scholarly journals E2F-dependent genetic oscillators control endoreplication

2019 ◽  
Author(s):  
Minhee Kim ◽  
Nam-Sung Moon
Keyword(s):  
Feedback Loop ◽  
Target Genes ◽  
S Phase ◽  
Entry And Exit ◽  
Pathological Conditions ◽  
Cdk2 Activity ◽  
Mechanistic Insight ◽  
E2f Transcription Factors ◽  
Phase Entry ◽  
Genetic Oscillators

AbstractPolyploidy is an integral part of development and is associated with cellular stress, aging and pathological conditions. The endoreplication cycle, comprised of successive alternations of G and S phases without cell division, is widely employed to produce polyploid cells. The endocycle is driven by continuous oscillations of Cyclin E/Cdk2 activity, which is governed by E2F transcription factors. In this study, we provide mechanistic insight on how E2F-dependent Cdk oscillations during endocycles are maintained in Drosophila salivary glands. Genetic experiments revealed that an alternative splicing isoform of E2F1, E2F1b, regulates the circuitry of timely S phase entry and exit by activating a subset of E2F target genes. E2F1b regulates the Drosophila ortholog of p27CIP/KIP-like Cdk inhibitor Dacapo to precisely time S phase entry by controlling the CycE/Cdk2 activity threshold. Upon entry to S phase, E2F1b-dependent PCNA expression establishes a negative feedback loop through the PIP box-mediated degradation of E2F1. Overall, our study uncovers a network of E2F-dependent genetic oscillators that are critical for the periodic transition between G and S phases during endoreplication.

scholarly journals Blunted DNA synthesis and delayed S-phase entry following inhibition of Cdk2 activity in the regenerating rat liver

2005 ◽  
Vol 85 (4) ◽  
pp. 562-571 ◽  
Author(s):  
Peter Stärkel ◽  
Christine De Saeger ◽  
Christine Sempoux ◽  
Eric Legrand ◽  
Isabelle Leclercq ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Rat Liver ◽  
S Phase ◽  
Cdk2 Activity ◽  
Regenerating Rat Liver ◽  
Phase Entry

scholarly journals Chk1 Phosphorylates Cdh1 to Promote SCFβTRCP-Dependent Degradation of Cdh1 During S-Phase

2019 ◽  
Author(s):  
Debjani Pal ◽  
Adrian E. Torres ◽  
Abbey L. Messina ◽  
Andrew Dickson ◽  
Kuntal De ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Feedback Loop ◽  
Cellular Proliferation ◽  
Genomic Stability ◽  
Cyclin A ◽  
S Phase ◽  
Anaphase Promoting Complex ◽  
Replication Machinery ◽  
Key Factor ◽  
Phase Entry

ABSTRACTThe interplay of the Anaphase-Promoting Complex/Cyclosome (APC/C) and Skp1-Cul1-F-box (SCF) E3 ubiquitin ligases is necessary for controlling cell cycle transitions and checkpoint responses, which are critical for maintaining genomic stability. Yet, the mechanisms underlying the coordinated activity of these enzymes are not completely understood. Recently, Cyclin A- and Plk1- mediated phosphorylation of Cdh1 was demonstrated to trigger its ubiquitination by SCFβTRCP at the G1/S transition. However, Cyclin A-Cdk and Plk1 activities peak in G2 so it is unclear why Cdh1 is targeted at G1/S but not in G2. Here, we show that phosphorylation of Cdh1 by Chk1 contributes to its recognition by SCFβTRCP, promotes efficient S-phase entry, and is important for cellular proliferation. Conversely, Chk1 activity in G2 inhibits Cdh1 accumulation. Overall, these data suggest a model whereby the rise and fall of Chk1 activity is a key factor in the feedback loop between APC/CCdh1 and the replication machinery that enhances the G1/S and S/G2 transitions, respectively.

scholarly journals v-Jun Overrides the Mitogen Dependence of S-Phase Entry by Deregulating Retinoblastoma Protein Phosphorylation and E2F-Pocket Protein Interactions as a Consequence of Enhanced Cyclin E-cdk2 Catalytic Activity

2000 ◽  
Vol 20 (7) ◽  
pp. 2529-2542 ◽  
Author(s):  
W. Clark ◽  
E. J. Black ◽  
A. MacLaren ◽  
U. Kruse ◽  
N. LaThangue ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Protein Interactions ◽  
Cyclin E ◽  
Specific Inhibitor ◽  
Cyclin A ◽  
S Phase ◽  
Pocket Protein ◽  
Cdk2 Activity ◽  
Rb Phosphorylation ◽  
Phase Entry

ABSTRACT v-Jun accelerates G1 progression and shares the capacity of the Myc, E2F, and E1A oncoproteins to sustain S-phase entry in the absence of mitogens; however, how it does so is unknown. To gain insight into the mechanism, we investigated how v-Jun affects mitogen-dependent processes which control the G1/S transition. We show that v-Jun enables cells to express cyclin A and cyclin A-cdk2 kinase activity in the absence of growth factors and that deregulation of cdk2 is required for S-phase entry. Cyclin A expression is repressed in quiescent cells by E2F acting in conjunction with its pocket protein partners Rb, p107, and p130; however, v-Jun overrides this control, causing phosphorylated Rb and proliferation-specific E2F-p107 complexes to persist after mitogen withdrawal. Dephosphorylation of Rb and destruction of cyclin A nevertheless occur normally at mitosis, indicating that v-Jun enables cells to rephosphorylate Rb and reaccumulate cyclin A without exogenous mitogenic stimulation each time the mitotic “clock” is reset. D-cyclin–cdk activity is required for Rb phosphorylation in v-Jun-transformed cells, since ectopic expression of the cdk4- and cdk6-specific inhibitor p16 INK4A inhibits both DNA synthesis and cell proliferation. Despite this, v-Jun does not stimulate D-cyclin–cdk activity but does induce a marked deregulation of cyclin E-cdk2. In particular, hormonal activation of a conditional v-Jun–estrogen receptor fusion protein in quiescent, growth factor-deprived cells stimulates cyclin E-cdk2 activity and triggers Rb phosphorylation and DNA synthesis. Thus, v-Jun overrides the mitogen dependence of S-phase entry by deregulating Rb phosphorylation, E2F-pocket protein interactions, and ultimately cyclin A-cdk2 activity. This is the first report, however, that cyclin E-cdk2, rather than D-cyclin–cdk, is likely to be the critical Rb kinase target of v-Jun.

The biochemical basis of CDK phosphorylation-independent regulation of E2F1 by the retinoblastoma protein

2011 ◽  
Vol 434 (2) ◽  
pp. 297-308 ◽  
Author(s):  
Matthew J. Cecchini ◽  
Frederick A. Dick
Keyword(s):  
Transcriptional Activation ◽  
Target Genes ◽  
Retinoblastoma Protein ◽  
S Phase ◽  
Specific Site ◽  
Biochemical Basis ◽  
Unique Region ◽  
Mechanistic Basis ◽  
E2f Transcription Factors ◽  
Cdk Phosphorylation

The pRB (retinoblastoma protein) has a central role in the control of the G1–S phase transition of the cell cycle that is mediated in part through the regulation of E2F transcription factors. Upon S-phase entry pRB is phosphorylated extensively, which in turn releases bound E2Fs to drive the expression of the genes required for S-phase progression. In the present study, we demonstrate that E2F1-maintains the ability to interact with ppRB (hyperphosphorylated pRB). This interaction is dependent upon the ‘specific’ E2F1-binding site located in the C-terminal domain of pRB. A unique region of the marked box domain of E2F1 contacts the ‘specific’ site to mediate the interaction with ppRB. The mechanistic basis of the interaction between E2F1 and ppRB is subtle. A single substitution between valine and proline residues in the marked box distinguishes E2F1's ability to interact with ppRB from the inability of E2F3 to bind to the ‘specific’ site in ppRB. The E2F1–pRB interaction at the ‘specific’ site also maintains the ability to regulate the transcriptional activation of E2F1 target genes. These data reveal a mechanism by which E2F1 regulation by pRB can persist, when pRB is hyperphosphorylated and presumed to be inactive.

scholarly journals Homeostatic control of START through negative feedback between Cln3-Cdk1 and Rim15/Greatwall kinase in budding yeast

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Nicolas Talarek ◽  
Elisabeth Gueydon ◽  
Etienne Schwob
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Cell Size ◽  
Negative Feedback ◽  
S Phase ◽  
Homeostatic Control ◽  
Cell Cycle Entry ◽  
Greatwall Kinase ◽  
E2f Transcription Factors ◽  
Phase Entry

How cells coordinate growth and division is key for size homeostasis. Phosphorylation by G1-CDK of Whi5/Rb inhibitors of SBF/E2F transcription factors triggers irreversible S-phase entry in yeast and metazoans, but why this occurs at a given cell size is not fully understood. We show that the yeast Rim15-Igo1,2 pathway, orthologous to Gwl-Arpp19/ENSA, is up-regulated in early G1 and helps promoting START by preventing PP2ACdc55 to dephosphorylate Whi5. RIM15 overexpression lowers cell size while IGO1,2 deletion delays START in cells with low CDK activity. Deletion of WHI5, CDC55 and ectopic CLN2 expression suppress the START delay of igo1,2∆ cells. Rim15 activity increases after cells switch from fermentation to respiration, where Igo1,2 contribute to chromosome maintenance. Interestingly Cln3-Cdk1 also inhibits Rim15 activity, which enables homeostatic control of Whi5 phosphorylation and cell cycle entry. We propose that Rim15/Gwl regulation of PP2A plays a hitherto unappreciated role in cell size homeostasis during metabolic rewiring of the cell cycle.

scholarly journals IKKα Regulates Mitogenic Signaling through Transcriptional Induction of Cyclin D1 via Tcf

2003 ◽  
Vol 14 (2) ◽  
pp. 585-599 ◽  
Author(s):  
Chris Albanese ◽  
Kongming Wu ◽  
Mark D'Amico ◽  
Christy Jarrett ◽  
David Joyce ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Cyclin D1 ◽  
Target Genes ◽  
Cell Cycle Control ◽  
S Phase ◽  
Mitogenic Signaling ◽  
Iκb Kinase ◽  
Transcriptional Induction ◽  
Phase Entry

The Wnt/β-catenin/Tcf and IκB/NF-κB cascades are independent pathways involved in cell cycle control, cellular differentiation, and inflammation. Constitutive Wnt/β-catenin signaling occurs in certain cancers from mutation of components of the pathway and from activating growth factor receptors, including RON and MET. The resulting accumulation of cytoplasmic and nuclear β-catenin interacts with the Tcf/LEF transcription factors to induce target genes. The IκB kinase complex (IKK) that phosphorylates IκB contains IKKα, IKKβ, and IKKγ. Here we show that the cyclin D1 gene functions as a point of convergence between the Wnt/β-catenin and IκB pathways in mitogenic signaling. Mitogenic induction of G1-S phase progression and cyclin D1 expression was PI3K dependent, and cyclin D1 −/− cells showed reduced PI3K-dependent S-phase entry. PI3K-dependent induction of cyclin D1 was blocked by inhibitors of PI3K/Akt/IκB/IKKα or β-catenin signaling. A single Tcf site in the cyclin D1 promoter was required for induction by PI3K or IKKα. In IKKα −/− cells, mitogen-induced DNA synthesis, and expression of Tcf-responsive genes was reduced. Reintroduction of IKKα restored normal mitogen induction of cyclin D1 through a Tcf site. In IKKα −/− cells, β-catenin phosphorylation was decreased and purified IKKα was sufficient for phosphorylation of β-catenin through its N-terminus in vitro. Because IKKα but not IKKβ induced cyclin D1 expression through Tcf activity, these studies indicate that the relative levels of IKKα and IKKβ may alter their substrate and signaling specificities to regulate mitogen-induced DNA synthesis through distinct mechanisms.

scholarly journals SnapShot: S-Phase Entry and Exit

Cell ◽  
2019 ◽  
Vol 179 (3) ◽  
pp. 802-802.e1 ◽  
Author(s):  
Andrew Burgess ◽  
Jenny Vuong ◽  
Kamila A. Marzec ◽  
Ulrik Nicolai de Lichtenberg ◽  
Seán I. O’Donoghue ◽  
...  
Keyword(s):  
S Phase ◽  
Entry And Exit ◽  
Phase Entry

scholarly journals CDC25A Phosphatase Is a Target of E2F and Is Required for Efficient E2F-Induced S Phase

1999 ◽  
Vol 19 (9) ◽  
pp. 6379-6395 ◽  
Author(s):  
Elena Vigo ◽  
Heiko Müller ◽  
Elena Prosperini ◽  
Guus Hateboer ◽  
Peter Cartwright ◽  
...  
Keyword(s):  
Cell Lines ◽  
Target Genes ◽  
Human Cancer ◽  
S Phase ◽  
Dna Binding Sites ◽  
Frequent Event ◽  
Efficient Induction ◽  
Functional Inactivation ◽  
E2f Transcription Factors ◽  
Estrogen Receptor Ligand

ABSTRACT Functional inactivation of the pRB pathway is a very frequent event in human cancer, resulting in deregulated activity of the E2F transcription factors. To understand the functional role of the E2Fs in cell proliferation, we have developed cell lines expressing E2F-1, E2F-2, and E2F-3 fused to the estrogen receptor ligand binding domain (ER). In this study, we demonstrated that activation of all three E2Fs could relieve the mitogen requirement for entry into S phase in Rat1 fibroblasts and that E2F activity leads to a shortening of the G0-G1 phase of the cell cycle by 6 to 7 h. In contrast to the current assumption that E2F-1 is the only E2F capable of inducing apoptosis, we showed that deregulated E2F-2 and E2F-3 activities also result in apoptosis. Using the ERE2F-expressing cell lines, we demonstrated that several genes containing E2F DNA binding sites are efficiently induced by the E2Fs in the absence of protein synthesis. Furthermore, CDC25A is defined as a novel E2F target whose expression can be directly regulated by E2F-1. Data showing that CDC25A is an essential target for E2F-1, since its activity is required for efficient induction of S phase by E2F-1, are provided. Finally, our results show that expression of two E2F target genes, namely CDC25A and cyclin E, is sufficient to induce entry into S phase in quiescent fibroblasts. Taken together, our results provide an important step in defining how E2F activity leads to deregulated proliferation.

scholarly journals Plant D–type cyclins and the control of G1 progression

2002 ◽  
Vol 357 (1422) ◽  
pp. 749-760 ◽  
Author(s):  
E. Ann Oakenfull ◽  
Catherine Riou-Khamlichi ◽  
A. H. Murray
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
S Phase ◽  
G1 Phase ◽  
Basic Pattern ◽  
Rb Protein ◽  
E2f Transcription Factors ◽  
Rb Phosphorylation ◽  
Phase Entry ◽  
Plant Homologue

The basic pattern of controls that operate during the G1 phase of the plant cell cycle shows much closer similarity to animals than to the yeasts and other fungi. The activity of D–type cyclin (CycD) kinases is induced in response to stimulatory signals, and these phosphorylate the plant homologue of the retinoblastoma tumour susceptibility (Rb) protein. It is likely that Rb phosphorylation results in the activation of genes under the control of E2F transcription factors, including those required for S phase entry. As the initial triggers of the cascade, attention has focused on the CycDs, and a family of 10 genes is present in Arabidopsis , divided into three major and three minor groups. Analysis to date suggests that these groups are functionally distinct.

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