Browse
Submit Data
Databases
API
Help

Dataset Information

27 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

DRG2 Regulates G2/M Progression via the Cyclin B1-Cdk1 Complex.

ABSTRACT: Developmentally regulated GTP-binding protein 2 (DRG2) plays an important role in cell growth. Here we explored the linkage between DRG2 and G2/M phase checkpoint function in cell cycle progression. We observed that knockdown of DRG2 in HeLa cells affected growth in a wound-healing assay, and tumorigenicity in nude mice xenografts. Flow cytometry assays and [(3)H] incorporation assays indicated that G2/M phase arrest was responsible for the decreased proliferation of these cells. Knockdown of DRG2 elicited down-regulation of the major mitotic promoting factor, the cyclin B1/Cdk1 complex, but up-regulation of the cell cycle arresting proteins, Wee1, Myt1, and p21. These findings identify a novel role of DRG2 in G2/M progression.

SUBMITTER: Jang SH

PROVIDER: S-EPMC5050535 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

DRG2 Regulates G2/M Progression via the Cyclin B1-Cdk1 Complex.

Jang Soo Hwa SH Kim Ah-Ram AR Park Neung-Hwa NH Park Jeong Woo JW Han In-Seob IS

Molecules and cells 20160927 9

Developmentally regulated GTP-binding protein 2 (DRG2) plays an important role in cell growth. Here we explored the linkage between DRG2 and G2/M phase checkpoint function in cell cycle progression. We observed that knockdown of DRG2 in HeLa cells affected growth in a wound-healing assay, and tumorigenicity in nude mice xenografts. Flow cytometry assays and [(3)H] incorporation assays indicated that G2/M phase arrest was responsible for the decreased proliferation of these cells. Knockdown of DR ...[more]

PMID: 27669826

Similar Datasets

Cyclin B1/Cdk1 coordinates mitochondrial respiration for cell-cycle G2/M progression.

Project description:A substantial amount of mitochondrial energy is required for cell-cycle progression. The mechanisms underlying the coordination of the mitochondrial respiration with cell-cycle progression, especially the G2/M transition, remain to be elucidated. Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function. Mitochondria-targeted cyclin B1/Cdk1 increases mitochondrial respiration with enhanced oxygen consumption and ATP generation, which provides cells with efficient bioenergy for G2/M transition and shortens overall cell-cycle time. Thus, cyclin B1/Cdk1-mediated phosphorylation of mitochondrial substrates allows cells to sense and respond to increased energy demand for G2/M transition and, subsequently, to upregulate mitochondrial respiration for successful cell-cycle progression.

| S-EPMC4156313 | biostudies-literature

c-Myc regulates the CDK1/cyclin B1 dependent?G2/M cell cycle progression by histone H4 acetylation in Raji cells.

Project description:Overexpression of c-Myc is involved in the tumorigenesis of B-lineage acute lymphoblastic leukemia (B?ALL), but the mechanism is not well understood. In the present study, a c?Myc?knockdown model (Raji?KD) was established using Raji cells, and it was indicated that c?Myc regulates the expression of genes associated with cell cycle progression in G2/M?phase, cyclin D kinase (CDK)1 and cyclin B1, by modulating 60 kDa Tat?interactive protein (TIP60)/males absent on the first (MOF)?mediated histone H4 acetylation (AcH4), which was then completely restored by re?introduction of the c?Myc gene into the Raji?KD cells. The expression of CDK1 and cyclin B1 was markedly suppressed in Raji?KD cells, resulting in G2/M arrest. In comparison to Raji cells, the proliferation of Raji?KD cells was significantly reduced, and it was recovered via re?introduction of the c?Myc gene. In the tumorigenesis assays, the loss of c?Myc expression significantly suppressed Raji cell?derived lymphoblastic tumor formation. Although c?Myc also promotes Raji cell apoptosis via the caspase?3?associated pathway, CDK1/cyclin B1?dependent?G2/M cell cycle progression remains the major driving force of c?Myc?controlled tumorigenesis. The present results suggested that c?Myc regulates cyclin B1? and CDK1?dependent G2/M cell cycle progression by TIP60/MOF-mediated AcH4 in Raji cells.

| S-EPMC5881754 | biostudies-literature

Cyclin B1-Cdk1 activation continues after centrosome separation to control mitotic progression.

Project description:Activation of cyclin B1-cyclin-dependent kinase 1 (Cdk1), triggered by a positive feedback loop at the end of G2, is the key event that initiates mitotic entry. In metaphase, anaphase-promoting complex/cyclosome-dependent destruction of cyclin B1 inactivates Cdk1 again, allowing mitotic exit and cell division. Several models describe Cdk1 activation kinetics in mitosis, but experimental data on how the activation proceeds in mitotic cells have largely been lacking. We use a novel approach to determine the temporal development of cyclin B1-Cdk1 activity in single cells. By quantifying both dephosphorylation of Cdk1 and phosphorylation of the Cdk1 target anaphase-promoting complex/cyclosome 3, we disclose how cyclin B1-Cdk1 continues to be activated after centrosome separation. Importantly, we discovered that cytoplasmic cyclin B1-Cdk1 activity can be maintained even when cyclin B1 translocates to the nucleus in prophase. These experimental data are fitted into a model describing cyclin B1-Cdk1 activation in human cells, revealing a striking resemblance to a bistable circuit. In line with the observed kinetics, cyclin B1-Cdk1 levels required to enter mitosis are lower than the amount of cyclin B1-Cdk1 needed for mitotic progression. We propose that gradually increasing cyclin B1-Cdk1 activity after centrosome separation is critical to coordinate mitotic progression.

| S-EPMC1858714 | biostudies-literature

FOXA1 transcriptionally up-regulates cyclin B1 expression to enhance chondrosarcoma progression.

Project description:Chondrosarcoma is a malignant and common bone tumor that is highly resistant to radiation and chemotherapy. At this moment, amputation surgery is the only option which unfortunately has serious impact to daily lives of the patients. Thus, there is an urgent need to understand causative molecular mechanisms underlying the disease for more accurate prognosis and more effective targeted treatment. In the current study, we identify the transcription factor FOXA1 through cDNA microarray screening comparing normal versus chondrosarcoma cells and investigate the mechanisms underlying its function in chondrosarcoma development. We show that FOXA1 enhances expression of the cyclin B1 gene, which in turn drives cell cycle progression through G2-M transition thus promotes cell cycle progression of chondrosarcoma cells.

| S-EPMC6220138 | biostudies-literature

Cyclin B1/Cdk1 phosphorylation of mitochondrial p53 induces anti-apoptotic response.

Project description:The pro-apoptotic function of p53 has been well defined in preventing genomic instability and cell transformation. However, the intriguing fact that p53 contributes to a pro-survival advantage of tumor cells under DNA damage conditions raises a critical question in radiation therapy for the 50% human cancers with intact p53 function. Herein, we reveal an anti-apoptotic role of mitochondrial p53 regulated by the cell cycle complex cyclin B1/Cdk1 in irradiated human colon cancer HCT116 cells with p53(+/+) status. Steady-state levels of p53 and cyclin B1/Cdk1 were identified in the mitochondria of many human and mouse cells, and their mitochondrial influx was significantly enhanced by radiation. The mitochondrial kinase activity of cyclin B1/Cdk1 was found to specifically phosphorylate p53 at Ser-315 residue, leading to enhanced mitochondrial ATP production and reduced mitochondrial apoptosis. The improved mitochondrial function can be blocked by transfection of mutant p53 Ser-315-Ala, or by siRNA knockdown of cyclin B1 and Cdk1 genes. Enforced translocation of cyclin B1 and Cdk1 into mitochondria with a mitochondrial-targeting-peptide increased levels of Ser-315 phosphorylation on mitochondrial p53, improved ATP production and decreased apoptosis by sequestering p53 from binding to Bcl-2 and Bcl-xL. Furthermore, reconstitution of wild-type p53 in p53-deficient HCT116 p53(-/-) cells resulted in an increased mitochondrial ATP production and suppression of apoptosis. Such phenomena were absent in the p53-deficient HCT116 p53(-/-) cells reconstituted with the mutant p53. These results demonstrate a unique anti-apoptotic function of mitochondrial p53 regulated by cyclin B1/Cdk1-mediated Ser-315 phosphorylation in p53-wild-type tumor cells, which may provide insights for improving the efficacy of anti-cancer therapy, especially for tumors that retain p53.

| S-EPMC2925892 | biostudies-literature

Proximal discrepancy in intrinsic atomic interaction arrests G2/M phase by inhibiting Cyclin B1/CDK1 to infer molecular and cellular biocompatibility of D-limonene.

Project description:The quest for different natural compounds for different biomedical applications especially in the treatment of cancer is at a high pace with increasing incidence of severity. D-limonene has been portrayed as one of the effective potential candidate centered to the context of breast cancer. The anticipation of its count as an effective biomedical agent required a detailed understanding of their molecular mechanism of biocompatibility. This study elucidates the mechanistic action of D-limonene channelized by the induction of apoptosis for controlling proliferation in breast cancer cells. The possible mechanism was explored through an experimental and computational approach to estimate cell proliferation inhibition, cell cycle phase distribution, apoptosis analysis using a flow cytometry, western blotting and molecular docking. The results showed reduced dose and time-dependent viability of MCF7 cells. The study suggested the arrest of the cell cycle at G2/M phase leading to apoptosis and other discrepancies of molecular activity mediated via significant alteration in protein expression pattern of anti-apoptotic proteins like Cyclin B1 and CDK1. Computational analysis showed firm interaction of D-limonene with Cyclin B1 and CDK1 proteins influencing their structural and functional integrity indicating the mediation of mechanism. This study concluded that D-limonene suppresses the proliferation of breast cancer cells by inducing G2/M phase arrest via deregulation of Cyclin B1/CDK1.

| S-EPMC9616896 | biostudies-literature

Phosphorylation of importin-?1 by CDK1-cyclin B1 controls mitotic spindle assembly.

Project description:Importin-? serves as an adaptor linking importin-? to proteins carrying a nuclear localization sequence (NLS). During interphase, this interaction enables nuclear protein import, while in mitosis it regulates spindle assembly factors (SAFs) and controls microtubule nucleation, stabilization and spindle function. Here, we show that human importin-?1 is regulated during the cell cycle and is phosphorylated at two sites (threonine 9 and serine 62) during mitosis by the major mitotic protein kinase CDK1-cyclin B. Mutational analysis indicates that the mitotic phosphorylation of importin-?1 inhibits its binding to importin-? and promotes the release of TPX2 and KIFC1, which are then targeted like importin-? to the spindle. Loss of importin-?1 or expression of a non-phosphorylated mutant of importin-?1 results in the formation of shortened spindles with reduced microtubule density and induces a prolonged metaphase, whereas phosphorylation-mimicking mutants are functional in mitosis. We propose that phosphorylation of importin-?1 is a general mechanism for the spatial and temporal control of mitotic spindle assembly by CDK1-cyclin B1 that acts through the release of SAFs such as TPX2 and KIFC1 from inhibitory complexes that restrict spindle assembly.

| S-EPMC6765185 | biostudies-literature

Structural basis of human separase regulation by securin and CDK1-cyclin B1.

Project description:In early mitosis, the duplicated chromosomes are held together by the ring-shaped cohesin complex1. Separation of chromosomes during anaphase is triggered by separase-a large cysteine endopeptidase that cleaves the cohesin subunit SCC1 (also known as RAD212-4). Separase is activated by degradation of its inhibitors, securin5 and cyclin B6, but the molecular mechanisms of separase regulation are not clear. Here we used cryogenic electron microscopy to determine the structures of human separase in complex with either securin or CDK1-cyclin B1-CKS1. In both complexes, separase is inhibited by pseudosubstrate motifs that block substrate binding at the catalytic site and at nearby docking sites. As in Caenorhabditis elegans7 and yeast8, human securin contains its own pseudosubstrate motifs. By contrast, CDK1-cyclin B1 inhibits separase by deploying pseudosubstrate motifs from intrinsically disordered loops in separase itself. One autoinhibitory loop is oriented by CDK1-cyclin B1 to block the catalytic sites of both separase and CDK19,10. Another autoinhibitory loop blocks substrate docking in a cleft adjacent to the separase catalytic site. A third separase loop contains a phosphoserine6 that promotes complex assembly by binding to a conserved phosphate-binding pocket in cyclin B1. Our study reveals the diverse array of mechanisms by which securin and CDK1-cyclin B1 bind and inhibit separase, providing the molecular basis for the robust control of chromosome segregation.

| S-EPMC8482764 | biostudies-literature

CDK1-Cyclin B1 Activates RNMT, Coordinating mRNA Cap Methylation with G1 Phase Transcription.

Project description:The creation of translation-competent mRNA is dependent on RNA polymerase II transcripts being modified by addition of the 7-methylguanosine (m7G) cap. The factors that mediate splicing, nuclear export, and translation initiation are recruited to the transcript via the cap. The cap structure is formed by several activities and completed by RNMT (RNA guanine-7 methyltransferase), which catalyzes N7 methylation of the cap guanosine. We report that CDK1-cyclin B1 phosphorylates the RNMT regulatory domain on T77 during G2/M phase of the cell cycle. RNMT T77 phosphorylation activates the enzyme both directly and indirectly by inhibiting interaction with KPNA2, an RNMT inhibitor. RNMT T77 phosphorylation results in elevated m7G cap methyltransferase activity at the beginning of G1 phase, coordinating mRNA capping with the burst of transcription that occurs following nuclear envelope reformation. RNMT T77 phosphorylation is required for the production of cohort of proteins, and inhibiting T77 phosphorylation reduces the cell proliferation rate.

| S-EPMC4781437 | biostudies-literature

p21-Mediated nuclear retention of cyclin B1-Cdk1 in response to genotoxic stress.

Project description:G2 arrest of cells suffering DNA damage in S phase is crucial to avoid their entry into mitosis, with the concomitant risks of oncogenic transformation. According to the current model, signals elicited by DNA damage prevent mitosis by inhibiting both activation and nuclear import of cyclin B1-Cdk1, a master mitotic regulator. We now show that normal human fibroblasts use additional mechanisms to block activation of cyclin B1-Cdk1. In these cells, exposure to nonrepairable DNA damage leads to nuclear accumulation of inactive cyclin B1-Cdk1 complexes. This nuclear retention, which strictly depends on association with endogenous p21, prevents activation of cyclin B1-Cdk1 by Cdc25 and Cdk-activating kinase as well as its recruitment to the centrosome. In p21-deficient normal human fibroblasts and immortal cell lines, cyclin B1 fails to accumulate in the nucleus and could be readily detected at the centrosome in response to DNA damage. Therefore, in normal cells, p21 exerts a dual role in mediating DNA damage-induced cell cycle arrest and exit before mitosis. In addition to blocking pRb phosphorylation, p21 directly prevents mitosis by inactivating and maintaining the inactive state of mitotic cyclin-Cdk complexes. This, with subsequent degradation of mitotic cyclins, further contributes to the establishment of a permanent G2 arrest.

| S-EPMC515331 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data