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.

Epidermal Growth Factor Induces Cyclin D1 in Human Pancreatic Carcinoma: Evidence for a Cyclin D1–Dependent Cell Cycle Progression

Pancreas ◽  
2001 ◽  
Vol 23 (3) ◽  
pp. 280-287 ◽  
Author(s):  
Bertram Poch ◽  
Frank Gansauge ◽  
Andreas Schwarz ◽  
Thomas Seufferlein ◽  
Thomas Schnelldorfer ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cyclin D1 ◽  
Pancreatic Carcinoma ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Dependent Cell ◽  
Epidermal Growth

scholarly journals Cellular Ras and Cyclin D1 Are Required during Different Cell Cycle Periods in Cycling NIH 3T3 Cells

1999 ◽  
Vol 19 (7) ◽  
pp. 4623-4632 ◽  
Author(s):  
Masahiro Hitomi ◽  
Dennis W. Stacey
Keyword(s):  
Cell Cycle ◽  
Dna Synthesis ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Time Lapse ◽  
S Phase ◽  
3T3 Cells ◽  
Cycle Progression ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

ABSTRACT Novel techniques were used to determine when in the cell cycle of proliferating NIH 3T3 cells cellular Ras and cyclin D1 are required. For comparison, in quiescent cells, all four of the inhibitors of cell cycle progression tested (anti-Ras, anti-cyclin D1, serum removal, and cycloheximide) became ineffective at essentially the same point in G1 phase, approximately 4 h prior to the beginning of DNA synthesis. To extend these studies to cycling cells, a time-lapse approach was used to determine the approximate cell cycle position of individual cells in an asynchronous culture at the time of inhibitor treatment and then to determine the effects of the inhibitor upon recipient cells. With this approach, anti-Ras antibody efficiently inhibited entry into S phase only when introduced into cells prior to the preceding mitosis, several hours before the beginning of S phase. Anti-cyclin D1, on the other hand, was an efficient inhibitor when introduced up until just before the initiation of DNA synthesis. Cycloheximide treatment, like anti-cyclin D1 microinjection, was inhibitory throughout G1 phase (which lasts a total of 4 to 5 h in these cells). Finally, serum removal blocked entry into S phase only during the first hour following mitosis. Kinetic analysis and a novel dual-labeling technique were used to confirm the differences in cell cycle requirements for Ras, cyclin D1, and cycloheximide. These studies demonstrate a fundamental difference in mitogenic signal transduction between quiescent and cycling NIH 3T3 cells and reveal a sequence of signaling events required for cell cycle progression in proliferating NIH 3T3 cells.

scholarly journals Ras links growth factor signaling to the cell cycle machinery via regulation of cyclin D1 and the Cdk inhibitor p27KIP1.

1997 ◽  
Vol 17 (7) ◽  
pp. 3850-3857 ◽  
Author(s):  
H Aktas ◽  
H Cai ◽  
G M Cooper
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Constitutive Expression ◽  
Ras Signaling ◽  
Cdk Inhibitor ◽  
Growth Factor Signaling ◽  
Cycle Progression ◽  
Cell Cycle Machinery

Activation of growth factor receptors by ligand binding initiates a cascade of events leading to cell growth and division. Progression through the cell cycle is controlled by cyclin-dependent protein kinases (Cdks), but the mechanisms that link growth factor signaling to the cell cycle machinery have not been established. We report here that Ras proteins play a key role in integrating mitogenic signals with cell cycle progression through G1. Ras is required for cell cycle progression and activation of both Cdk2 and Cdk4 until approximately 2 h before the G1/S transition, corresponding to the restriction point. Analysis of Cdk-cyclin complexes indicates that Ras signaling is required both for induction of cyclin D1 and for downregulation of the Cdk inhibitor p27KIP1. Constitutive expression of cyclin D1 circumvents the requirement for Ras signaling in cell proliferation, indicating that regulation of cyclin D1 is a critical target of the Ras signaling cascade.

scholarly journals 6-Methylsulfinylhexyl Isothiocyanate Inhibits Cell Cycle Progression in Quiescent Jb6 Cells Stimulated with Epidermal Growth Factor

2021 ◽  
pp. 19-28
Author(s):  
Takashi Hashimoto ◽  
Maki Kobayashi ◽  
Kazuki Kanazawa
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Dna Synthesis ◽  
Cell Cycle Progression ◽  
Nuclear Antigen ◽  
Cycle Progression ◽  
Epidermal Growth ◽  
Jb6 Cells

Objective: The effects of 6-MSITC on cell cycle progression were investigated in quiescent mouse epidermal JB6 cells. Background: 6-Methylsulfinylhexyl isothiocyanate (6-MSITC) derived from wasabi (Wasabia japonica) has been reported to prevent tumor development in vivo. Material and methods: Treatment with epidermal growth factor (EGF) to quiescent JB6 cells, which were serum-starved for 36 h, promoted cell cycle progression from the G0/G1 phase to the S phase. Effects of pretreatment with 6-MSITC on cell cycle progression were estimated by flowcytometry and real-time RT-PCR. Results: Pretreatment with 6-MSITC at 0.25-1.0 μg/ml prior to the growth stimulation with EGF significantly inhibited cell cycle progression. Pretreatment with 6-MSITC inhibited the gene expression of DNA synthesis-related proteins cyclin A2, dumbbell former 4, and proliferating cell nuclear antigen. Conclusion: These results showed that 6-MSITC inhibits cell cycle progression in quiescent cells, accompanied by the inhibition of gene expression of DNA synthesis proteins.

scholarly journals Ethanol, Zn2+ and insulin interact as progression factors to enhance DNA synthesis synergistically in the presence of Ca2+ and other cell cycle initiators in fibroblasts

2000 ◽  
Vol 346 (1) ◽  
pp. 241-247 ◽  
Author(s):  
Jin-Sheng HUANG ◽  
Qing-Bai SHE ◽  
Karan S. CRILLY ◽  
Zoltan KISS
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Dna Synthesis ◽  
Cell Cycle Progression ◽  
Synergistic Effects ◽  
Dependent Manner ◽  
Cycle Progression ◽  
3T3 Fibroblasts ◽  
Igf I ◽  
Nih 3T3

In serum-starved NIH 3T3 fibroblasts, ethanol (30-80 mM) promoted the effects of insulin and insulin-like growth factor I (IGF-I) on DNA synthesis in a Zn2+-dependent manner. Ethanol and Zn2+ were most effective when added shortly before or after insulin, indicating that all these agents facilitated cell cycle progression. The synergistic effects of ethanol, Zn2+ and insulin (or IGF-I) on DNA synthesis required 1.1-2.3 mM Ca2+, which seemed to act as the cell cycle initiator. When serum-starved cells were pretreated for 2 h with other cell cycle initiators such as 10% (v/v) serum, 50 ng/ml platelet-derived growth factor or 2 ng/ml fibroblast growth factor, subsequent co-treatments with 60 mM ethanol, Zn2+ and insulin for an 18 h period again synergistically increased DNA synthesis. Of the various signal transducing events examined, ethanol stimulated cellular uptake of 45Ca and it enhanced the stimulatory effects of insulin on p70 S6 kinase activity in a Zn2+-dependent manner. In contrast, ethanol inhibited insulin-induced activating phosphorylation of p42/p44 mitogen-activated protein kinases; these inhibitory ethanol effects were prevented by Zn2+. The results show that, in NIH 3T3 fibroblasts, ethanol can promote cell cycle progression in the presence of a cell cycle initiator as well as Zn2+ and insulin (or IGF-I).

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.

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.

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