scholarly journals Polyomavirus Large T Antigen Induces Alterations in Cytoplasmic Signalling Pathways Involving Shc Activation

1999 ◽  
Vol 73 (2) ◽  
pp. 1427-1437 ◽  
Author(s):  
Vanesa Gottifredi ◽  
Giuliana Pelicci ◽  
Eliana Munarriz ◽  
Rossella Maione ◽  
Pier Giuseppe Pelicci ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Factors ◽  
Growth Factor ◽  
Cell Cycle Progression ◽  
Susceptibility Gene ◽  
T Antigen ◽  
Adapter Protein ◽  
Large T Antigen ◽  
Cycle Progression ◽  
Kinase Substrate

ABSTRACT It has been extensively demonstrated that growth factors play a key role in the regulation of proliferation. Several lines of evidence support the hypothesis that for the induction of cell cycle progression in the absence of exogenous growth factors, oncogenes must either induce autocrine growth factor secretion or, alternatively, activate their receptors or their receptor substrates. Cells expressing polyomavirus large T antigen (PyLT) display reduced growth factor requirements, but the mechanisms underlying this phenomenon have yet to be explored. We conducted tests to see whether the reduction in growth factor requirements induced by PyLT was related to alterations of growth factor-dependent signals. To this end, we analyzed the phosphorylation status of a universal tyrosine kinase substrate, the transforming Shc adapter protein, in fibroblasts expressing the viral oncogene. We report that the level of Shc phosphorylation does not decrease in PyLT-expressing fibroblasts after growth factor withdrawal and that this PyLT-mediated effect does not require interaction with protein encoded by the retinoblastoma susceptibility gene. We also found that the chronic activation of the adapter protein is correlated with the binding of Shc to Grb-2 and with defects in the downregulation of mitogen-activated protein kinases. In fibroblasts expressing the nuclear oncoprotein, we also observed the formation of a PyLT-Shc complex that might be involved in constitutive phosphorylation of the adapter protein. Viewed comprehensively, these results suggest that the cell cycle progression induced by PyLT may depend not only on the direct inactivation of nuclear antioncogene products but also on the indirect induction, through the alteration of cytoplasmic pathways, of growth factor-dependent nuclear signals.

scholarly journals Dual Stimulation of Ras/Mitogen-Activated Protein Kinase and Rhoa by Cell Adhesion to Fibronectin Supports Growth Factor–Stimulated Cell Cycle Progression

2000 ◽  
Vol 151 (7) ◽  
pp. 1413-1422 ◽  
Author(s):  
Erik H.J. Danen ◽  
Petra Sonneveld ◽  
Arnoud Sonnenberg ◽  
Kenneth M. Yamada
Keyword(s):  
Cell Cycle ◽  
Growth Factors ◽  
Growth Factor ◽  
Protein Kinase ◽  
Cell Cycle Progression ◽  
Mitogen Activated Protein Kinase ◽  
Cycle Progression ◽  
Extracellular Matrix Components ◽  
Mitogen Activated Protein ◽  
Stimulation Of

In cellular transformation, activated forms of the small GTPases Ras and RhoA can cooperate to drive cells through the G1 phase of the cell cycle. Here, we show that a similar but substrate-regulated mechanism is involved in the anchorage-dependent proliferation of untransformed NIH-3T3 cells. Among several extracellular matrix components tested, only fibronectin supported growth factor–induced, E2F-dependent S phase entry. Although all substrates supported the mitogen-activated protein kinase (MAPK) response to growth factors, RhoA activity was specifically enhanced on fibronectin. Moreover, induction of cyclin D1 and suppression of p21Cip/Waf occurred specifically, in a Rho-dependent fashion, in cells attached to fibronectin. This ability of fibronectin to stimulate both Ras/MAPK- and RhoA-dependent signaling can explain its potent cooperation with growth factors in the stimulation of cell cycle progression.

Internal Tandem Duplication of Flt3 (ITD-Flt3) Bypasses Growth Factor Mediated Survivin Expression, while Disruption of Survivin Accelerates Cell Death in Hematopoietic Cells Expressing ITD-Flt3.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1256-1256
Author(s):  
Seiji Fukuda ◽  
Louis M. Pelus
Keyword(s):  
Cell Cycle ◽  
Growth Factors ◽  
Growth Factor ◽  
Cell Survival ◽  
Cell Cycle Progression ◽  
Hematopoietic Cells ◽  
Survivin Expression ◽  
Hematopoietic Growth Factors ◽  
Cycle Progression ◽  
Cd34 Cells

Abstract The inhibitor of apoptosis protein Survivin is barely detectable in normal adult tissues but is over-expressed in almost all cancers and hematopoietic malignancies and confers resistance to apoptosis and aberrant cell proliferation. We have shown that hematopoietic growth factors induce Survivin expression in normal CD34+ cells in both cell cycle dependent and independent fashion and that oncogenic Ras can enhance Survivin expression independent of growth factor stimulation. In addition, over-expression of Survivin blocks apoptosis of hematopoietic progenitor cells through a p21WAF1/Cip1 (p21) dependent mechanism. However the mechanisms responsible for Survivin overexpression in malignant hematopoietic cells is poorly understood. Flt3 is a type III tyrosine kinase receptor expressed mainly in the primitive hematopoietic compartment. Internal tandem duplication (ITD) mutations of the Flt3 gene that activate the Flt3 tyrosine kinase are frequently found in patients with AML and associated with poor prognosis. Furthermore, their ectopic expression in IL-3 dependent Ba/F3 cells results in IL-3-independent proliferation and a myeloproliferative disease in mice. In order to understand the mechanism by which ITD-Flt3 enhances cell survival, we examined whether ITD-Flt3 can bypass Survivin up-regulation independent of hematopoietic growth factors and if Survivin lies down stream of ITD-Flt3 in prolonging cell survival. Incubation of primary umbilical cord blood CD34+ cells with Flt3 ligand induced Survivin expression, indicating that Survivin lies down stream of Flt3 signaling pathways in CD34+ cells. While Survivin expression was comparable in Ba/F3 cells expressing ITD-Flt3 (W51, W73 and W78 mutants, kindly provided by Dr. DG Gilliland) and wild-type Flt3 when maintained in the presence of IL-3, ITD-Flt3 prevented down-modulation of Survivin expression induced by IL-3 withdrawal even during G0/G1 phase of cell cycle, suggesting that up-regulation of Survivin is not a consequence of cell cycle progression associated with ITD-Flt3 expression. The increase in Survivin by ITD-Flt3 was associated with reduced active caspase-3 and prolonged cell survival coincident with induction of p21 expression and Tyrosine 15 phosphorylation of CDK1 (Cdc2), which have been implicated in anti-apoptosis. These results are consistent with a p21 dependent anti-apoptosis effect of Survivin in primary hematopoietic progenitor cells and suggest the involvement of Survivin-p21 and CDK1 in ITD-Flt3 mediated cell survival. Overexpression of dominant negative T34A Survivin inhibits the enhanced survival induced by ITD-Flt3 in Ba/F3 cells following IL-3 withdrawal, suggesting that the survival effect of ITD-Flt3 is mediated by Survivin. Similar to ITD-Flt3, overexpression of ectopic wild-type Survivin results in enhanced cell survival in Ba/F3 cells but failed to induce cell cycle progression and IL-3-independent proliferation, indicating that Survivin alone is not sufficient for induction of growth factor independent proliferation and the cell cycle enhancing effect of ITD-Flt3. In summary, our findings indicate that ITD-Flt3 up-regulates Survivin expression independent of hematopoietic growth factors and that the ITD-Flt3/Survivin axis provides a survival advantage in transformed hematopoietic cells. Disruption of these pathways may increase apoptosis of malignant hematopoietic cells and provide therapeutic benefit.

scholarly journals Phytosulfokine-.ALPHA., a Peptidyl Plant Growth Factor, Stimulates Cell Cycle Progression in Carrot Non-Embryogenic Cells.

2003 ◽  
Vol 20 (3) ◽  
pp. 195-205 ◽  
Author(s):  
Chang-Ho EUN ◽  
Suk-Min KO ◽  
Katsumi HIGASHI ◽  
Dennis YEO ◽  
Yoshikatsu MATSUBAYASHI ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Plant Growth ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Embryogenic Cells

scholarly journals Role of AKT/mTORC1 pathway in pancreatic β-cell proliferation

2012 ◽  
pp. 235-243 ◽  
Author(s):  
Norman Balcazar Morales ◽  
Cecilia Aguilar de Plata
Keyword(s):  
Cell Cycle ◽  
Growth Factors ◽  
Cell Cycle Progression ◽  
Cell Mass ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cycle Progression ◽  
Mtorc1 Signaling

Growth factors, insulin signaling and nutrients are important regulators of β-cell mass and function. The events linking these signals to regulation of β-cell mass are not completely understood. Recent findings indicate that mTOR pathway integrates signals from growth factors and nutrients with transcription, translation, cell size, cytoskeleton remodeling and mitochondrial metabolism. mTOR is a part of two distinct complexes; mTORC1 and mTORC2. The mammalian TORC1 is sensitive to rapamycin and contains Raptor, deptor, PRAS40 and the G protein β-subunit-like protein (GβL). mTORC1 activates key regulators of protein translation; ribosomal S6 kinase (S6K) and eukaryote initiation factor 4E-binding protein 1. This review summarizes current findings about the role of AKT/mTORC1 signaling in regulation of pancreatic β cell mass and proliferation. mTORC1 is a major regulator of β-cell cycle progression by modulation of cyclins D2, D3 and cdk4/cyclin D activity. These studies uncovered key novel pathways controlling cell cycle progression in β-cells in vivo. This information can be used to develop alternative approaches to expand β-cell mass in vivo and in vitro without the risk of oncogenic transformation. The acquisition of such knowledge is critical for the design of improved therapeutic strategies for the treatment and cure of diabetes as well as to understand the effects of mTOR inhibitors in β-cell function.

scholarly journals Regulation of Cell Cycle Progression by Growth Factor-Induced Cell Signaling

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3327
Author(s):  
Zhixiang Wang
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Tyrosine Kinases ◽  
Cell Cycle Progression ◽  
Phase Cell ◽  
Growth Factor Signaling ◽  
Cycle Progression ◽  
M Phase

The cell cycle is the series of events that take place in a cell, which drives it to divide and produce two new daughter cells. The typical cell cycle in eukaryotes is composed of the following phases: G1, S, G2, and M phase. Cell cycle progression is mediated by cyclin-dependent kinases (Cdks) and their regulatory cyclin subunits. However, the driving force of cell cycle progression is growth factor-initiated signaling pathways that control the activity of various Cdk–cyclin complexes. While the mechanism underlying the role of growth factor signaling in G1 phase of cell cycle progression has been largely revealed due to early extensive research, little is known regarding the function and mechanism of growth factor signaling in regulating other phases of the cell cycle, including S, G2, and M phase. In this review, we briefly discuss the process of cell cycle progression through various phases, and we focus on the role of signaling pathways activated by growth factors and their receptor (mostly receptor tyrosine kinases) in regulating cell cycle progression through various phases.

scholarly journals The Activity of Differentiation Factors Induces Apoptosis in Polyomavirus Large T-Expressing Myoblasts

1998 ◽  
Vol 9 (6) ◽  
pp. 1449-1463 ◽  
Author(s):  
Gian Maria Fimia ◽  
Vanesa Gottifredi ◽  
Barbara Bellei ◽  
Maria Rosaria Ricciardi ◽  
Agostino Tafuri ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Growth Factor ◽  
Cell Cycle Progression ◽  
Transforming Growth Factor ◽  
Myogenic Differentiation ◽  
Transforming Growth Factor Β ◽  
Large Tumor ◽  
Cycle Progression

It is commonly accepted that pathways that regulate proliferation/differentiation processes, if altered in their normal interplay, can lead to the induction of programmed cell death. In a previous work we reported that Polyoma virus Large Tumor antigen (PyLT) interferes with in vitro terminal differentiation of skeletal myoblasts by binding and inactivating the retinoblastoma antioncogene product. This inhibition occurs after the activation of some early steps of the myogenic program. In the present work we report that myoblasts expressing wild-type PyLT, when subjected to differentiation stimuli, undergo cell death and that this cell death can be defined as apoptosis. Apoptosis in PyLT-expressing myoblasts starts after growth factors removal, is promoted by cell confluence, and is temporally correlated with the expression of early markers of myogenic differentiation. The block of the initial events of myogenesis by transforming growth factor β or basic fibroblast growth factor prevents PyLT-induced apoptosis, while the acceleration of this process by the overexpression of the muscle-regulatory factor MyoD further increases cell death in this system. MyoD can induce PyLT-expressing myoblasts to accumulate RB, p21, and muscle- specific genes but is unable to induce G00arrest. Several markers of different phases of the cell cycle, such as cyclin A, cdk-2, and cdc-2, fail to be down-regulated, indicating the occurrence of cell cycle progression. It has been frequently suggested that apoptosis can result from an unbalanced cell cycle progression in the presence of a contrasting signal, such as growth factor deprivation. Our data involve differentiation pathways, as a further contrasting signal, in the generation of this conflict during myoblast cell apoptosis.

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
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