following CLN3 activation, the G1 transcription complexes Swi4p-Swi6p (SBF) and Mbp1-Swi6p (MBF) can be activated by CLN3/CDC28-catalyzed phosphorylation of the SBF inhibitor Whi5p (10)(11)(12), and other unknown mechanisms, to enable transcription of over 200 downstream cell-cycle genes (13), including CLN1/2 and CLB5/6. Cln1p and Cln2p can then further enhance SBF-and MBF-dependent G1 transcription through positive feedback mechanisms (14)(15)(16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

Acetyl-CoA induces transcription of the key G1 cyclin CLN3 to promote entry into the cell division cycle in Saccharomyces cerevisiae

Shi

2013

Proc. Natl. Acad. Sci. U.S.A.

124

125

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In budding yeast cells, nutrient repletion induces rapid exit from quiescence and entry into a round of growth and division. The G1 cyclin CLN3 is one of the earliest genes activated in response to nutrient repletion. Subsequent to its activation, hundreds of cellcycle genes can then be expressed, including the cyclins CLN1/2 and CLB5/6. Although much is known regarding how CLN3 functions to activate downstream targets, the mechanism through which nutrients activate CLN3 transcription in the first place remains poorly understood. Here we show that a central metabolite of glucose catabolism, acetyl-CoA, induces CLN3 transcription by promoting the acetylation of histones present in its regulatory region. Increased rates of acetyl-CoA synthesis enable the Gcn5p-containing Spt-AdaGcn5-acetyltransferase transcriptional coactivator complex to catalyze histone acetylation at the CLN3 locus alongside ribosomal and other growth genes to promote entry into the cell division cycle.growth control | metabolism | epigenetics T he most basic building blocks of biological organisms are smallmolecule metabolites. In recent years, there has been renewed interest in understanding how the fundamental processes of cell growth and proliferation are coordinated with cellular metabolism. Nutrient-starved yeast cells arrest in a quiescent, or G0, phase of the cell division cycle. Addition of nutrients stimulates exit from the G0 and transition into the G1 phase, and then ∼800 genes are periodically transcribed as a function of the cell cycle (1, 2). CLN3 is observed to be one of the earliest genes transcribed within this set (1-3). Cln3p regulates G1 length by coordinating growth and division and may influence cell size when passing Start, the point at which cells commit to division (4-7). In cln3Δ mutants, cells become larger and stay in the G1 phase longer, resulting in decreased growth and budding rates compared with WT (8, 9) (Fig. S1). Following CLN3 activation, the G1 transcription complexes Swi4p-Swi6p (SBF) and Mbp1-Swi6p (MBF) can be activated by CLN3/CDC28-catalyzed phosphorylation of the SBF inhibitor Whi5p (10-12), and other unknown mechanisms, to enable transcription of over 200 downstream cell-cycle genes (13), including CLN1/2 and CLB5/6. Cln1p and Cln2p can then further enhance SBF-and MBF-dependent G1 transcription through positive feedback mechanisms (14)(15)(16)(17)(18)(19)(20).Although many studies have focused on the mechanisms by which Cln3p regulates G1 transcription, the mechanisms that lead to transcriptional activation of CLN3 itself still remain unresolved. Since the discovery of CLN3 more than 20 y ago (6, 7), the gene and its encoded protein have been reported to be regulated at multiple levels. At the transcriptional level, CLN3 is activated by glucose (21, 22), which is reportedly mediated by Azf1p, a zinc-finger transcription factor (23). Following transcription, CLN3 mRNA availability is regulated by a RNAbinding protein, Whi3p (24). At the translational level, CLN3 is regulated by TOR (target of rapamyc...

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Commitment to a Cellular Transition Precedes Genome-wide Transcriptional Change

Cited by 82 publications

References 66 publications

Evolution of networks and sequences in eukaryotic cell cycle control

Evolution of networks and sequences in eukaryotic cell cycle control

Why minimal is not optimal: Driving the mammalian cell cycle—and drug discovery—with a physiologic CDK control network

Acetyl-CoA induces transcription of the key G1 cyclin CLN3 to promote entry into the cell division cycle in Saccharomyces cerevisiae

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