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 NF-κB Function in Growth Control: Regulation of Cyclin D1 Expression and G0/G1-to-S-Phase Transition

1999 ◽  
Vol 19 (4) ◽  
pp. 2690-2698 ◽  
Author(s):  
Michael Hinz ◽  
Daniel Krappmann ◽  
Alexandra Eichten ◽  
Andreas Heder ◽  
Claus Scheidereit ◽  
...  
Keyword(s):  
Phase Transition ◽  
Cell Cycle ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Ectopic Expression ◽  
Tumor Development ◽  
Growth Control ◽  
S Phase ◽  
Checkpoint Control ◽  
Cycle Progression

ABSTRACT Nuclear factor kappa B (NF-κB) has been implicated in the regulation of cell proliferation, transformation, and tumor development. We provide evidence for a direct link between NF-κB activity and cell cycle regulation. NF-κB was found to stimulate transcription of cyclin D1, a key regulator of G1checkpoint control. Two NF-κB binding sites in the human cyclin D1 promoter conferred activation by NF-κB as well as by growth factors. Both levels and kinetics of cyclin D1 expression during G1phase were controlled by NF-κB. Moreover, inhibition of NF-κB caused a pronounced reduction of serum-induced cyclin D1-associated kinase activity and resulted in delayed phosphorylation of the retinoblastoma protein. Furthermore, NF-κB promotes G1-to-S-phase transition in mouse embryonal fibroblasts and in T47D mammary carcinoma cells. Impaired cell cycle progression of T47D cells expressing an NF-κB superrepressor (IκBαΔN) could be rescued by ectopic expression of cyclin D1. Thus, NF-κB contributes to cell cycle progression, and one of its targets might be cyclin D1.

Developmental regulation of a cyclin-dependent kinase inhibitor controls postembryonic cell cycle progression in Caenorhabditis elegans

Development ◽  
1998 ◽  
Vol 125 (18) ◽  
pp. 3585-3597 ◽  
Author(s):  
Y. Hong ◽  
R. Roy ◽  
V. Ambros
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Developmental Regulation ◽  
Ectopic Expression ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Environmental Signals ◽  
C Elegans

C. elegans cki-1 encodes a member of the CIP/KIP family of cyclin-dependent kinase inhibitors, and functions to link postembryonic developmental programs to cell cycle progression. The expression pattern of cki-1::GFP suggests that cki-1 is developmentally regulated in blast cells coincident with G1, and in differentiating cells. Ectopic expression of CKI-1 can prematurely arrest cells in G1, while reducing cki-1 activity by RNA-mediated interference (RNAi) causes extra larval cell divisions, suggesting a role for cki-1 in the developmental control of G1/S. cki-1 activity is required for the suspension of cell cycling that occurs in dauer larvae and starved L1 larvae in response to environmental signals. In vulva precursor cells (VPCs), a pathway of heterochronic genes acts via cki-1 to maintain VPCs in G1 during the L2 stage.

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 Ectopic expression of cyclin D1 but not cyclin E induces anchorage-independent cell cycle progression.

1997 ◽  
Vol 17 (9) ◽  
pp. 5640-5647 ◽  
Author(s):  
D Resnitzky
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Kinase Activity ◽  
Cyclin E ◽  
Ectopic Expression ◽  
S Phase ◽  
G1 Arrest ◽  
Independent Manner ◽  
Cycle Progression

Normal fibroblasts are dependent on adhesion to a substrate for cell cycle progression. Adhesion-deprived Rat1 cells arrest in the G1 phase of the cell cycle, with low cyclin E-dependent kinase activity, low levels of cyclin D1 protein, and high levels of the cyclin-dependent kinase inhibitor p27kip1. To understand the signal transduction pathway underlying adhesion-dependent growth, it is important to know whether prevention of any one of these down-regulation events under conditions of adhesion deprivation is sufficient to prevent the G1 arrest. To that end, sublines of Rat1 fibroblasts capable of expressing cyclin E, cyclin D1, or both in an inducible manner were used. Ectopic expression of cyclin D1 was sufficient to allow cells to enter S phase in an adhesion-independent manner. In contrast, cells expressing exogenous cyclin E at a level high enough to overcome the p27kip1-imposed inhibition of cyclin E-dependent kinase activity still arrested in G1 when deprived of adhesion. Moreover, expression of both cyclins D1 and E in the same cells did not confer any additional growth advantage upon adhesion deprivation compared to the expression of cyclin D1 alone. Exogenously expressed cyclin D1 was down-regulated under conditions of adhesion deprivation, despite the fact that it was expressed from a heterologous promoter. The ability of cyclin D1-induced cells to enter S phase in an adhesion-independent manner disappears as soon as cyclin D1 proteins disappear. These results suggest that adhesion-dependent cell cycle progression is mediated through cyclin D1, at least in Rat1 fibroblasts.

scholarly journals The SPARC-related Factor SMOC-2 Promotes Growth Factor-induced Cyclin D1 Expression and DNA Synthesis via Integrin-linked Kinase

2008 ◽  
Vol 19 (1) ◽  
pp. 248-261 ◽  
Author(s):  
Peijun Liu ◽  
Jining Lu ◽  
Wellington V. Cardoso ◽  
Cyrus Vaziri
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Dna Synthesis ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Ectopic Expression ◽  
Receptor Activation ◽  
Related Factor ◽  
Cycle Progression ◽  
Integrin Linked Kinase

Secreted modular calcium-binding protein-2 (SMOC-2) is a recently-identified SPARC-related protein of unknown function. In mRNA profiling experiments we, found that SMOC-2 expression was elevated in quiescent (G0) mouse fibroblasts and repressed after mitogenic stimulation with serum. The G0-specific expression of SMOC-2 was similar to that of platelet-derived growth factor-β receptor (PDGFβR), a major mitogenic receptor. Therefore, we tested a possible role for SMOC-2 in growth factor-induced cell cycle progression. SMOC-2 overexpression augmented DNA synthesis induced by serum and fibroblast mitogens (including PDGF-BB and basic fibroblast growth factor). Conversely, SMOC-2 ablation by using small interfering RNA attenuated DNA synthesis in response to PDGF-BB and other growth factors. Mitogen-induced expression of cyclin D1 was attenuated in SMOC-2–ablated cells, and cyclin D1-overexpressing cells were resistant to inhibition of mitogenesis after SMOC-2 ablation. Therefore, cyclin D1 is limiting for G1 progression in SMOC-2–deficient cells. SMOC-2 ablation did not inhibit PDGF-induced PDGFβR autophosphorylation or PDGF-BB–dependent activation of mitogen-activated protein kinase and Akt kinases, suggesting that SMOC-2 is dispensable for growth factor receptor activation. However, integrin-linked kinase (ILK) activity was reduced in SMOC-2–ablated cells. Ectopic expression of hyperactive ILK corrected the defective mitogenic response of SMOC-2–deficient cells. Therefore, SMOC-2 contributes to cell cycle progression by maintaining ILK activity during G1. These results identify a novel role for SMOC-2 in cell cycle control.

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

Homing efficiency, cell cycle kinetics, and survival of quiescent and cycling human CD34+ cells transplanted into conditioned NOD/SCID recipients

Blood ◽  
2002 ◽  
Vol 99 (5) ◽  
pp. 1585-1593 ◽  
Author(s):  
Anna Jetmore ◽  
P. Artur Plett ◽  
Xia Tong ◽  
Frances M. Wolber ◽  
Robert Breese ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Hematopoietic Cells ◽  
Cycle Progression ◽  
Hematopoietic Stem ◽  
Human Cd34 ◽  
Nonobese Diabetic ◽  
Cd34 Cells ◽  
G1 Cells ◽  
Active Proliferation

Differences in engraftment potential of hematopoietic stem cells (HSCs) in distinct phases of cell cycle may result from the inability of cycling cells to home to the bone marrow (BM) and may be influenced by the rate of entry of BM-homed HSCs into cell cycle. Alternatively, preferential apoptosis of cycling cells may contribute to their low engraftment potential. This study examined homing, cell cycle progression, and survival of human hematopoietic cells transplanted into nonobese diabetic severe combined immunodeficient (NOD/SCID) recipients. At 40 hours after transplantation (AT), only 1% of CD34+ cells, or their G0(G0CD34+) or G1(G1CD34+) subfractions, was detected in the BM of recipient mice, suggesting that homing of engrafting cells to the BM was not specific. BM of NOD/SCID mice receiving grafts containing approximately 50% CD34+ cells harbored similar numbers of CD34+ and CD34− cells, indicating that CD34+ cells did not preferentially traffic to the BM. Although more than 64% of human hematopoietic cells cycled in culture at 40 hours, more than 92% of cells recovered from NOD/SCID marrow were quiescent. Interestingly, more apoptotic human cells were detected at 40 hours AT in the BM of mice that received xenografts of expanded cells in S/G2+M than in recipients of G0/G1 cells (34.6% ± 5.9% and 17.1% ± 6.3%, respectively; P < .01). These results suggest that active proliferation inhibition in the BM of irradiated recipients maintains mitotic quiescence of transplanted HSCs early AT and may trigger apoptosis of cycling cells. These data also illustrate that trafficking of transplanted cells to the BM is not selective, but lodgment of BM-homed cells may be specific.

scholarly journals Akt/Protein Kinase B-Dependent Phosphorylation and Inactivation of WEE1Hu Promote Cell Cycle Progression at G2/M Transition

2005 ◽  
Vol 25 (13) ◽  
pp. 5725-5737 ◽  
Author(s):  
Kazuhiro Katayama ◽  
Naoya Fujita ◽  
Takashi Tsuruo
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Phosphorylation Site ◽  
Cytoplasmic Localization ◽  
M Cell ◽  
Serine Threonine Kinase ◽  
Cycle Progression ◽  
M Phase ◽  
Promote Cell Cycle Progression

ABSTRACT The serine/threonine kinase Akt is known to promote cell growth by regulating the cell cycle in G1 phase through activation of cyclin/Cdk kinases and inactivation of Cdk inhibitors. However, how the G2/M phase is regulated by Akt remains unclear. Here, we show that Akt counteracts the function of WEE1Hu. Inactivation of Akt by chemotherapeutic drugs or the phosphatidylinositide-3-OH kinase inhibitor LY294002 induced G2/M arrest together with the inhibitory phosphorylation of Cdc2. Because the increased Cdc2 phosphorylation was completely suppressed by wee1hu gene silencing, WEE1Hu was associated with G2/M arrest induced by Akt inactivation. Further analyses revealed that Akt directly bound to and phosphorylated WEE1Hu during the S to G2 phase. Serine-642 was identified as an Akt-dependent phosphorylation site. WEE1Hu kinase activity was not affected by serine-642 phosphorylation. We revealed that serine-642 phosphorylation promoted cytoplasmic localization of WEE1Hu. The nuclear-to-cytoplasmic translocation was mediated by phosphorylation-dependent WEE1Hu binding to 14-3-3θ but not 14-3-3β or -σ. These results indicate that Akt promotes G2/M cell cycle progression by inducing phosphorylation-dependent 14-3-3θ binding and cytoplasmic localization of WEE1Hu.

Sign in / Sign up

Export Citation Format

Share Document