The CRL2LRR-1 ubiquitin ligase regulates cell cycle progression during C. elegans development.

In the germline of Caenorhabditis elegans hermaphrodites, meiotic cell cycle progression occurs in spatially restricted regions. Immediately after leaving the distal mitotic region, germ cells enter meiosis and thereafter remain in the pachytene stage of first meiotic prophase for an extended period. At the dorsoventral gonadal flexure, germ cells exit pachytene and subsequently become arrested in diakinesis. We have found that exit from pachytene is dependent on the function of three members of the MAP kinase signaling cascade. One of these genes, mek-2, is a newly identified C. elegans MEK (MAP kinase kinase). The other two genes, mpk-1/sur-1 (MAP kinase) and let-60 ras, were previously identified based on their roles in vulval induction and are shown here to act in combination with mek-2 to permit exit from pachytene. Through genetic mosaic analysis, we demonstrate that the expression of mpk-1/sur-1 is required within the germline to permit exit from pachytene.

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The E3 ubiquitin ligase HECTD1 contributes to cell cycle progression through an effect on mitosis

10.1101/2021.12.17.473173 ◽

2021 ◽

Author(s):

Natalie Vaughan ◽

Nico Scholz ◽

Catherine Lindon ◽

Julien D, F Licchesi

Keyword(s):

Cell Cycle ◽

Ubiquitin Ligase ◽

Cell Cycle Progression ◽

Spindle Assembly Checkpoint ◽

Time Lapse ◽

Ubiquitin Chain ◽

Cycle Progression ◽

Anaphase Onset ◽

Ubiquitin Ligase Activity ◽

Complex Protein

Mechanistic studies of how protein ubiquitylation regulates the cell cycle, in particular during mitosis, has provided unique insights which have contributed to the emergence of the Ubiquitin code. In contrast to RING E3 ubiquitin ligases such as the APC/c ligase complex, the contribution of other E3 ligase families during cell cycle progression remains less well understood. Similarly, the contribution of ubiquitin chain types beyond homotypic K48 chains in S-phase or branched K11/K48 chains assembled by APC/c during mitosis, also remains to be fully determined. Our recent findings that HECTD1 ubiquitin ligase activity assembles branched K29/K48 ubiquitin linkages prompted us to evaluate its function during the cell cycle. We used transient knockdown and genetic knockout to show that HECTD1 depletion in HEK293T and HeLa cells decreases cell proliferation and we established that this is mediated through loss of its ubiquitin ligase activity. Interestingly, we found that HECTD1 depletion increases the proportion of cells with aligned chromosomes (Prometa/Metaphase). We confirmed this molecularly using phospho-Histone H3 (Ser28) as a marker of mitosis. Time-lapse microscopy of NEBD to anaphase onset established that HECTD1-depleted cells take on average longer to go through mitosis. To explore the mechanisms involved, we used proteomics to explore the endogenous HECTD1 interactome in mitosis and validated the Mitosis Checkpoint Complex protein BUB3 as a novel HECTD1 interactor. In line with this, we found that HECTD1 depletion reduces the activity of the Spindle Assembly Checkpoint. Overall, our data suggests a novel role for HECTD1 ubiquitin ligase activity in mitosis.

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

Development ◽

10.1242/dev.125.18.3585 ◽

1998 ◽

Vol 125 (18) ◽

pp. 3585-3597 ◽

Cited By ~ 23

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.

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NEK7 is required for G1 progression and procentriole formation

Molecular Biology of the Cell ◽

10.1091/mbc.e16-09-0643 ◽

2017 ◽

Vol 28 (15) ◽

pp. 2123-2134 ◽

Cited By ~ 12

Author(s):

Akshari Gupta ◽

Yuki Tsuchiya ◽

Midori Ohta ◽

Gen Shiratsuchi ◽

Daiju Kitagawa

Keyword(s):

Cell Cycle ◽

Ubiquitin Ligase ◽

Cell Cycle Progression ◽

Primary Cilia ◽

S Phase ◽

Cycle Progression ◽

Restriction Point ◽

Centriole Duplication ◽

Abnormal Accumulation ◽

Phase Entry

The decision to commit to the cell cycle is made during G1 through the concerted action of various cyclin–CDK complexes. Not only DNA replication, but also centriole duplication is initiated as cells enter the S-phase. The NIMA-related kinase NEK7 is one of many factors required for proper centriole duplication, as well as for timely cell cycle progression. However, its specific roles in these events are poorly understood. In this study, we find that depletion of NEK7 inhibits progression through the G1 phase in human U2OS cells via down-regulation of various cyclins and CDKs and also inhibits the earliest stages of procentriole formation. Depletion of NEK7 also induces formation of primary cilia in human RPE1 cells, suggesting that NEK7 acts at least before the restriction point during G1. G1-arrested cells in the absence of NEK7 exhibit abnormal accumulation of the APC/C cofactor Cdh1 at the vicinity of centrioles. Furthermore, the ubiquitin ligase APC/CCdh1continuously degrades the centriolar protein STIL in these cells, thus inhibiting centriole assembly. Collectively our results demonstrate that NEK7 is involved in the timely regulation of G1 progression, S-phase entry, and procentriole formation.

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The E3 ubiquitin ligase TRIP12 participates in cell cycle progression and chromosome stability

Scientific Reports ◽

10.1038/s41598-020-57762-9 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 6

Author(s):

D. Larrieu ◽

M. Brunet ◽

C. Vargas ◽

N. Hanoun ◽

L. Ligat ◽

...

Keyword(s):

Cell Cycle ◽

Ubiquitin Ligase ◽

Cell Cycle Progression ◽

E3 Ubiquitin Ligase ◽

Chromosome Stability ◽

Cycle Progression

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Faculty Opinions recommendation of Cyclin E and CDK-2 regulate proliferative cell fate and cell cycle progression in the C. elegans germline.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.11247956.12234054 ◽

2011 ◽

Author(s):

Michael Miller ◽

Pauline Cottee

Keyword(s):

Cell Cycle ◽

Cell Fate ◽

Cell Cycle Progression ◽

Cyclin E ◽

Cycle Progression ◽

C Elegans ◽

Proliferative Cell

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Cell adhesion induces p27Kip1-associated cell-cycle arrest through down-regulation of the SCFSkp2 ubiquitin ligase pathway in mantle-cell and other non-Hodgkin B-cell lymphomas

Blood ◽

10.1182/blood-2006-11-060350 ◽

2007 ◽

Vol 110 (5) ◽

pp. 1631-1638 ◽

Cited By ~ 71

Author(s):

Tint Lwin ◽

Lori A. Hazlehurst ◽

Sophie Dessureault ◽

Raymond Lai ◽

Wenlong Bai ◽

...

Keyword(s):

Cell Cycle ◽

Cell Adhesion ◽

Tumor Cell ◽

Ubiquitin Ligase ◽

Cell Cycle Progression ◽

Response To Therapy ◽

G1 Arrest ◽

Down Regulation ◽

Cycle Progression ◽

Mantle Cell

Abstract Mounting evidence suggests that dynamic interactions between a tumor and its microenvironment play a critical role in tumor development, cell-cycle progression, and response to therapy. In this study, we used mantle cell lymphoma (MCL) as a model to characterize the mechanisms by which stroma regulate cell-cycle progression. We demonstrated that adhesion of MCL and other non-Hodgkin lymphoma (NHL) cells to bone marrow stromal cells resulted in a reversible G1 arrest associated with elevated p27Kip1 and p21 (WAF1) proteins. The adhesion-mediated p27Kip1 and p21 increases were posttranslationally regulated via the down-regulation of Skp2, a subunit of SCFSkp2 ubiquitin ligase. Overexpression of Skp2 in MCL decreased p27Kip1, whereas inhibition of Skp2 by siRNA increased p27Kip1 and p21 levels. Furthermore, we found cell adhesion up-regulated Cdh1 (an activating subunit of anaphase-promoting complex [APC] ubiquitin ligase), and reduction of Cdh1 by siRNA induced Skp2 accumulation and hence p27Kip1 degradation, thus implicating Cdh1 as an upstream effector of the Skp2/p27Kip1 signaling pathway. Overall, this report, for the first time, demonstrates that cell-cell contact controls the tumor cell cycle via ubiquitin-proteasome proteolytic pathways in MCL and other NHLs. The understanding of this novel molecular pathway may prove valuable in designing new therapeutic approaches for modifying tumor cell growth and response to therapy.

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