scholarly journals The Role of Cell Cycle Regulators in Cell Survival—Dual Functions of Cyclin-Dependent Kinase 20 and p21Cip1/Waf1

2020 ◽  
Vol 21 (22) ◽  
pp. 8504
Author(s):  
Lo Lai ◽  
Ga Yoon Shin ◽  
Hongyu Qiu
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Survival ◽  
Heart Diseases ◽  
Cell Cycle Checkpoints ◽  
Cell Cycle Regulators ◽  
Cyclin Dependent Kinase ◽  
Cellular Functions ◽  
Mammalian Cell Cycle ◽  
Cell Death Mechanisms

The mammalian cell cycle is important in controlling normal cell proliferation and the development of various diseases. Cell cycle checkpoints are well regulated by both activators and inhibitors to avoid cell growth disorder and cancerogenesis. Cyclin dependent kinase 20 (CDK20) and p21Cip1/Waf1 are widely recognized as key regulators of cell cycle checkpoints controlling cell proliferation/growth and involving in developing multiple cancers. Emerging evidence demonstrates that these two cell cycle regulators also play an essential role in promoting cell survival independent of the cell cycle, particularly in those cells with a limited capability of proliferation, such as cardiomyocytes. These findings bring new insights into understanding cytoprotection in these tissues. Here, we summarize the new progress of the studies on these two molecules in regulating cell cycle/growth, and their new roles in cell survival by inhibiting various cell death mechanisms. We also outline their potential implications in cancerogenesis and protection in heart diseases. This information renews the knowledge in molecular natures and cellular functions of these regulators, leading to a better understanding of the pathogenesis of the associated diseases and the discovery of new therapeutic strategies.

scholarly journals Hcm1 integrates signals from Cdk1 and calcineurin to control cell proliferation

2015 ◽  
Vol 26 (20) ◽  
pp. 3570-3577 ◽  
Author(s):  
Heather E. Arsenault ◽  
Jagoree Roy ◽  
Claudine E. Mapa ◽  
Martha S. Cyert ◽  
Jennifer A. Benanti
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Transcription Factor ◽  
Chromosome Segregation ◽  
Genome Stability ◽  
Control Cell ◽  
Cell Cycle Regulators ◽  
Cyclin Dependent Kinase ◽  
Expression Of Genes ◽  
Response To Stress

Cyclin-dependent kinase (Cdk1) orchestrates progression through the cell cycle by coordinating the activities of cell-cycle regulators. Although phosphatases that oppose Cdk1 are likely to be necessary to establish dynamic phosphorylation, specific phosphatases that target most Cdk1 substrates have not been identified. In budding yeast, the transcription factor Hcm1 activates expression of genes that regulate chromosome segregation and is critical for maintaining genome stability. Previously we found that Hcm1 activity and degradation are stimulated by Cdk1 phosphorylation of distinct clusters of sites. Here we show that, upon exposure to environmental stress, the phosphatase calcineurin inhibits Hcm1 by specifically removing activating phosphorylations and that this regulation is important for cells to delay proliferation when they encounter stress. Our work identifies a mechanism by which proliferative signals from Cdk1 are removed in response to stress and suggests that Hcm1 functions as a rheostat that integrates stimulatory and inhibitory signals to control cell proliferation.

scholarly journals Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1

2021 ◽  
Author(s):  
Rosemarie E. Gough ◽  
Matthew C. Jones ◽  
Thomas Zacharchenko ◽  
Shimin Le ◽  
Miao Yu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Adhesion ◽  
Cell Division ◽  
Mechanical Response ◽  
Direct Interaction ◽  
Cyclin Dependent Kinase ◽  
Cell Cycle Regulator ◽  
Direct Binding

AbstractTalin is a mechanosensitive component of adhesion complexes that directly couples integrins to the actin cytoskeleton. In response to force, talin undergoes switch-like behaviour of its multiple rod domains that modulate interactions with its binding partners. Cyclin-dependent kinase-1 (CDK1) is a key regulator of the cell cycle, exerting its effects through synchronised phosphorylation of a large number of protein targets. CDK1 activity also maintains adhesion during interphase, and its inhibition is a prerequisite for the tightly choreographed changes in cell shape and adhesiveness that are required for successful completion of mitosis. Using a combination of biochemical, structural and cell biological approaches, we demonstrate a direct interaction between talin and CDK1 that occurs at sites of integrin-mediated adhesion. Mutagenesis demonstrated that CDK1 contains a functional talin-binding LD motif, and the binding site within talin was pinpointed to helical bundle R8 through the use of recombinant fragments. Talin also contains a consensus CDK1 phosphorylation motif centred on S1589; a site that was phosphorylated by CDK1in vitro. A phosphomimetic mutant of this site within talin lowered the binding affinity of KANK and weakened the mechanical response of the region, potentially altering downstream mechanotransduction pathways. The direct binding of the master cell cycle regulator, CDK1, to the primary integrin effector, talin, therefore provides a primordial solution for coupling the cell proliferation and cell adhesion machineries, and thereby enables microenvironmental control of cell division in multicellular organisms.SummaryThe direct binding of the master cell cycle regulator, CDK1, to the primary integrin effector, talin, provides a primordial solution for coupling the cell proliferation and cell adhesion machineries, and thereby enables microenvironmental control of cell division.

HDAC1 overexpression enhances β-cell proliferation by down-regulating Cdkn1b/p27

2018 ◽  
Vol 475 (24) ◽  
pp. 3997-4010 ◽  
Author(s):  
Carrie Draney ◽  
Matthew C. Austin ◽  
Aaron H. Leifer ◽  
Courtney J. Smith ◽  
Kyle B. Kener ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Survival ◽  
Cell Mass ◽  
Cyclin B1 ◽  
Β Cell ◽  
Histone Deacetylase 1 ◽  
Cell Cycle Inhibitor ◽  
Homeobox Transcription Factor ◽  
Glucose Stimulated Insulin Secretion

The homeobox transcription factor Nkx6.1 is sufficient to increase functional β-cell mass, where functional β-cell mass refers to the combination of β-cell proliferation, glucose-stimulated insulin secretion (GSIS) and β-cell survival. Here, we demonstrate that the histone deacetylase 1 (HDAC1), which is an early target of Nkx6.1, is sufficient to increase functional β-cell mass. We show that HDAC activity is necessary for Nkx6.1-mediated proliferation, and that HDAC1 is sufficient to increase β-cell proliferation in primary rat islets and the INS-1 832/13 β-cell line. The increase in HDAC1-mediated proliferation occurs while maintaining GSIS and increasing β-cell survival in response to apoptotic stimuli. We demonstrate that HDAC1 overexpression results in decreased expression of the cell cycle inhibitor Cdkn1b/p27 which is essential for inhibiting the G1 to S phase transition of the cell cycle. This corresponds with increased expression of key cell cycle activators, such as Cyclin A2, Cyclin B1 and E2F1, which are activated by activation of the Cdk4/Cdk6/Cyclin D holoenzymes due to down-regulation of Cdkn1b/p27. Finally, we demonstrate that overexpression of Cdkn1b/p27 inhibits HDAC1-mediated β-cell proliferation. Our data suggest that HDAC1 is critical for the Nkx6.1-mediated pathway that enhances functional β-cell mass.

Abnormalities in Cell Cycle Control in Cancer and Their Clinical Implications

1998 ◽  
Vol 84 (4) ◽  
pp. 421-433 ◽  
Author(s):  
Alessandro Sgambato ◽  
Giovanna Flamini ◽  
Achille Cittadini ◽  
I. Bernard Weinstein
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Transformation ◽  
Cell Cycle Control ◽  
Genomic Stability ◽  
Clinical Implications ◽  
Mammalian Cell Cycle ◽  
Carcinogenic Process ◽  
Review Current

Recent studies indicate that the functions of several genes that control the cell cycle are altered during the carcinogenic process and that these changes perturb both cell proliferation and genomic stability, thus promoting cell transformation and enhancing the process of tumor progression. The purpose of this paper is to review current information on the role of cyclins and related genes in the control of the mammalian cell cycle, the types of abnormalities in these genes found in human tumors and the possible clinical implications of these findings.

scholarly journals Cell Cycle Control of Schwann Cell Proliferation: Role of Cyclin-Dependent Kinase-2

2000 ◽  
Vol 20 (12) ◽  
pp. 4627-4634 ◽  
Author(s):  
Ravi Tikoo ◽  
George Zanazzi ◽  
Dov Shiffman ◽  
James Salzer ◽  
Moses V. Chao
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Schwann Cell ◽  
Cell Cycle Control ◽  
Cyclin Dependent Kinase

scholarly journals DIPG-42. THE COMBINATION OF THE CDK4/6 INHIBITOR PALBOCICLIB WITH THE RAPALOGUE TEMSIROLIMUS INHIBITS DIPG CELL PROLIFERATION VIA SYNERGISTIC ATTENUATION OF CELL CYCLE REGULATORS

2017 ◽  
Vol 19 (suppl_4) ◽  
pp. iv14-iv14 ◽  
Author(s):  
DJ Asby ◽  
AS Bienemann ◽  
LJ Wright ◽  
C Killick-Cole ◽  
WGB Singleton ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Regulators

Platelet Factor 4 (PF4) Causes Cell Cycle Arrest in Megakaryocytes (Megs) by Inactivating CDC2 (CDK1) and CDK2

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1238-1238
Author(s):  
Liqing Xiao ◽  
Mortimer Poncz ◽  
Michele Lambert
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Platelet Count ◽  
Steady State ◽  
Cell Cycle Arrest ◽  
Cell Line ◽  
Cell Surface Receptor ◽  
Brdu Incorporation ◽  
Cell Cycle Regulators ◽  
Cycle Arrest

Abstract Abstract 1238 PF4 (CXCL4), a platelet specific chemokine released in large amounts from activated platelet α -granules, is a negative regulator of megakaryopoiesis. In mouse studies, we have shown that PF4 levels regulate steady-state platelet count and impact chemotherapy and radiation-induced thrombocytopenia. In a clinical study in leukemia patients, we found that PF4 levels were inversely related to steady-state platelet count and to recovery after chemotherapy. The molecular basis for the effect of PF4 in megakaryopoiesis is largely unknown. Our studies in cell models suggested that PF4 might act through the cell surface receptor low-density lipoprotein related protein-1 (LRP1). Using an early megakaryoblastic cell line, which expresses LRP1, Meg-like cell line (Meg01), we show that PF4 exerts an anti-proliferative effect on the cells through inactivation of cell cycle regulators CDC2 (CDK1) and CDK2. PF4 treatment (200 μg/ml for 48 hrs) of Meg01 cells induced a decrease in cells in G1 (from 68% of cells to 51%, p=0.001) with a concurrent increase in the percentage of cells in S (12% of cells to 21%, p = 0.02 for no PF4 vs. PF4 treatment) and G2 (from 20% to 28% of cells) phase, without significant bromodeoxyuridine (BrdU) incorporation by the cells in the S phase, suggesting that PF4 causes a cell cycle arrest resulting in decreased cell proliferation. The cell cycle arrest and lack of BrDU incorporation was confirmed in primary murine Megs. No apoptosis was detected in PF4 treated Meg01 or primary cells. To determine the molecular mechanisms by which PF4 causes cell cycle arrest, we used Western blots interrogating cell cycle proteins. We detected a transient increase in the inhibitory phosphorylation (at Tyr15) of CDC2 after PF4 treatment, as well as a decrease in phosphorylation of the activating site (Thr160) on CDK2. In addition, we found PF4 treatment resulted in the degradation of Cdc25c, the upstream phosphatase of Tyr15 of CDC2. In primary murine Megs, we detected a significant decrease of total CDC2, biologically equivalent to the CDC2 inactivation seen in Meg01 cells. The CDK inhibitor Roscovitine inhibited Meg01 cell proliferation and had minimum additive effect with PF4. Overexpression of the constitutively active CDC2 mutant CDC2AF with the inhibitory phosphorylation sites Thr14 and Tyr15 replaced by Ala and Phe, respectively, desensitized the cells to PF4 treatment. These results suggested that PF4 inhibits megakaryopoiesis by decreasing the proliferation of megakaryocytes in their early developmental stage by inactivating cell cycle regulators CDC2 and CDK2. Unraveling the mechanisms by which PF4 inhibits megakaryopoiesis may lead to the development of novel therapeutics to regulate platelet counts. Disclosures: No relevant conflicts of interest to declare.

Interaction between the p53 genotype of lung cancer and response to mTOR inhibitor combined with irradiation therapy

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22028-e22028
Author(s):  
Y. Nagata ◽  
T. Tojo ◽  
K. Ohnishi ◽  
A. Takahashi ◽  
T. Ohnishi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Survival ◽  
Cell Cycle Arrest ◽  
Mtor Inhibitor ◽  
P53 Gene ◽  
S Phase ◽  
Cycle Arrest ◽  
Irradiation Therapy

e22028 Background: Frequent activation of the PI3K/Akt/mTOR pathway and aberrations of tumor suppressor gene p53 are associated with therapeutic resistance in lung cancer. Nevertheless, the possibility of the variants of p53 genotype to affect response to mTOR inhibitor combined with irradiation therapy remains still unclear. Methods: Human non-small lung cancer cell line H1299 with p53 null genotype, was transfected with wild type or mutated p53 gene (H1299/wtp53 (WT), H1299/mp53 (MT)). Both cell survival and cell proliferation were estimated by colony formation assay to assess differences between WT and MT in sensitivity to rapamycin and ability of rapamycin to enhance radiation sensitivity. Cells were treated according to the individual study; DMSO (control), rapamycin (100 nM for 1 hour), irradiation (IR) (increasing doses), combination (RR) (rapamycin followed by irradiation). Changes in the cell cycle were also analyzed by flow cytometry. Results: Rapamycin decreased cell survival only in WT (P < 0.01, vs. control). MT was resistant to rapamycin exhibiting slightly inhibited cell proliferation. Compared with IR, RR with no less than 6 Gy radiation enhanced inhibitory effects on both cell survival and proliferation independent of p53 genotype (P < 0.01 in WT and P < 0.01 in MT, respectively), that indicating additive interaction. Cell cycle analysis demonstrated rapamycin induced G1 cell cycle arrest in both types of cells compared with controls (P < 0.01 in WT and P < 0.05 in MT, respectively) at 24 hours after treatment. Enhancement of G1 arrest by RR was observed in both WT (P < 0.01, vs. IR) and MT (P < 0.01, vs. IR) at the same time point. In addition, RR caused a greater reduction of cells in S phase than that of IR regardless of p53 gene status (P < 0.01 in WT and P < 0.01 in MT, respectively). Conclusions: Rapamycin is an effective radiosensitizer in a p53 independent manner, in which increased G1 cell cycle arrest and decrease in S phase cells are responsible for increased growth inhibitory effect. It will enable us to provide more appropriate treatment to patients with mutated p53 gene. No significant financial relationships to disclose.

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