p21 Inhibits Thr161 Phosphorylation of Cdc2 to Enforce the G2 DNA Damage Checkpoint*

The cyclin-dependent kinase inhibitor p21 is required for a sustained G2 arrest after activation of the DNA damage checkpoint. Here we have addressed the mechanism by which p21 can contribute to this arrest in G2. We show that p21 blocks the activating phosphorylation of Cdc2 on Thr161. p21 does not interfere with the dephosphorylation of two inhibitory phosphorylation sites on Cdc2, Thr14 and Tyr15, indicating that p21 targets a different event in Cdc2 activation as the well described DNA damage checkpoint pathway involving Chk1 and Cdc25C. Taken together our data show that a cell is equipped with at least two independent pathways to ensure efficient inhibition of Cdc2 activity in response to DNA damage, influencing both positive and negative regulatory phosphorylation events on Cdc2.

• Publication year

  2000

• Venue

  Journal of Biological Chemistry

• Publication date

  2000-09-29

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1074/jbc.M005437200PMID 10913154
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• [Oncogene].

  2019cited by this paper
• FEBS Lett

  2000cited by this paper
• Inhibition of cell proliferation by lithium is associated with interference in cdc2 activation

  1999cited by this paper
• Nuclear localization of Cdc25 is regulated by DNA damage and a 14-3-3 protein

  1999cited by this paper
• 14-3-3Sigma is required to prevent mitotic catastrophe after DNA damage.

  1999cited by this paper
• 14-3-3σ is required to prevent mitotic catastrophe after DNA damage

  1999cited by this paper
• Activated Polo-Like Kinase Plx1 Is Required at Multiple Points during Mitosis in Xenopus laevis

  1998cited by this paper
• Nuclear Localization of Cyclin B1 Controls Mitotic Entry After DNA Damage

  1998cited by this paper
• p21Waf1 inhibits the activity of cyclin dependent Kinase 2 by preventing its activating phosphorylation

  1998cited by this paper
• Nuclear Accumulation of p21Cip1 at the Onset of Mitosis: a Role at the G2/M-Phase Transition

  1998cited by this paper
• p21waf1 can block cells at two points in the cell cycle, but does not interfere with processive DNA-replication or stress-activated kinases

  1998cited by this paper
• p53 regulates Cdc2 independently of inhibitory phosphorylation to reinforce radiation-induced G2 arrest in human cells

  1998cited by this paper
• Requirement for p53 and p21 to sustain G2 arrest after DNA damage.

  1998cited by this paper
• MPF localization is controlled by nuclear export

  1998cited by this paper
• Control of cyclin B1 localization through regulated binding of the nuclear export factor CRM1.

  1998cited by this paper
• Nuclear export of cyclin B1 and its possible role in the DNA damage‐induced G2 checkpoint

  1998cited by this paper
• 14-3-3σ Is a p53-Regulated Inhibitor of G2/M Progression

  1997cited by this paper
• Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216.

  1997cited by this paper
• 14-3-3sigma is a p53-regulated inhibitor of G2/M progression.

  1997cited by this paper
• Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25.

  1997cited by this paper
• rad-Dependent Response of the chk1-Encoded Protein Kinase at the DNA Damage Checkpoint

  1996cited by this paper
• Purification and Molecular Cloning of Plx1, a Cdc25-Regulatory Kinase from Xenopus Egg Extracts

  1996cited by this paper
• Uncoupling of Obesity from Insulin Resistance Through a Targeted Mutation in aP2, the Adipocyte Fatty Acid Binding Protein

  1996cited by this paper
• Inhibition of cyclin-dependent kinases by p21.

  1995cited by this paper
• Alternative mechanisms of CAK assembly require an assembly factor or an activating kinase.

  1995cited by this paper
• MAT1 (‘menage à trois’) a new RING finger protein subunit stabilizing cyclin H‐cdk7 complexes in starfish and Xenopus CAK.

  1995cited by this paper
• Cell cycle regulation of the activity and subcellular localization of Plk1, a human protein kinase implicated in mitotic spindle function

  1995cited by this paper
• Both p16 and p21 Families of Cyclin-dependent Kinase (CDK) Inhibitors Block the Phosphorylation of Cyclin-dependent Kinases by the CDK-activating Kinase (*)

  1995cited by this paper
• Principles of CDK regulation

  1995cited by this paper
• A novel cyclin associates with M015/CDK7 to form the CDK-activating kinase

  1994cited by this paper
• Membrane localization of the kinase which phosphorylates p34cdc2 on threonine 14.

  1994cited by this paper
• Mitosis in transition.

  1994cited by this paper
• Cell cycle expression and p53 regulation of the cyclin-dependent kinase inhibitor p21.

  1994cited by this paper
• The decision to enter mitosis.

  1994cited by this paper
• A cyclin associated with the CDK-activating kinase MO15

  1994cited by this paper
• WAF1, a potential mediator of p53 tumor suppression.

  1993cited by this paper
• Phosphorylation and activation of human cdc25‐C by cdc2‐‐cyclin B and its involvement in the self‐amplification of MPF at mitosis.

  1993cited by this paper
• Fission yeast chkl protein kinase links the rad checkpoint pathway to cdc2

  1993cited by this paper
• Elimination of cdc2 phosphorylation sites in the cdc25 phosphatase blocks initiation of M-phase.

  1993cited by this paper
• Periodic changes in phosphorylation of the Xenopus cdc25 phosphatase regulate its activity.

  1992cited by this paper
• Regulation of the cdc25 protein during the cell cycle in Xenopus extracts.

  1992cited by this paper
• Activation of human cyclin-dependent kinases in vitro.

  1992cited by this paper
• Cyclin A is required at two points in the human cell cycle.

  1992cited by this paper
• Phosphopeptide mapping and phosphoamino acid analysis by two-dimensional separation on thin-layer cellulose plates.

  1991cited by this paper

• PARP inhibitor response is enhanced in prostate cancer when XRCC1 expression is reduced

  2025cites this paper
• Cellular Senescence in Cancer: Mechanisms, Roles in Tumor Progression, and Therapeutic Implications

  2025cites this paper
• Overcoming Radioresistance in Prostate Cancer by Targeting DNA Damage Repair.

  2025cites this paper
• N-cadherin Alleviates Apoptosis and Senescence of Nucleus Pulposus Cells via Suppressing ROS-dependent ERS in the Hyper-osmolarity Microenvironment

  2024cites this paper
• CIP/KIP and INK4 families as hostages of oncogenic signaling

  2024cites this paper
• GRK2-mediated AKT activation controls cell cycle progression and G2 checkpoint in a p53-dependent manner

  2024cites this paper
• Liquiritigenin Induces Cell Cycle Arrest and Apoptosis in Lung Squamous Cell Carcinoma

  2024cites this paper
• Scutebarbatine A induces ROS-mediated DNA damage and apoptosis in breast cancer cells by modulating MAPK and EGFR/Akt signaling pathway.

  2023cites this paper
• Variation in pentose phosphate pathway-associated metabolism dictates cytotoxicity outcomes determined by tetrazolium reduction assays

  2023cites this paper
• Effective‐by‐method for the preparation of folic acid‐coated TiO2 nanoparticles with high targeting potential for apoptosis induction against bladder cancer cells (T24)

  2023cites this paper
• miR-6077 promotes cisplatin/pemetrexed resistance in lung adenocarcinoma via CDKN1A/cell cycle arrest and KEAP1/ferroptosis pathways

  2022cites this paper
• Synthetic Homoisoflavane Derivatives of Cremastranone Suppress Growth of Colorectal Cancer Cells through Cell Cycle Arrest and Induction of Apoptosis

  2022cites this paper
• Inhibition of the lncRNA MIAT prevents podocyte injury and mitotic catastrophe in diabetic nephropathy

  2022cites this paper
• Albumin-induced premature senescence in human renal proximal tubular cells and its relationship with intercellular fibrosis

  2022cites this paper
• Poly-ADP ribosylation of p21 by tankyrases promotes p21 degradation and regulates cell cycle progression.

  2022cites this paper
• The Complex Roles of DNA Repair Pathways, Inhibitors, Hyperthermia, and Contact Inhibition in Cell Cycle Halts.

  2022cites this paper
• Comparable radiation sensitivity in p53 wild-type and p53 deficient tumor cells associated with different cell death modalities

  2021cites this paper
• Oxidative Stress-Induced Unscheduled CDK1–Cyclin B1 Activity Impairs ER–Mitochondria-Mediated Bioenergetic Metabolism

  2021cites this paper
• IL-6 derived from therapy-induced senescence facilitates the glycolytic phenotype in glioblastoma cells.

  2021cites this paper
• The role of p53/p21/p16 in DNA damage signaling and DNA repair

  2021cites this paper
• Mechanisms of Hepatitis B Virus-Induced Hepatocarcinogenesis.

  2021cites this paper
• Identification of a novel catalytic inhibitor of topoisomerase II alpha that engages distinct mechanisms in p53wt or p53-/- cells to trigger G2/M arrest and senescence.

  2021cites this paper
• Y2O3 Nanoparticles and X-ray Radiation-Induced Effects in Melanoma Cells

  2021cites this paper
• Nkx2.5 Functions as a Conditional Tumor Suppressor Gene in Colorectal Cancer Cells via Acting as a Transcriptional Coactivator in p53-Mediated p21 Expression

  2021cites this paper
• Molecular and biological functions of gingerol as a natural effective therapeutic drug for cervical cancer

  2021cites this paper
• Radiosensitizing high-Z metal nanoparticles for enhanced radiotherapy of glioblastoma multiforme

  2020cites this paper
• AMPK Activity Contributes to G2 Arrest and DNA Damage Decrease via p53/p21 Pathways in Oxidatively Damaged Mouse Zygotes

  2020cites this paper
• Cellular senescence in cancer: from mechanisms to detection

  2020cites this paper
• A unified model for the G1/S cell cycle transition

  2020cites this paper
• The HDAC inhibitor OBP-801 suppresses the growth of myxofibrosarcoma cells.

  2020cites this paper
• Overexpression of p21 Has Inhibitory Effect on Human Hematopoiesis by Blocking Generation of CD43+ Cells via Cell-Cycle Regulation

  2020cites this paper
• Regulation of resection by chromatin associated proteins

  2019cites this paper
• Citrate-Induced p85α–PTEN Complex Formation Causes G2/M Phase Arrest in Human Pharyngeal Squamous Carcinoma Cell Lines

  2019cites this paper
• Suppressed hepatocyte proliferation via a ROS-HNE-P21 pathway is associated with nicotine- and cotinine-enhanced alcoholic fatty liver in mice.

  2019cites this paper
• PKCβ1 regulates meiotic cell cycle in mouse oocyte

  2019influential citation
• The Role of the Cyclin Dependent Kinase Inhibitor p21cip1/waf1 in Targeting Cancer: Molecular Mechanisms and Novel Therapeutics

  2019cites this paper
• Fusarubin and Anhydrofusarubin Isolated from A Cladosporium Species Inhibit Cell Growth in Human Cancer Cell Lines

  2019cites this paper
• DNA Damage Stress: Cui Prodest?

  2019cites this paper
• Estrogen receptor α dependent regulation of estrogen related receptor β and its role in cell cycle in breast cancer

  2018cites this paper
• Notch1 activation enhances proliferation via activation of cdc2 and delays differentiation of myeloid progenitors.

  2018influential citation
• Tetrandrine enhances radiosensitivity through the CDC25C/CDK1/cyclin B1 pathway in nasopharyngeal carcinoma cells

  2018cites this paper
• WITHDRAWN—Administrative Duplicate Publication: The Hexane Fraction of Bursera microphylla A. Gray Induces p21-Mediated Anti-Proliferative and Pro-Apoptotic Effects in Human Cancer-Derived Cell Lines

  2018cites this paper
• The molecular mechanism of cell cycle arrest in the Bursa of Fabricius in chick exposed to Aflatoxin B1

  2018cites this paper
• The Hexane Fraction of Bursera microphylla A Gray Induces p21-Mediated Antiproliferative and Proapoptotic Effects in Human Cancer–Derived Cell Lines

  2017cites this paper
• Analyzing the G 2 / M Checkpoint 51 51

  2017cites this paper
• Inhibition of coiled coil domain containing protein 69 enhances platinum-induced apoptosis in ovarian cancer cells

  2017cites this paper
• Oridonin induces G2/M cell cycle arrest and apoptosis in human oral squamous cell carcinoma

  2017cites this paper
• Cdk2 strengthens the intra-S checkpoint and counteracts cell cycle exit induced by DNA damage

  2017cites this paper
• Melanoma antigen A12 regulates cell cycle via tumor suppressor p21 expression

  2017cites this paper
• Deubiquitylation and stabilization of p21 by USP11 is critical for cell-cycle progression and DNA damage responses

  2017cites this paper
• Downregulation of serum RAB27B confers improved prognosis and is associated with hepatocellular carcinoma progression through PI3K-AKT-P21 signaling

  2017cites this paper
• Analysis of radio-sensitization patents in China from 2006 to 2015

  2017cites this paper
• The imidazoacridinone C-1311 induces p53-dependent senescence or p53-independent apoptosis and sensitizes cancer cells to radiation

  2017cites this paper
• Isoliquiritigenin exhibits anti-proliferative properties in the pituitary independent of estrogen receptor function.

  2016cites this paper
• The medicinal fungus Antrodia cinnamomea regulates Dna repair and enhances the radiosensitivity of human esophageal cancer cells

  2016cites this paper
• Dual Role of p21 in the Progression of Cancer and Its Treatment.

  2016cites this paper
• Targeting p53 in cancer: from innovative yeast screening strategies to new drugs

  2016influential citation
• The medicinal fungus Antrodia cinnamomea regulates Dna repair and enhances the radiosensitivity of human esophageal cancer cells

  2016cites this paper
• Diversity and implication of MAPK signal transduction involved in the regulation of chemotherapy-induced DNA damage response

  2016cites this paper
• The Role of p53/p21/p16 in DNA-Damage Signaling and DNA Repair

  2016cites this paper
• Sonic hedgehog signaling pathway mediates development of hepatocellular carcinoma

  2016cites this paper
• Prolonged cyclic strain inhibits human endothelial cell growth.

  2016cites this paper
• Cdk activity drives senescence from G2 phase

  2016cites this paper
• Nickel(II)-induced nasal epithelial toxicity and oxidative mitochondrial damage.

  2016cites this paper
• p21 is Responsible for Ionizing Radiation-induced Bypass of Mitosis.

  2016cites this paper
• The molecular mechanism of G2/M cell cycle arrest induced by AFB1 in the jejunum

  2016cites this paper
• Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization

  2016cites this paper
• The medicinal fungus Antrodia cinnamomea regulates DNA repair and enhances the radiosensitivity of human esophageal cancer cells

  2016cites this paper
• Chinese Herbal Mixture, Tien-Hsien Liquid, Induces G2/M Cycle Arrest and Radiosensitivity in MCF-7 Human Breast Cancer Cells through Mechanisms Involving DNMT1 and Rad51 Downregulation

  2016cites this paper
• Viral modulation of host cell anti-apoptotic mechanisms and cellular stress to promote viral pathogenesis

  2016cites this paper
• Phytoestrogen Bakuchiol Exhibits In Vitro and In Vivo Anti-breast Cancer Effects by Inducing S Phase Arrest and Apoptosis

  2016cites this paper
• Viscum Album Var Hot Water Extract Mediates Anti-cancer Effects through G1 Phase Cell Cycle Arrest in SK-Hep1 Human Hepatocarcinoma cells.

  2015influential citation
• Proteasome inhibition mediates p53 reactivation and anti-cancer activity of 6-Gingerol in cervical cancer cells

  2015influential citation
• Epigenetics and chromosome segregation in human pre-implantation embryos

  2015cites this paper
• Senescence from G2 arrest, revisited

  2015cites this paper
• Adenovirus-mediated ING4 Gene Transfer in Osteosarcoma Suppresses Tumor Growth via Induction of Apoptosis and Inhibition of Tumor Angiogenesis

  2015cites this paper
• USP39 promotes the growth of human hepatocellular carcinoma in vitro and in vivo.

  2015cites this paper
• ecoce en utilisant l'embryon d'oursin

  2015cites this paper
• USP 39 promotes the growth of human hepatocellular carcinoma in vitro and in vivo

  2015cites this paper
• Adenovirus-mediated ING4 Gene Transfer in Osteosarcoma Suppresses Tumor Growth via Induction of Apoptosis and Inhibition of Tumor Angiogenesis

  2015cites this paper
• Quantitative proteomics reveals middle infrared radiation-interfered networks in breast cancer cells.

  2015cites this paper
• Less understood issues: p21Cip1 in mitosis and its therapeutic potential

  2014cites this paper
• Requires p21 Phase Arrest and 2 Regulation Involves G T-Cadherin-Mediated Cell Growth

  2014cites this paper
• p21Waf1/Cip1 deficiency causes multiple mitotic defects in tumor cells

  2014cites this paper
• Aberrant histone modification in endometriosis.

  2014cites this paper
• Biology of the cell cycle inhibitor p21CDKN1A: molecular mechanisms and relevance in chemical toxicology

  2014cites this paper
• Enhanced in-vitro and in-vivo suppression of A375 melanoma by combined IL-24/OSM adenoviral-mediated gene therapy

  2014cites this paper
• c-ABL tyrosine kinase modulates p53-dependent p21 induction and ensuing cell fate decision in response to DNA damage.

  2014cites this paper
• LL-202, a newly synthesized flavonoid, inhibits tumor growth via inducing G(2)/M phase arrest and cell apoptosis in MCF-7 human breast cancer cells in vitro and in vivo.

  2014cites this paper
• Enter the nucleus to exit the cycle

  2014cites this paper
• Transient activation of p53 in G2 phase is sufficient to induce senescence.

  2014cites this paper
• Growth Factor Receptor Signaling, DNA Damage Response, and Cancer Cell Susceptibility to Chemotherapy and Relapses

  2013cites this paper
• CtIP is required for DNA damage-dependent induction of P21

  2013cites this paper
• Radiation Induced DNA Damage, Repair and Therapeutics

  2013cites this paper
• 4-Hydroxynonenal Induces G2/M Phase Cell Cycle Arrest by Activation of the Ataxia Telangiectasia Mutated and Rad3-related Protein (ATR)/Checkpoint Kinase 1 (Chk1) Signaling Pathway*

  2013cites this paper
• p21CDKN1A and DNA Repair Systems: Recent Findings and Future Perspectives

  2013cites this paper
• HER2 stabilizes survivin while concomitantly down-regulating survivin gene transcription by suppressing Notch cleavage.

  2013cites this paper
• Renal Hyperplasia and Hypertrophy

  2013cites this paper
• Intrinsic apoptotic pathway and G2/M cell cycle arrest involved in tubeimoside I-induced EC109 cell death.

  2013cites this paper
• Anisomycin suppresses Jurkat T cell growth by the cell cycle-regulating proteins

  2013cites this paper