Cell cycle arrest in G0/G1 phase by contact inhibition and TGF-beta 1 in mink Mv1Lu lung epithelial cells

1996 ◽  
Vol 270 (5) ◽  
pp. L879-L888 ◽  
Author(s):  
F. Wu ◽  
S. Buckley ◽  
K. C. Bui ◽  
A. Yee ◽  
H. Y. Wu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transforming Growth Factor ◽  
Cyclin B1 ◽  
Contact Inhibition ◽  
Lung Epithelial Cells ◽  
Tgf Beta ◽  
Cyclin D2 ◽  
Dependent Protein ◽  
Retinoblastoma Tumor ◽  
Cdc 2

We postulated that contact inhibition and transforming growth factor (TGF)-beta 1 may target the same molecules to negatively regulate the Mv1Lu cell cycle in G0/G1. Both contact inhibition and TGF-beta 1 suppressed the expression of a 45-kDa protein (p45); cyclins D2 and B1; cyclin-dependent protein kinase (Cdk)-4, Cdc-2, and Cdc-2-associated activity; and the phosphorylation of retinoblastoma tumor-suppressor protein (pRb) but did not affect the expression of cyclins D1, E, and A or the expression of Cdk-2 and Cdk-5. Expression of p45 reappeared 12 h after release from contact inhibition and 6-8 h after release from TGF-beta 1, while TGF-beta 1 prevented release from contact inhibition and maintained suppression of both p45 and cyclin D2. Additionally, cyclin D2 phosphorylation and its associated kinase activity were strongly inhibited by contact inhibition and TGF-beta 1. Thus suppression of p45, cyclin D2/Cdk-4, and cyclin B1/Cdc-2 expression and/or activities is targeted both by contact inhibition and by TGF-beta 1 and may define common mechanisms through which these negative growth signals are integrated.

Early gene responses to transforming growth factor-beta in cells lacking growth-suppressive RB function

1991 ◽  
Vol 11 (10) ◽  
pp. 4952-4958
Author(s):  
A Zentella ◽  
F M Weis ◽  
D A Ralph ◽  
M Laiho ◽  
J Massagué
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Lung Epithelial Cells ◽  
Early Gene ◽  
Tgf Beta ◽  
Suppressive Function ◽  
Growth Factor Beta ◽  
Pai 1

The growth-suppressive function of the retinoblastoma susceptibility gene product, RB, has been implicated in the mediation of growth inhibition and negative regulation of certain proliferation related genes by transforming growth factor-beta 1 (TGF-beta 1). Early gene responses to TGF-beta 1 were examined in order to determine their dependence on the cell cycle and on the growth-suppressive function of RB. TGF-beta 1, which rapidly elevates the steady-state level of junB and PAI-1 mRNAs and decreases that of c-myc mRNA, induces these responses in S-phase populations of Mv1Lu lung epithelial cells containing RB in a phosphorylated state. Since in this state RB is presumed to lack growth-suppressive activity, the response to TGF-beta 1 was also examined in DU145 human prostate carcinoma cells whose mutant RB product lacks growth-suppressive function. In these cells, TGF-beta 1 also decreases c-myc expression at the transcription initiation level. These results suggests that the c-myc, junB, and PAI-1 responses to TGF-beta 1 are not restricted to the G1 phase of the cell cycle and that down-regulation of c-myc expression by TGF-beta 1 can occur through a mechanism independent from the growth-suppressive function of RB.

scholarly journals Early gene responses to transforming growth factor-beta in cells lacking growth-suppressive RB function.

1991 ◽  
Vol 11 (10) ◽  
pp. 4952-4958 ◽  
Author(s):  
A Zentella ◽  
F M Weis ◽  
D A Ralph ◽  
M Laiho ◽  
J Massagué
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Lung Epithelial Cells ◽  
Early Gene ◽  
Tgf Beta ◽  
Suppressive Function ◽  
Growth Factor Beta ◽  
Pai 1

The growth-suppressive function of the retinoblastoma susceptibility gene product, RB, has been implicated in the mediation of growth inhibition and negative regulation of certain proliferation related genes by transforming growth factor-beta 1 (TGF-beta 1). Early gene responses to TGF-beta 1 were examined in order to determine their dependence on the cell cycle and on the growth-suppressive function of RB. TGF-beta 1, which rapidly elevates the steady-state level of junB and PAI-1 mRNAs and decreases that of c-myc mRNA, induces these responses in S-phase populations of Mv1Lu lung epithelial cells containing RB in a phosphorylated state. Since in this state RB is presumed to lack growth-suppressive activity, the response to TGF-beta 1 was also examined in DU145 human prostate carcinoma cells whose mutant RB product lacks growth-suppressive function. In these cells, TGF-beta 1 also decreases c-myc expression at the transcription initiation level. These results suggests that the c-myc, junB, and PAI-1 responses to TGF-beta 1 are not restricted to the G1 phase of the cell cycle and that down-regulation of c-myc expression by TGF-beta 1 can occur through a mechanism independent from the growth-suppressive function of RB.

Cloning of a growth arrest-specific and transforming growth factor beta-regulated gene, TI 1, from an epithelial cell line

1991 ◽  
Vol 11 (10) ◽  
pp. 5338-5345
Author(s):  
B Kallin ◽  
R de Martin ◽  
T Etzold ◽  
V Sorrentino ◽  
L Philipson
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Lung Epithelial Cells ◽  
Epithelial Cell Line ◽  
Type I ◽  
Tgf Beta ◽  
Protein Synthesis Inhibitors ◽  
Plasminogen Activator Inhibitor 1 ◽  
Growth Factor Beta

By cDNA cloning and differential screening, five genes that are regulated by transforming growth factor beta (TGF beta) in mink lung epithelial cells were identified. A novel membrane protein gene, TI 1, was identified which was downregulated by TGF beta and serum in quiescent cells. In actively growing cells, the TI 1 gene is rapidly and transiently induced by TGF beta, and it is overexpressed in the presence of protein synthesis inhibitors. It appears to be related to a family of transmembrane glycoproteins that are expressed on lymphocytes and tumor cells. The four other genes were all induced by TGF beta and correspond to the genes of collagen alpha type I, fibronectin, plasminogen activator inhibitor 1, and the monocyte chemotactic cell-activating factor (JE gene) previously shown to be TGF beta regulated.

scholarly journals Transforming growth factor-beta-induced growth inhibition and cellular hypertrophy in cultured vascular smooth muscle cells.

1988 ◽  
Vol 107 (2) ◽  
pp. 771-780 ◽  
Author(s):  
G K Owens ◽  
A A Geisterfer ◽  
Y W Yang ◽  
A Komoriya
Keyword(s):  
Cell Cycle ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Muscle Cells ◽  
Tgf Beta ◽  
Aortic Smooth Muscle Cells ◽  
Aortic Smooth Muscle ◽  
Cellular Hypertrophy

We have explored the hypothesis that hypertrophy of vascular smooth muscle cells may be regulated, in part, by growth inhibitory factors that alter the pattern of the growth response to serum mitogens by characterizing the effects of the potent growth inhibitor, transforming growth factor-beta (TGF-beta), on both hyperplastic and hypertrophic growth of cultured rat aortic smooth muscle cells. TGF-beta inhibited serum-induced proliferation of rat aortic smooth muscle cells (ED50 = 2 pM); this is consistent with previously reported observations in bovine aortic smooth muscle cells (Assoian et al. 1982. J. Biol. Chem. 258:7155-7160). Growth inhibition was due in part to a greater than twofold increase in the cell cycle transit time in cells that continued to proliferate in the presence of TGF-beta. TGF-beta concurrently induced cellular hypertrophy as assessed by flow cytometric analysis of cellular protein content (47% increase) and forward angle light scatter (32-50% increase), an index of cell size. In addition to being time and concentration dependent, this hypertrophy was reversible. Simultaneous flow cytometric evaluation of forward angle light scatter and cellular DNA content demonstrated that TGF-beta-induced hypertrophy was not dependent on withdrawal of cells from the cell cycle nor was it dependent on growth arrest of cells at a particular point in the cell cycle in that both cycling cells in the G2 phase of the cell cycle and those in G1 were hypertrophied with respect to the corresponding cells in vehicle-treated controls. Chronic treatment with TGF-beta (100 pM, 9 d) was associated with accumulation of cells in the G2 phase of the cell cycle in the virtual absence of cells in S phase, whereas subsequent removal of TGF-beta from these cultures was associated with the appearance of a significant fraction of cycling cells with greater than 4c DNA content, consistent with development of tetraploidy. Results of these studies support a role for TGF-beta in the control of smooth muscle cell growth and suggest that at least one mechanism whereby hypertrophy and hyperploidy may occur in this, as well as other cell types, is by alterations in the response to serum mitogens by potent growth inhibitors such as TGF-beta.

scholarly journals Early progression of thymocytes along the CD4/CD8 developmental pathway is regulated by a subset of thymic epithelial cells expressing transforming growth factor beta.

1994 ◽  
Vol 179 (5) ◽  
pp. 1495-1506 ◽  
Author(s):  
Y Takahama ◽  
J J Letterio ◽  
H Suzuki ◽  
A G Farr ◽  
A Singer
Keyword(s):  
Cell Cycle ◽  
Epithelial Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Precursor Cells ◽  
Thymic Epithelial Cells ◽  
Tgf Beta ◽  
Developmental Pathway ◽  
Beta Proteins ◽  
Growth Factor Beta

Precursor cells differentiate into mature CD4+ and CD8+ T cells in the inductive environment of the thymus by undergoing a series of distinct developmental steps marked by expression of the coreceptor molecules CD4 and CD8. Among the earliest cells to enter the CD4/CD8 developmental pathway are CD4-CD8lo precursors cells that differentiate into CD4+CD8+ thymocytes. Here we show that differentiation of precursor cells into CD4+CD8+ thymocytes requires at least one cell division and that their progression through a cell cycle is specifically retarded in the thymus by interaction with thymic epithelial cells that express transforming growth factor beta (TGF-beta) proteins. We also demonstrate that TGF-beta proteins, either in solution or bound to cell membranes, can regulate cell cycle progression and differentiation of CD4-CD8lo precursor cells into CD4+CD8+ thymocytes. The regulatory effect of TGF-beta is specific for CD4-CD8lo precursor cells as TGF-beta proteins do not regulate the earlier generation of CD4-CD8lo precursor cells from CD4-CD8- thymocytes. Finally, we demonstrate that TGF-beta proteins are expressed in vivo in the intact thymus on subcapsular and cortical thymic epithelium where they can contact developing CD4-CD8lo precursor cells. Thus, thymic epithelial cells expressing TGF-beta proteins can actively regulate the rate at which CD4+CD8+ thymocytes are generated from CD4-CD8lo precursor cells.

scholarly journals Control of junB and extracellular matrix protein expression by transforming growth factor-beta 1 is independent of simian virus 40 T antigen-sensitive growth-sensitive growth-inhibitory events.

1991 ◽  
Vol 11 (2) ◽  
pp. 972-978 ◽  
Author(s):  
M Laiho ◽  
L Rönnstrand ◽  
J Heino ◽  
J A Decaprio ◽  
J W Ludlow ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Extracellular Matrix ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Simian Virus 40 ◽  
Plasminogen Activator Inhibitor ◽  
Simian Virus ◽  
T Antigen ◽  
Tgf Beta ◽  
Plasminogen Activator Inhibitor 1

Treatment of Mv1Lu mink lung epithelial cells with transforming growth factor-beta 1 (TGF-beta 1) prevents phosphorylation of the retinoblastoma susceptibility gene product, RB, in late G1 phase of the cell cycle, which is thought to retain RB in a growth-suppressive state. This effect is paralleled by cell cycle arrest in late G1 (M. Laiho, J. A. DeCapric, J. W. Ludlow, D. M. Livingston, and J. Massagué, Cell 62:175-185, 1990). Arrest can be prevented by expression of simian virus 40 T antigen, which binds to underphosphorylated RB, presumably blocking its growth-suppressive activity. The response of cells to TGF-beta 1, however, is complex and includes changes in the levels of expression of genes encoding nuclear transcription factors and extracellular matrix components. To define the relationships among various components of the TGF-beta 1 response, we have investigated the effect of TGF-beta 1 on cells whose growth-inhibitory response to this factor is prevented by T antigen. TGF-beta 1 addition to exponentially growing Mv1Lu cells increased the levels of junB mRNA and of three extracellular matrix proteins: plasminogen activator inhibitor-1, fibronectin, and thrombospondin. Kinetically, the effects on junB and plasminogen activator inhibitor-1 expression occurred faster (half-maximal at 1 to 2 h) than the effects on fibronectin and thrombospondin expression (half-maximal at 6 to 10 h). These effects either preceded or overlapped, respectively, the withdrawal of Mv1Lu cells from the cell cycle. Expression of a transfected T-antigen gene in Mv1Lu cells, however, did not prevent any of these responses to TGF-beta 1. The results indcate that TGF-B1-stimulated expression of junB and extracellular matrix proteins in Mv1Lu cells can occur independently of the T-antigen-sensitive events that lead to growth arrest.

scholarly journals High expression of transforming growth factor-beta long cell cycle times and a unique clustering of S-phase cells in patients with acute promyelocytic leukemia [see comments]

Blood ◽  
1992 ◽  
Vol 79 (4) ◽  
pp. 1037-1048 ◽  
Author(s):  
A Raza ◽  
N Yousuf ◽  
A Abbas ◽  
A Umerani ◽  
A Mehdi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Growth Factor ◽  
Acute Promyelocytic Leukemia ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Promyelocytic Leukemia ◽  
S Phase ◽  
Tgf Beta ◽  
Growth Factor Beta

Expression of transforming growth factor-beta (TGF-beta), which inhibits the proliferation of hematopoietic progenitors, was investigated simultaneously with cell cycle characteristics in 63 bone marrow biopsies from 23 cases with acute promyelocytic leukemia (APL). Bromodeoxyuridine (BrdU) was administered to every patient (17 newly diagnosed) for determination of the labeling index (LI) and the durations of S-phase (Ts) and the cell cycle (Tc) of leukemic promyelocytes. APL cases had lower LI both in the bone marrow aspirate (6.1% v 11.4%, P = .008) and biopsy (21.1% v 28.0%, P = .001) and longer Tc (93.6 hours v 56.0 hours, P = .002) when compared with other French-American-British subtypes. TGF-beta expression (detected by a monoclonal anti-TGF-beta 2/beta 3 antibody) was dramatically high, especially in interstitial areas of the biopsies. S-phase cells were found as geographically restricted islands of proliferation (GRIPs) in 20 of 22 cases. Weekly biopsies showed an increment in TGF-beta on day 7 of therapy in 13 of 17 cases, while in vivo differentiation was noted in 9 of 15. We conclude that the presence of high TGF-beta expression may explain the biologic basis for the slowly cycling nature of leukemic promyelocytes in APL as well as the unique clustering of S- phase cells observed in GRIPs.

scholarly journals High expression of transforming growth factor-beta long cell cycle times and a unique clustering of S-phase cells in patients with acute promyelocytic leukemia [see comments]

Blood ◽  
1992 ◽  
Vol 79 (4) ◽  
pp. 1037-1048
Author(s):  
A Raza ◽  
N Yousuf ◽  
A Abbas ◽  
A Umerani ◽  
A Mehdi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Growth Factor ◽  
Acute Promyelocytic Leukemia ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Promyelocytic Leukemia ◽  
S Phase ◽  
Tgf Beta ◽  
Growth Factor Beta

Abstract Expression of transforming growth factor-beta (TGF-beta), which inhibits the proliferation of hematopoietic progenitors, was investigated simultaneously with cell cycle characteristics in 63 bone marrow biopsies from 23 cases with acute promyelocytic leukemia (APL). Bromodeoxyuridine (BrdU) was administered to every patient (17 newly diagnosed) for determination of the labeling index (LI) and the durations of S-phase (Ts) and the cell cycle (Tc) of leukemic promyelocytes. APL cases had lower LI both in the bone marrow aspirate (6.1% v 11.4%, P = .008) and biopsy (21.1% v 28.0%, P = .001) and longer Tc (93.6 hours v 56.0 hours, P = .002) when compared with other French-American-British subtypes. TGF-beta expression (detected by a monoclonal anti-TGF-beta 2/beta 3 antibody) was dramatically high, especially in interstitial areas of the biopsies. S-phase cells were found as geographically restricted islands of proliferation (GRIPs) in 20 of 22 cases. Weekly biopsies showed an increment in TGF-beta on day 7 of therapy in 13 of 17 cases, while in vivo differentiation was noted in 9 of 15. We conclude that the presence of high TGF-beta expression may explain the biologic basis for the slowly cycling nature of leukemic promyelocytes in APL as well as the unique clustering of S- phase cells observed in GRIPs.

scholarly journals Transforming growth factor beta inhibits the proliferation of the blast cells of acute myeloblastic leukemia

Blood ◽  
1988 ◽  
Vol 72 (1) ◽  
pp. 159-164 ◽  
Author(s):  
N Tessier ◽  
T Hoang
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Acute Myeloblastic Leukemia ◽  
Negative Regulator ◽  
Thymidine Uptake ◽  
Tgf Beta ◽  
Bladder Cell ◽  
Growth Factor Beta

Abstract The effect of transforming growth factor beta (TGF beta) on proliferation and differentiation of peripheral blast precursors in acute myeloblastic leukemia (AML) was investigated. TGF beta induced a dose-dependent inhibition of blast clonogenic cells in suspension and methylcellulose cultures in the presence of optimal concentrations of stimulators provided by conditioned media from the bladder cell line HTB9 (HTB9-CM) or the recombinant granulocyte-macrophage colony- stimulating factor (GM-CSF). On removal of TGF beta, blast clonogenic cell proliferation recovers to the same level as that observed in control cultures, indicating that the effect is reversible. There was no induction of cell differentiation, as indicated by morphological and functional studies (production of superoxyde anions). Cell cycle analysis by thymidine uptake and flow cytometry with a DNA binding dye indicated that TGF beta caused a delay in progression into S and G2/M phases of the cell cycle without affecting cell viability. Thus, TGF beta appears to have a cytostatic rather than cytolytic effect on blast precursors and might therefore play a role as a negative regulator in hematopoiesis.

scholarly journals Mammalian egg activation: from Ca2+ spiking to cell cycle progression

Reproduction ◽  
2005 ◽  
Vol 130 (6) ◽  
pp. 813-823 ◽  
Author(s):  
Keith T Jones
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Polar Body ◽  
Signal Transduction Pathway ◽  
Cyclin B1 ◽  
Egg Activation ◽  
Anaphase Promoting Complex ◽  
Sister Chromatids ◽  
Dependent Protein ◽  
Second Polar Body

Mammalian eggs arrest at metaphase of the second meiotic division (MetII). Sperm break this arrest by inducing a series of Ca2+spikes that last for several hours. During this time cell cycle resumption is induced, sister chromatids undergo anaphase and the second polar body is extruded. This is followed by decondensation of the chromatin and the formation of pronuclei. Ca2+spiking is both the necessary and solely sufficient sperm signal to induce full egg activation. How MetII arrest is established, how the Ca2+spiking is induced and how the signal is transduced into cell cycle resumption are the topics of this review. Although the roles of most components of the signal transduction pathway remain to be fully investigated, here I present a model in which a sperm-specific phospholipase C (PLCζ) generates Ca2+spikes to activate calmodulin-dependent protein kinase II and so switch on the Anaphase-Promoting Complex/Cyclosome (APC/C). APC/C activation leads to securin and cyclin B1 degradation and in so doing allows sister chromatids to be segregated and to decondense.

Sign in / Sign up

Export Citation Format

Share Document