scholarly journals Cytoskeletal integrity is required throughout the mitogen stimulation phase of the cell cycle and mediates the anchorage-dependent expression of cyclin D1.

1996 ◽  
Vol 7 (1) ◽  
pp. 101-111 ◽  
Author(s):  
R M Böhmer ◽  
E Scharf ◽  
R K Assoian
Keyword(s):  
Cell Cycle ◽  
Cell Adhesion ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Human Fibroblasts ◽  
Cytochalasin D ◽  
Phase Cell ◽  
Dependent Part ◽  
Molecular Events ◽  
Normal Human

The proliferation of many nontransformed cells depends on cell adhesion. We report here that disrupting the cytoskeleton in normal human fibroblasts causes the same cell cycle phenotype that is observed after blocking cell adhesion: suspended cells and cytochalasin D-treated monolayers fail to progress through G1 despite normal mitogen-induced expression of c-myc mRNA. Midway between G0 and the beginning of S-phase, cell cycle progression becomes independent of adhesion and the cytoskeleton. At this stage, the cells are also mitogen independent. Molecular analyses showed that Rb hyperphosphorylation and the induction of cyclin D1 occur slightly earlier than the transition to cytoskeleton independence. Moreover, these molecular events are blocked by cytochalasin D. Overall, our data indicate the following: 1) anchorage and cytoskeletal integrity are required throughout the mitogen-dependent part of G1; 2) mitogens and the cytoskeleton jointly regulate the phosphorylation of Rb; and 3) this interdependence is manifest in the regulation of cyclin D1.

scholarly journals Cell cycle progression after cleavage failure

2004 ◽  
Vol 165 (5) ◽  
pp. 609-615 ◽  
Author(s):  
Yumi Uetake ◽  
Greenfield Sluder
Keyword(s):  
Cell Cycle ◽  
Cell Line ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Human Fibroblasts ◽  
Human Cell Line ◽  
Cycle Progression ◽  
Binucleate Cells ◽  
Normal Human ◽  
Cleavage Failure

Failure of cells to cleave at the end of mitosis is dangerous to the organism because it immediately produces tetraploidy and centrosome amplification, which is thought to produce genetic imbalances. Using normal human and rat cells, we reexamined the basis for the attractive and increasingly accepted proposal that normal mammalian cells have a “tetraploidy checkpoint” that arrests binucleate cells in G1, thereby preventing their propagation. Using 10 μM cytochalasin to block cleavage, we confirm that most binucleate cells arrest in G1. However, when we use lower concentrations of cytochalasin, we find that binucleate cells undergo DNA synthesis and later proceed through mitosis in >80% of the cases for the hTERT-RPE1 human cell line, primary human fibroblasts, and the REF52 cell line. These observations provide a functional demonstration that the tetraploidy checkpoint does not exist in normal mammalian somatic cells.

scholarly journals The RASSF1A Tumor Suppressor Restrains Anaphase-Promoting Complex/Cyclosome Activity during the G1/S Phase Transition To Promote Cell Cycle Progression in Human Epithelial Cells

2008 ◽  
Vol 28 (10) ◽  
pp. 3190-3197 ◽  
Author(s):  
Angelique W. Whitehurst ◽  
Rosalyn Ram ◽  
Latha Shivakumar ◽  
Boning Gao ◽  
John D. Minna ◽  
...  
Keyword(s):  
Phase Transition ◽  
Cell Cycle ◽  
Tumor Suppressor ◽  
Epithelial Cells ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Phase Cell ◽  
Anaphase Promoting Complex ◽  
Cycle Progression

ABSTRACT Multiple molecular lesions in human cancers directly collaborate to deregulate proliferation and suppress apoptosis to promote tumorigenesis. The candidate tumor suppressor RASSF1A is commonly inactivated in a broad spectrum of human tumors and has been implicated as a pivotal gatekeeper of cell cycle progression. However, a mechanistic account of the role of RASSF1A gene inactivation in tumor initiation is lacking. Here we have employed loss-of-function analysis in human epithelial cells for a detailed investigation of the contribution of RASSF1 to cell cycle progression. We found that RASSF1A has dual opposing regulatory connections to G1/S phase cell cycle transit. RASSF1A associates with the Ewing sarcoma breakpoint protein, EWS, to limit accumulation of cyclin D1 and restrict exit from G1. Surprisingly, we found that RASSF1A is also required to restrict SCFβTrCP activity to allow G/S phase transition. This restriction is required for accumulation of the anaphase-promoting complex/cyclosome (APC/C) inhibitor Emi1 and the concomitant block of APC/C-dependent cyclin A turnover. The consequence of this relationship is inhibition of cell cycle progression in normal epithelial cells upon RASSF1A depletion despite elevated cyclin D1 concentrations. Progression to tumorigenicity upon RASSF1A gene inactivation should therefore require collaborating genetic aberrations that bypass the consequences of impaired APC/C regulation at the G1/S phase cell cycle transition.

scholarly journals Role of the F-Box Protein Skp2 in Adhesion-Dependent Cell Cycle Progression

2001 ◽  
Vol 153 (7) ◽  
pp. 1381-1390 ◽  
Author(s):  
Andrea C. Carrano ◽  
Michele Pagano
Keyword(s):  
Cell Cycle ◽  
Cell Adhesion ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Ectopic Expression ◽  
Suspension Cells ◽  
Cycle Progression ◽  
G1 Cells ◽  
F Box Protein

Cell adhesion to the extracellular matrix (ECM) is a requirement for proliferation that is typically lost in malignant cells. In the absence of adhesion, nontransformed cells arrest in G1 with increased levels of the cyclin-dependent kinase inhibitor p27. We have reported previously that the degradation of p27 requires its phosphorylation on Thr-187 and is mediated by Skp2, an F-box protein that associates with Skp1, Cul1, and Roc1/Rbx1 to form the SCFSkp2 ubiquitin ligase complex. Here, we show that the accumulation of Skp2 protein is dependent on both cell adhesion and growth factors but that the induction of Skp2 mRNA is exclusively dependent on cell adhesion to the ECM. Conversely, the expression of the other three subunits of the SCFSkp2 complex is independent of cell anchorage. Phosphorylation of p27 on Thr-187 is also not affected significantly by the loss of cell adhesion, demonstrating that increased p27 stability is not dependent on p27 dephosphorylation. Significantly, ectopic expression of Skp2 in nonadherent G1 cells resulted in p27 downregulation, entry into S phase, and cell division. The ability to induce adhesion-independent cell cycle progression was potentiated by coexpressing Skp2 with cyclin D1 but not with cyclin E, indicating that Skp2 and cyclin D1 cooperate to rescue proliferation in suspension cells. Our study shows that Skp2 is a key target of ECM signaling that controls cell proliferation.

scholarly journals Transcriptional Activation of Cyclin D1 Promoter by FAK Contributes to Cell Cycle Progression

2001 ◽  
Vol 12 (12) ◽  
pp. 4066-4077 ◽  
Author(s):  
Jihe Zhao ◽  
Richard Pestell ◽  
Jun-Lin Guan
Keyword(s):  
Cell Cycle ◽  
Cell Adhesion ◽  
Cyclin D1 ◽  
Signaling Pathways ◽  
Transcriptional Activation ◽  
Cell Cycle Progression ◽  
Dominant Negative ◽  
Transcriptional Level ◽  
Cycle Progression ◽  
Regulation Of Cell Cycle

Integrin-mediated cell adhesion to the extracellular matrix is required for normal cell growth. Cyclin D1 is a key regulator of G1-to-S phase progression of the cell cycle. Our previous studies have demonstrated that integrin signaling through focal adhesion kinase (FAK) plays a role in the regulation of cell cycle progression, which correlates with changes in the expression of cyclin D1 and the cdk inhibitor, p21, induced by FAK. In this report, we first investigated the roles of both cyclin D1 and p21 in the regulation of cell cycle progression by FAK. We found that overexpression of a dominant-negative FAK mutant ΔC14 suppressed cell cycle progression in p21−/− cells as effectively as in the control p21+/+ cells. Furthermore, we found that overexpression of ectopic cyclin D1 could rescue cell cycle inhibition by ΔC14. These results suggested that cyclin D1, but not p21, was the primary functional target of FAK signaling pathways in cell cycle regulation. We then investigated the mechanisms underlying the regulation of cyclin D1 expression by FAK signaling. Using Northern blotting and cyclin D1 promoter/luciferase assays, we showed that FAK signaling regulated cyclin D1 expression at the transcriptional level. Using a series of cyclin D1 promoter mutants in luciferase assays as well as electrophoretic mobility shift assays (EMSA), we showed that the EtsB binding site mediated cyclin D1 promoter regulation by FAK. Finally, we showed that FAK regulation of cyclin D1 depends on integrin-mediated cell adhesion and is likely through its activation of the Erk signaling pathway. Together, these studies demonstrate that transcriptional regulation of cyclin D1 by FAK signaling pathways contributes to the regulation of cell cycle progression in cell adhesion.

scholarly journals The RASSF1A Tumor Suppressor Blocks Cell Cycle Progression and Inhibits Cyclin D1 Accumulation

2002 ◽  
Vol 22 (12) ◽  
pp. 4309-4318 ◽  
Author(s):  
Latha Shivakumar ◽  
John Minna ◽  
Toshiyuki Sakamaki ◽  
Richard Pestell ◽  
Michael A. White
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cyclin D1 ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Phase Cell ◽  
Cycle Progression ◽  
Cycle Arrest

ABSTRACT The RASSF1A locus at 3p21.3 is epigenetically inactivated at high frequency in a variety of solid tumors. Expression of RASSF1A is sufficient to revert the tumorigenicity of human cancer cell lines. We show here that RASSF1A can induce cell cycle arrest by engaging the Rb family cell cycle checkpoint. RASSF1A inhibits accumulation of native cyclin D1, and the RASSF1A-induced cell cycle arrest can be relieved by ectopic expression of cyclin D1 or of other downstream activators of the G1/S-phase transition (cyclin A and E7). Regulation of cyclin D1 is responsive to native RASSF1A activity, because RNA interference-mediated downregulation of endogenous RASSF1A expression in human epithelial cells results in abnormal accumulation of cyclin D1 protein. Inhibition of cyclin D1 by RASSF1A occurs posttranscriptionally and is likely at the level of translational control. Rare alleles of RASSF1A, isolated from tumor cell lines, encode proteins that fail to block cyclin D1 accumulation and cell cycle progression. These results strongly suggest that RASSF1A is an important human tumor suppressor protein acting at the level of G1/S-phase cell cycle progression.

scholarly journals PARP14 regulates cyclin D1 expression to promote cell-cycle progression

Oncogene ◽  
2021 ◽  
Author(s):  
Michael J. O’Connor ◽  
Tanay Thakar ◽  
Claudia M. Nicolae ◽  
George-Lucian Moldovan
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Promote Cell Cycle Progression

scholarly journals A DNA-Damage-Induced Cell Cycle Checkpoint in Arabidopsis

Genetics ◽  
2003 ◽  
Vol 164 (1) ◽  
pp. 323-334
Author(s):  
S B Preuss ◽  
A B Britt
Keyword(s):  
Cell Cycle ◽  
Gamma Radiation ◽  
Cell Cycle Progression ◽  
Cell Cycle Checkpoint ◽  
Phase Cell ◽  
Cycle Arrest ◽  
Cycle Checkpoint ◽  
Radiation Induced ◽  
High Doses ◽  
Regulation Of Cell Cycle

Abstract Although it is well established that plant seeds treated with high doses of gamma radiation arrest development as seedlings, the cause of this arrest is unknown. The uvh1 mutant of Arabidopsis is defective in a homolog of the human repair endonuclease XPF, and uvh1 mutants are sensitive to both the toxic effects of UV and the cytostatic effects of gamma radiation. Here we find that gamma irradiation of uvh1 plants specifically triggers a G2-phase cell cycle arrest. Mutants, termed suppressor of gamma (sog), that suppress this radiation-induced arrest and proceed through the cell cycle unimpeded were recovered in the uvh1 background; the resulting irradiated plants are genetically unstable. The sog mutations fall into two complementation groups. They are second-site suppressors of the uvh1 mutant's sensitivity to gamma radiation but do not affect the susceptibility of the plant to UV radiation. In addition to rendering the plants resistant to the growth inhibitory effects of gamma radiation, the sog1 mutation affects the proper development of the pollen tetrad, suggesting that SOG1 might also play a role in the regulation of cell cycle progression during meiosis.

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