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.

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.

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 A novel inhibitor of cyclin-Cdk activity detected in transforming growth factor beta-arrested epithelial cells.

1994 ◽  
Vol 14 (6) ◽  
pp. 3683-3694 ◽  
Author(s):  
J M Slingerland ◽  
L Hengst ◽  
C H Pan ◽  
D Alexander ◽  
M R Stampfer ◽  
...  
Keyword(s):  
Phase Transition ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Mammalian Cells ◽  
Transforming Growth Factor ◽  
Cyclin E ◽  
Cyclin A ◽  
S Phase ◽  
Tgf Beta ◽  
Growth Factor Beta

Transforming growth factor beta (TGF-beta) is a potent inhibitor of epithelial cell growth. Cyclins E and A in association with Cdk2 have been shown to play a role in the G1-to-S phase transition in mammalian cells. We have studied the effects of TGF-beta-mediated growth arrest on G1/S cyclins E and A. Inhibition of cyclin A-associated kinase by TGF-beta is primarily due to a decrease in cyclin A mRNA and protein. By contrast, while TGF-beta inhibits accumulation of cyclin E mRNA, the reduction in cyclin E protein is minimal. Instead, we find that the activation of cyclin E-associated kinase that normally accompanies the G1-to-S phase transition is inhibited. A novel inhibitor of cyclin-Cdk complexes was detected in TGF-beta-treated cell lysates. Inhibition is mediated by a heat-stable protein that targets both Cdk2 and Cdc2 kinases. In G0-arrested cells, a similar inhibitor of Cdk2 kinase was detected. These data suggest the existence of an inhibitor of cyclin-dependent kinases induced under different conditions to mediate antiproliferative responses.

scholarly journals Transforming growth factor beta 1 selectively regulates early murine hematopoietic progenitors and inhibits the growth of IL-3-dependent myeloid leukemia cell lines.

1988 ◽  
Vol 168 (2) ◽  
pp. 737-750 ◽  
Author(s):  
J R Keller ◽  
C Mantel ◽  
G K Sing ◽  
L R Ellingsworth ◽  
S K Ruscetti ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Cell Growth ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Potent Inhibitor ◽  
Leukemia Cell ◽  
Leukemic Cell ◽  
Tgf Beta ◽  
Growth Factor Beta

Transforming growth factor beta 1 (TGF-beta 1) has been shown to be associated with active centers of hematopoiesis and lymphopoiesis in the developing fetus. Therefore, the effects of TGF-beta 1 on mouse hematopoiesis were studied. TGF-beta 1 is a potent inhibitor of IL-3-induced bone marrow proliferation, but it does not inhibit the proliferation induced by granulocyte/macrophage, colony-stimulating factor (CSF), granulocyte CSF, and erythropoietin (Epo). TGF-beta 1 also inhibits IL-3-induced multipotential colony formation of bone marrow cells in soft agar, which includes early erythroid differentiation, while Epo-induced terminal differentiation is unaffected. In addition, IL-3-induced granulocyte/macrophage colonies were inhibited; however, small clusters of differentiated myeloid cells were consistently seen in cultures containing IL-3 and TGF-beta 1. Thus, TGF-beta 1 selectively inhibits early hematopoietic progenitor growth and differentiation but not more mature progenitors. TGF-beta 1 is also a potent inhibitor of IL-3-dependent and -independent myelomonocytic leukemic cell growth, while the more mature erythroid and macrophage leukemias are insensitive. Therefore, TGF-beta 1 functions as a selective regulator of differentiating normal hematopoietic cells, and suppresses myeloid leukemic cell growth.

scholarly journals Basic fibroblast growth factor counteracts the suppressive effect of transforming growth factor-beta 1 on human myeloid progenitor cells

Blood ◽  
1993 ◽  
Vol 81 (4) ◽  
pp. 909-915 ◽  
Author(s):  
JL Gabrilove ◽  
G Wong ◽  
E Bollenbacher ◽  
K White ◽  
S Kojima ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Cell Growth ◽  
Transforming Growth Factor Beta ◽  
Progenitor Cell ◽  
Transforming Growth Factor ◽  
Fibroblast Growth ◽  
Tgf Beta ◽  
Gm Csf ◽  
Growth Factor Beta

Abstract We have previously shown that basic fibroblast growth factor (bFGF) is mitogenic for human bone marrow stromal cells and enhances myelopoiesis in human long-term bone marrow culture. In the present study, we examined the mechanism by which bFGF enhances granulopoiesis. We observed that bFGF significantly abrogated the inhibitory effect of transforming growth factor-beta 1 (TGF-beta 1) on granulocyte- macrophage colony-stimulating factor (GM-CSF)-supported progenitor cell growth (P = .009). The partial reversal of TGF-beta 1-mediated suppression was dependent on the dose of bFGF used. In addition, we noted that the inclusion of neutralizing antibody to TGF-beta 1 significantly augmented the clonogenic response to GM-CSF. We have also shown that 10 ng/mL or 100 ng/mL of bFGF resulted in a 30% to 100% increase in GM-CSF-mediated progenitor cell growth (P = .0001). These data suggest that bFGF may enhance myelopoiesis by modulating the inhibitory response to TGF-beta 1.

scholarly journals Transforming growth factor-beta 1 cooperates with anti-immunoglobulin for the induction of apoptosis in group I (biopsy-like) Burkitt lymphoma cell lines

Blood ◽  
1996 ◽  
Vol 87 (3) ◽  
pp. 1147-1154 ◽  
Author(s):  
I MacDonald ◽  
H Wang ◽  
R Grand ◽  
RJ Armitage ◽  
WC Fanslow ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Cell Lines ◽  
Transforming Growth Factor Beta ◽  
Burkitt Lymphoma ◽  
Transforming Growth Factor ◽  
Growth Arrest ◽  
Tgf Beta ◽  
Group I ◽  
Growth Factor Beta

Group I Burkitt lymphoma (BL) cell lines, which retain the original biopsy phenotype, have been shown to enter apoptosis in response to a number of external stimuli including serum deprivation, thermal shock, addition of calcium ionophore, and ligation of surface immunoglobulin (Ig) by antibody. Transforming growth factor-beta 1 (TGF beta 1) is known to cause growth arrest in BL lines. Here we show that while it is by itself capable of promoting some degree of apoptosis in group IBL cells, TGF beta 1 cooperates with anti-immunoglobulin to this end. Trimeric soluble recombinant human CD40 ligand (sCD40L) was able to inhibit apoptosis induced by the combination of agonists to some degree, but such rescue proved to be short-lived. Both TGF beta 1 and anti-Ig individually caused BL cells to undergo growth arrest at the G1 phase of cell cycle before their entry into apoptosis: the consequence of sCD40L addition was to maintain the cells in cycle for longer. No induction of the apoptosis-protecting gene, bcl-2, occurred in the presence of sCD40L. These findings are discussed, particularly highlighting the relationship existing between survival and the cell cycle. The strong cooperative effects observed between anti-Ig and TGF beta 1 in promoting apoptosis and the inability of CD40 to signal for long-term rescue raise the potential for a novel therapeutic attack on B-cell lymphoma.

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