lin-35 Rb and cki-1 Cip/Kip cooperate in developmental regulation of G1 progression in C. elegans

Development ◽  
2001 ◽  
Vol 128 (21) ◽  
pp. 4349-4359 ◽  
Author(s):  
Mike Boxem ◽  
Sander van den Heuvel
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Kinase Inhibitors ◽  
Developmental Regulation ◽  
Negative Regulator ◽  
Cyclin D ◽  
C Elegans ◽  
Downstream Target ◽  
Important Negative Regulator ◽  
Regulation Of Cell Cycle

We have investigated the regulation of cell-cycle entry in C. elegans, taking advantage of its largely invariant and completely described pattern of somatic cell divisions. In a genetic screen, we identified mutations in cyd-1 cyclin D and cdk-4 Cdk4/6. Recent results indicated that during Drosophila development, cyclin D-dependent kinases regulate cell growth rather than cell division. However, our data indicate that C. elegans cyd-1 primarily controls G1 progression. To investigate whether cyd-1 and cdk-4 solely act to overcome G1 inhibition by retinoblastoma family members, we constructed double mutants that completely eliminate the function of the retinoblastoma family and cyclin D-Cdk4/6 kinases. Inactivation of lin-35 Rb, the single Rb-related gene in C. elegans, substantially reduced the DNA replication and cell-division defects in cyd-1 and cdk-4 mutant animals. These results demonstrate that lin-35 Rb is an important negative regulator of G1/S progression and probably a downstream target for cyd-1 and cdk-4. However, as the suppression by lin-35 Rb is not complete, cyd-1 and cdk-4 probably have additional targets. An additional level of control over G1 progression is provided by Cip/Kip kinase inhibitors. We demonstrate that lin-35 Rb and cki-1 Cip/Kip contribute non-overlapping levels of G1/S inhibition in C. elegans. Surprisingly, loss of cki-1, but not lin-35, results in precocious entry into S phase. We suggest that a rate limiting role for cki-1 Cip/Kip rather than lin-35 Rb explains the lack of cell-cycle phenotype of lin-35 mutant animals.

scholarly journals Casein Kinase II is Required for Proper Cell Division and Acts as a Negative Regulator of Centrosome Duplication in C. elegans Embryos

2016 ◽  
Author(s):  
Jeffrey C. Medley ◽  
Megan M. Kabara ◽  
Michael D. Stubenvoll ◽  
Lauren E. DeMeyer ◽  
Mi Hye Song
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cell Cycle Progression ◽  
Casein Kinase Ii ◽  
Casein Kinase ◽  
Negative Regulator ◽  
Centrosome Duplication ◽  
Dependent Manner ◽  
C Elegans ◽  
Mother Centriole

Summary statementThe conserved protein kinase CK2 negatively regulates centrosome assembly and is required for proper cell cycle progression and cytokinesis in early C. elegans embryos.AbstractCentrosomes are the primary microtubule-organizing centers that orchestrate microtubule dynamics during the cell cycle. The correct number of centrosomes is pivotal for establishing bipolar mitotic spindles that ensure accurate segregation of chromosomes. Thus, centrioles must duplicate once per cell cycle, one daughter per mother centriole, the process of which requires highly coordinated actions among core factors and modulators. Protein phosphorylation is shown to regulate the stability, localization and activity of centrosome proteins. Here, we report the function of Casein Kinase II (CK2) in early C. elegans embryos. The catalytic subunit (KIN-3/CK2α) of CK2 localizes to nuclei, centrosomes and midbodies. Inactivating CK2 leads to cell division defects, including chromosome missegregation, cytokinesis failure and aberrant centrosome behavior. Furthermore, depletion or inhibiting kinase activity of CK2 results in elevated ZYG-1 levels at centrosomes, restoring centrosome duplication and embryonic viability to zyg-1 mutants. Our data suggest that CK2 functions in cell division and negatively regulates centrosome duplication in a kinase-dependent manner.

Developmental regulation of a cyclin-dependent kinase inhibitor controls postembryonic cell cycle progression in Caenorhabditis elegans

Development ◽  
1998 ◽  
Vol 125 (18) ◽  
pp. 3585-3597 ◽  
Author(s):  
Y. Hong ◽  
R. Roy ◽  
V. Ambros
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Developmental Regulation ◽  
Ectopic Expression ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Environmental Signals ◽  
C Elegans

C. elegans cki-1 encodes a member of the CIP/KIP family of cyclin-dependent kinase inhibitors, and functions to link postembryonic developmental programs to cell cycle progression. The expression pattern of cki-1::GFP suggests that cki-1 is developmentally regulated in blast cells coincident with G1, and in differentiating cells. Ectopic expression of CKI-1 can prematurely arrest cells in G1, while reducing cki-1 activity by RNA-mediated interference (RNAi) causes extra larval cell divisions, suggesting a role for cki-1 in the developmental control of G1/S. cki-1 activity is required for the suspension of cell cycling that occurs in dauer larvae and starved L1 larvae in response to environmental signals. In vulva precursor cells (VPCs), a pathway of heterochronic genes acts via cki-1 to maintain VPCs in G1 during the L2 stage.

scholarly journals The Role of Phosphatases in Nuclear Envelope Disassembly and Reassembly and Their Relevance to Pathologies

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 687 ◽  
Author(s):  
Florentin Huguet ◽  
Shane Flynn ◽  
Paola Vagnarelli
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Nuclear Envelope ◽  
Current Understanding ◽  
The Past ◽  
Pathological Conditions ◽  
Regulation Of Cell Cycle

The role of kinases in the regulation of cell cycle transitions is very well established, however, over the past decade, studies have identified the ever-growing importance of phosphatases in these processes. It is well-known that an intact or otherwise non-deformed nuclear envelope (NE) is essential for maintaining healthy cells and any deviation from this can result in pathological conditions. This review aims at assessing the current understanding of how phosphatases contribute to the remodelling of the nuclear envelope during its disassembling and reformation after cell division and how errors in this process may lead to the development of diseases.

scholarly journals Regulation of cell cycle drivers by Cullin-RING ubiquitin ligases

2020 ◽  
Vol 52 (10) ◽  
pp. 1637-1651 ◽  
Author(s):  
Sang-Min Jang ◽  
Christophe E. Redon ◽  
Bhushan L. Thakur ◽  
Meriam K. Bahta ◽  
Mirit I. Aladjem
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cell Cycle Progression ◽  
Ubiquitin Ligases ◽  
Anaphase Promoting Complex ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Cellular Pathways ◽  
Regulation Of Cell Cycle ◽  
F Box Protein

Abstract The last decade has revealed new roles for Cullin-RING ubiquitin ligases (CRLs) in a myriad of cellular processes, including cell cycle progression. In addition to CRL1, also named SCF (SKP1-Cullin 1-F box protein), which has been known for decades as an important factor in the regulation of the cell cycle, it is now evident that all eight CRL family members are involved in the intricate cellular pathways driving cell cycle progression. In this review, we summarize the structure of CRLs and their functions in driving the cell cycle. We focus on how CRLs target key proteins for degradation or otherwise alter their functions to control the progression over the various cell cycle phases leading to cell division. We also summarize how CRLs and the anaphase-promoting complex/cyclosome (APC/C) ligase complex closely cooperate to govern efficient cell cycle progression.

scholarly journals Suspended Animation Extends Survival Limits of Caenorhabditis elegans and Saccharomyces cerevisiae at Low Temperature

2010 ◽  
Vol 21 (13) ◽  
pp. 2161-2171 ◽  
Author(s):  
Kin Chan ◽  
Jesse P. Goldmark ◽  
Mark B. Roth
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Cell Division ◽  
Caenorhabditis Elegans ◽  
Cell Division Cycle ◽  
Wild Type ◽  
Suspended Animation ◽  
C Elegans ◽  
High Viability ◽  
Cold Sensitive

The orderly progression through the cell division cycle is of paramount importance to all organisms, as improper progression through the cycle could result in defects with grave consequences. Previously, our lab has shown that model eukaryotes such as Saccharomyces cerevisiae, Caenorhabditis elegans, and Danio rerio all retain high viability after prolonged arrest in a state of anoxia-induced suspended animation, implying that in such a state, progression through the cell division cycle is reversibly arrested in an orderly manner. Here, we show that S. cerevisiae (both wild-type and several cold-sensitive strains) and C. elegans embryos exhibit a dramatic decrease in viability that is associated with dysregulation of the cell cycle when exposed to low temperatures. Further, we find that when the yeast or worms are first transitioned into a state of anoxia-induced suspended animation before cold exposure, the associated cold-induced viability defects are largely abrogated. We present evidence that by imposing an anoxia-induced reversible arrest of the cell cycle, the cells are prevented from engaging in aberrant cell cycle events in the cold, thus allowing the organisms to avoid the lethality that would have occurred in a cold, oxygenated environment.

scholarly journals Cyclin D-Cdk4,6 drives cell cycle progression via the retinoblastoma protein’s C-terminal helix

2018 ◽  
Author(s):  
Benjamin R. Topacio ◽  
Evgeny Zatulovskiy ◽  
Sandra Cristea ◽  
Shicong Xie ◽  
Carrie S. Tambo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cell Cycle Progression ◽  
Alpha Helix ◽  
G1 Arrest ◽  
Cyclin D ◽  
Cycle Progression ◽  
C Terminus ◽  
Docking Mechanism ◽  
Tumor Suppressive Function

SummaryThe cyclin-dependent kinases Cdk4 and Cdk6 form complexes with D-type cyclins to drive cell proliferation. A well-known target of cyclin D-Cdk4,6 is the retinoblastoma protein, Rb, which inhibits cell cycle progression until its inactivation by phosphorylation. However, the role of cyclin D-Cdk4,6 phosphorylation of Rb in cell cycle progression is unclear because Rb can be phosphorylated by other cyclin-Cdk complexes and cyclin D-Cdk4,6 complexes have other targets that may drive cell division. Here, we show that cyclin D-Cdk4,6 docks one side of an alpha-helix in the C-terminus of Rb, which is not recognized by cyclins E, A, and B. This helix-based docking mechanism is shared by the p107 and p130 Rb-family members across metazoans. Mutation of the Rb C-terminal helix prevents phosphorylation, promotes G1 arrest, and enhances Rb’s tumor suppressive function. Our work conclusively demonstrates that the cyclin D-Rb interaction drives cell division and defines a new class of cyclin-based docking mechanisms.

scholarly journals Notch Signaling and Developmental Cell-Cycle Arrest in Drosophila Polar Follicle Cells

2009 ◽  
Vol 20 (24) ◽  
pp. 5064-5073 ◽  
Author(s):  
Li-Fang Shyu ◽  
Jianjun Sun ◽  
Hui-Min Chung ◽  
Yi-Chun Huang ◽  
Wu-Min Deng
Keyword(s):  
Cell Cycle ◽  
Notch Signaling ◽  
Cell Cycle Arrest ◽  
Developmental Regulation ◽  
Cell Types ◽  
Follicle Cells ◽  
Cycle Arrest ◽  
G2 Phase ◽  
G2 Cell Cycle Arrest ◽  
Regulation Of Cell Cycle

Temporal and spatial regulation of cell division is critical for proper development of multicellular organisms. An important aspect of this regulation is cell-cycle arrest, which in many cell types is coupled with differentiated status. Here we report that the polar cells—a group of follicle cells differentiated early during Drosophila oogenesis—are arrested at G2 phase and can serve as a model cell type for investigation of developmental regulation of cell-cycle arrest. On examining the effects of String, a mitosis-promoting phosphatase Cdc25 homolog, and Notch signaling in polar cells, we found that misexpression of String can trigger mitosis in existing polar cells to induce extra polar cells. Normally, differentiation of the polar cells requires Notch signaling. We found that the Notch-induced extra polar cells arise through recruitment of the neighboring cells rather than promotion of proliferation, and they are also arrested at G2 phase. Notch signaling is probably involved in down-regulating String in polar cells, thus inducing the G2 cell-cycle arrest.

scholarly journals Probing and manipulating embryogenesis via nanoscale thermometry and temperature control

2020 ◽  
Vol 117 (26) ◽  
pp. 14636-14641 ◽  
Author(s):  
Joonhee Choi ◽  
Hengyun Zhou ◽  
Renate Landig ◽  
Hai-Yin Wu ◽  
Xiaofei Yu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cell Communication ◽  
Cycle Duration ◽  
Cell Stage ◽  
C Elegans ◽  
Local Perturbations ◽  
Cell Division Timing ◽  
Nanoscale Thermometry

Understanding the coordination of cell-division timing is one of the outstanding questions in the field of developmental biology. One active control parameter of the cell-cycle duration is temperature, as it can accelerate or decelerate the rate of biochemical reactions. However, controlled experiments at the cellular scale are challenging, due to the limited availability of biocompatible temperature sensors, as well as the lack of practical methods to systematically control local temperatures and cellular dynamics. Here, we demonstrate a method to probe and control the cell-division timing inCaenorhabditis elegansembryos using a combination of local laser heating and nanoscale thermometry. Local infrared laser illumination produces a temperature gradient across the embryo, which is precisely measured by in vivo nanoscale thermometry using quantum defects in nanodiamonds. These techniques enable selective, controlled acceleration of the cell divisions, even enabling an inversion of division order at the two-cell stage. Our data suggest that the cell-cycle timing asynchrony of the early embryonic development inC. elegansis determined independently by individual cells rather than via cell-to-cell communication. Our method can be used to control the development of multicellular organisms and to provide insights into the regulation of cell-division timings as a consequence of local perturbations.

scholarly journals Genome-wide CRISPR screen identifies noncanonical NF-κB signaling as a regulator of density-dependent proliferation

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Maria Fomicheva ◽  
Ian G Macara
Keyword(s):  
Cell Cycle ◽  
Epithelial Cells ◽  
Kinase Inhibitors ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Negative Regulator ◽  
Density Dependent ◽  
Genome Wide ◽  
A Genome ◽  
Crispr Screen

Epithelial cells possess intrinsic mechanisms to maintain an appropriate cell density for normal tissue morphogenesis and homeostasis. Defects in such mechanisms likely contribute to hyperplasia and cancer initiation. To identify genes that regulate the density-dependent proliferation of murine mammary epithelial cells, we developed a fluorescence-activated cell sorting assay based on fluorescence ubiquitination cell cycle indicator, which marks different stages of the cell cycle with distinct fluorophores. Using this powerful assay, we performed a genome-wide CRISPR/Cas9 knockout screen, selecting for cells that proliferate normally at low density but continue to divide at high density. Unexpectedly, one top hit was Traf3, a negative regulator of NF-κB signaling that has never previously been linked to density-dependent proliferation. We demonstrate that loss of Traf3 specifically activates noncanonical NF-κB signaling. This in turn triggers an innate immune response and drives cell division independently of known density-dependent proliferation mechanisms, including YAP/TAZ signaling and cyclin-dependent kinase inhibitors, by blocking entry into quiescence.

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