scholarly journals P21 and Retinoblastoma Protein Control the Absence of DNA Replication in Terminally Differentiated Muscle Cells

2000 ◽  
Vol 149 (2) ◽  
pp. 281-292 ◽  
Author(s):  
Asoke Mal ◽  
Debasis Chattopadhyay ◽  
Mrinal K. Ghosh ◽  
Randy Y.C. Poon ◽  
Tony Hunter ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Retinoblastoma Protein ◽  
Muscle Cells ◽  
Cyclin Dependent Kinase ◽  
Adenovirus E1a ◽  
Protein Levels ◽  
Quiescent Cells ◽  
Cdk2 Activity ◽  
Multinucleated Myotubes

During differentiation, skeletal muscle cells withdraw from the cell cycle and fuse into multinucleated myotubes. Unlike quiescent cells, however, these cells cannot be induced to reenter S phase by means of growth factor stimulation. The studies reported here document that both the retinoblastoma protein (Rb) and the cyclin-dependent kinase (cdk) inhibitor p21 contribute to this unresponsiveness. We show that the inactivation of Rb and p21 through the binding of the adenovirus E1A protein leads to the induction of DNA replication in differentiated muscle cells. Moreover, inactivation of p21 by E1A results in the restoration of cyclin E–cdk2 activity, a kinase made nonfunctional by the binding of p21 and whose protein levels in differentiated muscle cells is relatively low in amount. We also show that restoration of kinase activity leads to the phosphorylation of Rb but that this in itself is not sufficient for allowing differentiated muscle cells to reenter the cell cycle. All the results obtained are consistent with the fact that Rb is functioning downstream of p21 and that the activities of these two proteins may be linked in sustaining the postmitotic state.

scholarly journals The Cyclin-dependent Kinase Cdk2 Regulates Thymocyte Apoptosis

1999 ◽  
Vol 189 (6) ◽  
pp. 957-968 ◽  
Author(s):  
Anne Hakem ◽  
Takehiko Sasaki ◽  
Ivona Kozieradzki ◽  
Josef M. Penninger
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Retinoblastoma Protein ◽  
Cyclin Dependent Kinase ◽  
Tumor Suppressor P53 ◽  
Caspase Activation ◽  
Mitochondrial Permeability ◽  
Protein Inhibition ◽  
Cdk2 Activity ◽  
Thymocyte Apoptosis

Aberrant activation of cell cycle molecules has been postulated to play a role in apoptosis (“catastrophic cell cycle”). Here we show that in noncycling developing thymocytes, the cyclin- dependent kinase Cdk2 is activated in response to all specific and nonspecific apoptotic stimuli tested, including peptide-specific thymocyte apoptosis. Cdk2 was found to function upstream of the tumor suppressor p53, transactivation of the death promoter Bax, alterations of mitochondrial permeability, Bcl-2, caspase activation, and caspase-dependent proteolytic cleavage of the retinoblastoma protein. Inhibition of Cdk2 completely protected thymocytes from apoptosis, mitochondrial changes, and caspase activation. These data provide the first evidence that Cdk2 activity is crucial for the induction of thymocyte apoptosis.

scholarly journals Cell cycle function of a Medicago sativa A2-type cyclin interacting with a PSTAIRE-type cyclin-dependent kinase and a retinoblastoma protein

2000 ◽  
Vol 23 (1) ◽  
pp. 73-83 ◽  
Author(s):  
Francois Roudier ◽  
Elena Fedorova ◽  
Janos Gyorgyey ◽  
Attila Feher ◽  
Spencer Brown ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Medicago Sativa ◽  
Retinoblastoma Protein ◽  
Cyclin Dependent Kinase

scholarly journals Novel localization and possible functions of cyclin E in early sea urchin development

2002 ◽  
Vol 115 (1) ◽  
pp. 113-121 ◽  
Author(s):  
Bradley J. Schnackenberg ◽  
William F. Marzluff
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Sea Urchin ◽  
Kinase Activity ◽  
Cyclin E ◽  
Sperm Head ◽  
Mitotic Spindles ◽  
Paternal Genome ◽  
Cell Cycles ◽  
Cdk2 Activity

In somatic cells, cyclin E-cdk2 activity oscillates during the cell cycle and is required for the regulation of the G1/S transition. Cyclin E and its associated kinase activity remain constant throughout early sea urchin embryogenesis, consistent with reports from studies using several other embryonic systems. Here we have expanded these studies and show that cyclin E rapidly and selectively enters the sperm head after fertilization and remains concentrated in the male pronucleus until pronuclear fusion, at which time it disperses throughout the zygotic nucleus. We also show that cyclin E is not concentrated at the centrosomes but is associated with condensed chromosomes throughout mitosis for at least the first four cell cycles. Isolated mitotic spindles are enriched for cyclin E and cdk2, which are localized to the chromosomes. The chromosomal cyclin E is associated with active kinase during mitosis. We propose that cyclin E may play a role in the remodeling of the sperm head and re-licensing of the paternal genome after fertilization. Furthermore, cyclin E does not need to be degraded or dissociated from the chromosomes during mitosis; instead, it may be required on chromosomes during mitosis to immediately initiate the next round of DNA replication.

scholarly journals Cyclin E1 and cyclin-dependent kinase 2 are critical for initiation, but not for progression of hepatocellular carcinoma

2018 ◽  
Vol 115 (37) ◽  
pp. 9282-9287 ◽  
Author(s):  
Roland Sonntag ◽  
Nives Giebeler ◽  
Yulia A. Nevzorova ◽  
Jörg-Martin Bangen ◽  
Dirk Fahrenkamp ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Gene Signature ◽  
Cyclin Dependent Kinase ◽  
Regulatory Subunits ◽  
Cyclin E1 ◽  
Quiescent Cells ◽  
Similar Expression Profile ◽  
Regulation Of Cell Cycle

E-type cyclins E1 (CcnE1) and E2 (CcnE2) are regulatory subunits of cyclin-dependent kinase 2 (Cdk2) and thought to control the transition of quiescent cells into the cell cycle. Initial findings indicated that CcnE1 and CcnE2 have largely overlapping functions for cancer development in several tumor entities including hepatocellular carcinoma (HCC). In the present study, we dissected the differential contributions of CcnE1, CcnE2, and Cdk2 for initiation and progression of HCC in mice and patients. To this end, we tested the HCC susceptibility in mice with constitutive deficiency for CcnE1 or CcnE2 as well as in mice lacking Cdk2 in hepatocytes. Genetic inactivation of CcnE1 largely prevented development of liver cancer in mice in two established HCC models, while ablation of CcnE2 had no effect on hepatocarcinogenesis. Importantly, CcnE1-driven HCC initiation was dependent on Cdk2. However, isolated primary hepatoma cells typically acquired independence on CcnE1 and Cdk2 with increasing progression in vitro, which was associated with a gene signature involving secondary induction of CcnE2 and up-regulation of cell cycle and DNA repair pathways. Importantly, a similar expression profile was also found in HCC patients with elevated CcnE2 expression and poor survival. In general, overall survival in HCC patients was synergistically affected by expression of CcnE1 and CcnE2, but not through Cdk2. Our study suggests that HCC initiation specifically depends on CcnE1 and Cdk2, while HCC progression requires expression of any E-cyclin, but no Cdk2.

scholarly journals The proteasome controls ESCRT-III–mediated cell division in an archaeon

Science ◽  
2020 ◽  
Vol 369 (6504) ◽  
pp. eaaz2532 ◽  
Author(s):  
Gabriel Tarrason Risa ◽  
Fredrik Hurtig ◽  
Sian Bray ◽  
Anne E. Hafner ◽  
Lena Harker-Kirschneck ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Dna Replication ◽  
Division Ring ◽  
Cell Cycle Control ◽  
Sulfolobus Acidocaldarius ◽  
Cyclin Dependent Kinase ◽  
Membrane Remodeling

Sulfolobus acidocaldarius is the closest experimentally tractable archaeal relative of eukaryotes and, despite lacking obvious cyclin-dependent kinase and cyclin homologs, has an ordered eukaryote-like cell cycle with distinct phases of DNA replication and division. Here, in exploring the mechanism of cell division in S. acidocaldarius, we identify a role for the archaeal proteasome in regulating the transition from the end of one cell cycle to the beginning of the next. Further, we identify the archaeal ESCRT-III homolog, CdvB, as a key target of the proteasome and show that its degradation triggers division by allowing constriction of the CdvB1:CdvB2 ESCRT-III division ring. These findings offer a minimal mechanism for ESCRT-III–mediated membrane remodeling and point to a conserved role for the proteasome in eukaryotic and archaeal cell cycle control.

scholarly journals Both estrogen and raloxifene cause G1 arrest of vascular smooth muscle cells

2003 ◽  
Vol 178 (2) ◽  
pp. 319-329 ◽  
Author(s):  
K Takahashi ◽  
M Ohmichi ◽  
M Yoshida ◽  
K Hisamoto ◽  
S Mabuchi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Cyclin D1 ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
G1 Arrest ◽  
Cyclin Dependent Kinase ◽  
Inhibitory Effects

The proliferation of vascular smooth muscle cells (VSMC) is a crucial pathophysiological process in the development of atherosclerosis. Although estrogen is known to inhibit the proliferation of VSMC, the mechanism responsible for this effect remains to be elucidated. In addition, the effect of raloxifene on VSMC remains unknown. We have shown here that 17beta-estradiol (E(2)) and raloxifene significantly inhibited the platelet-derived growth factor (PDGF)-stimulated proliferation of cultured human VSMC. Flow cytometry demonstrated that PDGF-stimulated S-phase progression of the cell cycle in VSMC was also suppressed by E(2) or raloxifene. We found that PDGF-induced phosphorylation of retinoblastoma protein (pRb), whose hyperphosphorylation is a hallmark of the G1-S transition in the cell cycle, was significantly inhibited by E(2) and raloxifene. These effects were associated with a decrease in cyclin D1 expression, without a change in cyclin-dependent kinase 4 or cyclin-dependent kinase inhibitor, p27(kip1) expression. ICI 182,780 abolished the inhibitory effects of E(2) and raloxifene on PDGF-induced pRb phosphorylation. Next, we examined which estrogen receptor (ER) is necessary for these effects of E(2) and raloxifene. Since VSMC express both ERalpha and ERbeta, A10, a rat aortic smooth muscle cell line that expresses ERbeta but not ERalpha, was used. The dose-dependent stimulation of A10 cell proliferation by PDGF was not inhibited by E(2) or raloxifene in contrast to the results obtained in VSMC. Moreover, E(2) and raloxifene significantly inhibited the PDGF-induced cyclin D1 promoter activity in A10 cells transfected with cDNA for ERalpha but not in the parental cells. These results suggested that E(2) and raloxifene exert an antiproliferative effect in VSMC treated with PDGF, at least in part through inhibition of pRb phosphorylation, and that the inhibitory effects of E(2) and raloxifene may be mainly mediated by ERalpha.

scholarly journals The accumulation of an E2F-p130 transcriptional repressor distinguishes a G0 cell state from a G1 cell state.

1996 ◽  
Vol 16 (12) ◽  
pp. 6965-6976 ◽  
Author(s):  
E J Smith ◽  
G Leone ◽  
J DeGregori ◽  
L Jakoi ◽  
J R Nevins
Keyword(s):  
Cell Cycle ◽  
Target Genes ◽  
Kinase Activity ◽  
Transcriptional Repressor ◽  
Negative Control ◽  
Cyclin Dependent Kinase ◽  
Cell State ◽  
Quiescent Cells ◽  
Cycle Dependent ◽  
E2f Proteins

Previous studies have demonstrated cell cycle-dependent specificities in the interactions of E2F proteins with Rb family members. We now show that the formation of an E2F-p130 complex is unique to cells in a quiescent, G0 state. The E2F-p130 complex does not reform when cells reenter a proliferative state and cycle through G1. The presence of an E2F-p130 complex in quiescent cells coincides with the E2F-mediated repression of transcription of the E2F1 gene, and we show that the E2F sites in the E2F1 promoter are important as cells enter quiescence but play no apparent role in cycling cells. In addition, the decay of the E2F-p130 complex as cells reenter the cell cycle requires the action of G1 cyclin-dependent kinase activity. We conclude that the accumulation of the E2F-p130 complex in quiescent cells provides a negative control of certain key target genes and defines a functional distinction between these G0 cells and cells that exist transiently in G1.

scholarly journals CDK2 activity determines the timing of cell-cycle commitment and sequential DNA replication

2020 ◽  
Author(s):  
Sungsoo Kim ◽  
Alessandra Leong ◽  
Chellam Nayar ◽  
Minah Kim ◽  
Hee Won Yang
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Mammalian Cells ◽  
Genome Stability ◽  
Threshold Level ◽  
Cyclin Dependent Kinases ◽  
Safety Mechanism ◽  
Cdk2 Activity ◽  
Tightly Coupled ◽  
Rb Phosphorylation

AbstractTo enter the cell cycle, mammalian cells must cross a point of no return (the commitment point), after which they proceed through the cell cycle regardless of changes in external signaling. This process is tightly regulated by the cyclin-dependent kinases (CDKs) and downstream molecules such as retinoblastoma (Rb). Here we show that CDK2 activity coordinates the timing of cell-cycle commitment and DNA replication. CDK4/6 activation initiates Rb phosphorylation and E2F activity, causing a gradual increase in CDK2 activity. Once CDK2 activity reaches a threshold level, CDK2 triggers the commitment point by maintaining Rb phosphorylation and subsequently initiates DNA replication. While the timing of the commitment point is tightly coupled with DNA replication, our experiments, which acutely increased CDK2 activity, suggest that the timing of the commitment point is before DNA replication. These findings highlight how cells utilize a safety mechanism to maintain genome stability by protecting against incomplete DNA replication.

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