scholarly journals Identification of a signal-transduction pathway shared by haematopoietic growth factors with diverse biological specificity

1987 ◽  
Vol 244 (3) ◽  
pp. 683-691 ◽  
Author(s):  
S W Evans ◽  
D Rennick ◽  
W L Farrar
Keyword(s):  
Signal Transduction ◽  
Protein Kinase C ◽  
Growth Factors ◽  
Interleukin 2 ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Kinase C ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

The haematopoietic growth factors multi-colony-stimulating factor, granulocyte/macrophage colony-stimulating factor, granulocyte colony-stimulating factor and interleukin 2 specifically control the production and proliferation of distinct leucocyte series. Each growth factor acts on a unique surface receptor associated with an appropriate signal-transduction apparatus. In this report we identify a 68 kDa substrate which is phosphorylated after stimulation of different cell types with multi-colony-stimulating factor, granulocyte colony-stimulating factor and interleukin 2. The 68 kDa substrate is also phosphorylated in each cell line stimulated with synthetic diacylglycerol, a direct activator of protein kinase C. Interestingly, granulocyte/macrophage colony-stimulating factor does not induce phosphorylation of the 68 kDa molecule. The 68 kDa molecule that is phosphorylated after stimulation with each ligand yielded similar peptide maps after chymotryptic digestion; furthermore, the substrate was always phosphorylated on threonine residues. Phosphorylation of the same residues in the 68 kDa substrate suggests that activation of protein kinase C is one common signal-transduction event associated with the action of multi-colony-stimulating factor, granulocyte colony-stimulating factor and interleukin 2.

Role of Protein Kinase C in Expression of Granulocyte Colony Stimulating Factor and Granulocyte-Macrophage Colony Stimulating Factor in Lung Cancer Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4210-4210
Author(s):  
Yoshiki Uemura ◽  
Makoto Kobayashi ◽  
Hideshi Nakata ◽  
Tetsuya Kubota ◽  
Hirokuni Taguchi
Keyword(s):  
Lung Cancer ◽  
Protein Kinase ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Kinase C ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Many cases of tumors that produce granulocyte-colony stimulating factor (G-CSF) or granulocyte macrophage-colony stimulating factor (GM-CSF) have been reported. However, the biological properties regulatory mechanisms of the overproduction of G-CSFor GM-CSF by tumor cells are not well known. We present the role of protein kinase C (PKC) pathways in the constitutive expression of G-CSF and GM-CSF by lung cancer cells. We previously established two lung cancer cell lines, OKa-C-1 and MI-4, that constitutively produce an abundant dose of G-CSF and GM-CSF. We showed that the PKC activator; phorbol 12-myristate 13-acetate (PMA) stimulated the production of GM-CSF in a dose-dependent manner and inversely reduced G-CSF in the cell lines. These effects of PMA were antagonized by PKC inhibitor; staurosporine. The induction of GM-CSF expression by PMA was mediated through the activations of nuclear factor (NF)-kB activation. The induction of G-CSF expression by staurosporine was mediated through p44/42 mitogen-activated protein kinase (MAPK) pathway signaling. PMA accelerated cell growth and inhibited cell death in the cell line. Whereas staurosporine acted inversely. GM-CSF induced by PMA might stimulate cell growth and suppress cell death. G-CSF expression by staurosporine appears to be related to the activation of p44/42 MAPK, and GM-CSF by PMA to NF-kB in OKa-C-1 and MI-4 cells. Figure Figure

Enhancement of ovine trophoblast interferon by granulocyte macrophage-colony stimulating factor: possible involvement of protein kinase C

1997 ◽  
Vol 19 (2) ◽  
pp. 121-130 ◽  
Author(s):  
K Imakawa ◽  
KD Carlson ◽  
WJ McGuire ◽  
RK Christenson ◽  
A Taylor
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Calphostin C ◽  
Kinase C ◽  
Messenger System ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Interferon-tau (oIFNtau), the major secretory product of ovine conceptuses between days 13 and 21 (day 0=day of estrus) of pregnancy, is implicated in the process of maternal recognition of pregnancy. Culturing of day-14 and day-16 conceptus tissues in the presence of human granulocyte macrophage-colony stimulating factor (hGM-CSF) or interleukin-3 (IL-3) produces a marked increase in oIFNtau mRNA and protein expression. Since GM-CSF and IL-3 are localized at the luminal and glandular epithelia of the ovine endometrium, maternally derived GM-CSF and IL-3 may affect conceptus production of oIFNtau in a paracrine manner. However, the molecular mechanisms by which endometrial GM-CSF and IL-3 up-regulate oIFNtau production have not been defined. As an initial investigation of the signaling pathway regulating the GM-CSF induction of the oIFNtau gene, day-16 conceptuses were treated with an inducer, phorbol 12-myristate 13-acetate (PMA) and an inhibitor, calphostin C of the protein kinase C (PKC) pathway. Treatment with either 150 units/ml hGM-CSF (P<0.01) or 10 nM PMA (P<0.05) resulted in a significant increase in oIFNtau mRNA expression. Pretreatment of conceptuses with 1 microM PMA for 12 h to produce PKC-deficient tissues or treatment with 50 mM calphostin C abolished the hGM-CSF-induced increase in oIFNtau mRNA. An in vitro expression system was established for the analysis of oIFNtau gene regulatory sequences. The oIFNtau010 gene has been isolated previously and found to be the principal oIFNtau gene up-regulated during the preimplantation period. 5'-Flanking regions of the oIFNtau010 gene, 2 kb and 0.8 kb, were cloned into a basic chloramphenicol acetyltransferase reporter plasmid. These oIFNtau010 promoter constructs, along with expression controls, were transfected into human choriocarcinoma cells (JAR and JEG3) and their responsiveness to hGM-CSF and second messenger system activators including PMA, calcium ionophore (A23187) and 8-bromo-cAMP were characterized. The oIFNtau010 promoter constructs were up-regulated by hGM-CSF and PMA treatments (P<0.01). Combined treatment with PMA and A23187 prevented the promoter activation seen with PMA alone. The conceptus culture data, along with the results from the transfection experiments, suggest that the stimulatory effect of GM-CSF on oIFNtau is mediated through the PKC second messenger system.

scholarly journals Protein kinase C activators can interact synergistically with granulocyte colony-stimulating factor or interleukin-6 to stimulate colony formation from enriched granulocyte-macrophage colony-forming cells

Blood ◽  
1993 ◽  
Vol 81 (4) ◽  
pp. 894-900 ◽  
Author(s):  
CM Heyworth ◽  
TM Dexter ◽  
SE Nicholls ◽  
AD Whetton
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Interleukin 6 ◽  
Colony Formation ◽  
Soft Agar ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Kinase C ◽  
Macrophage Colony ◽  
Stimulating Factor

The effects of direct activators of protein kinase C (PKC) (the phorbol ester tetradecanoyl phorbol myristic acid [TPA] or bryostatin) on the ability of a highly enriched population of granulocyte-macrophage colony-forming cells (GM-CFC) to proliferate and develop in soft agar was assessed. In the absence of colony stimulating factors, the PKC activators did not stimulate colony formation. However, in the presence of optimal concentrations of granulocyte colony-stimulating factor (G- CSF) or interleukin-6 (IL-6), TPA or bryostatin markedly elevated the number of colonies formed from the GM-CFC. In the absence of TPA, IL-6, and G-CSF, respectively, both stimulated the formation of about 3% of the colonies observed when IL-3 was present. When TPA plus G-CSF or IL- 6 were added together, this figure increased to 48% and 54%, respectively. In both instances, the types of mature cells formed was altered from colonies of mature neutrophilic cells to a mixture consisting predominantly of macrophages with some neutrophils. Similar results were observed when bryostatin replaced TPA in these assays. When single cell colony-forming assays were performed, the same results were obtained. The presence of G-CSF, or IL-6, and the activator of PKC used (TPA or bryostatin) was required throughout the colony-forming assay for an optimal synergistic effect to be observed. These data indicate that agents that activate PKC can promote the proliferation and development of GM-CFC via a synergistic interaction with G-CSF or IL-6. Furthermore, there is an apparent role for PKC in development and possibly lineage commitment of GM-CFC.

scholarly journals Stimulation of phosphoinositol turnover and protein kinase C activation by granulocyte-macrophage colony-stimulating factor in HL-60 cells

Blood ◽  
1992 ◽  
Vol 80 (4) ◽  
pp. 1045-1051
Author(s):  
M Nishimura ◽  
K Kaku ◽  
Y Azuno ◽  
K Okafuji ◽  
Y Inoue ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Cell Differentiation ◽  
Protein Kinase ◽  
Cyclic Nucleotides ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Kinase C ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Phosphoinositol turnover, diacylglycerol generation, protein kinase C (PK-C) activity, and intracellular cyclic nucleotides were studied in an established human leukemia cell line, HL-60, in response to one of the hematopoietic cytokines, granulocyte-macrophage colony-stimulating factor (GM-CSF). Continuous exposure of HL-60 cells to GM-CSF induced the cell differentiation that was evaluated by the nitroblue tetrazolium (NBT) reducing activity. GM-CSF also exhibited a proliferative effect on HL-60 cells. GM-CSF at 1 nmol/L, an optimal concentration for cell growth and cell differentiation, induced significant changes in the intracellular inositoltriphosphate (IP3). Diacylglycerol generation was also stimulated by GM-CSF treatment. GM- CSF increased the membrane PK-C activity by 10-fold of the control, whereas no measurable change in cyclic nucleotides was observed. These data indicated that phosphoinositol turnover and the activation of PK-C were included in the GM-CSF signal transducing pathway in HL-60 cell. Phosphoinositol response leading to PK-C activation may act as a trigger signal of cell differentiation by GM-CSF.

scholarly journals An Activated Protein Kinase C α Gives a Differentiation Signal for Hematopoietic Progenitor Cells and Mimicks Macrophage Colony-stimulating Factor–stimulated Signaling Events

1998 ◽  
Vol 140 (6) ◽  
pp. 1511-1518 ◽  
Author(s):  
Andrew Pierce ◽  
Clare M. Heyworth ◽  
Sian E. Nicholls ◽  
Elaine Spooncer ◽  
T. Michael Dexter ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Progenitor Cells ◽  
Hematopoietic Progenitor Cells ◽  
Colony Stimulating Factor ◽  
Hematopoietic Progenitor ◽  
Kinase C ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Highly enriched, bipotent, hematopoietic granulocyte macrophage colony-forming cells (GM-CFC) require cytokines for their survival, proliferation, and development. GM-CFC will form neutrophils in the presence of the cytokines stem cell factor and granulocyte colony-stimulating factor, whereas macrophage colony-stimulating factor leads to macrophage formation. Previously, we have shown that the commitment to the macrophage lineage is associated with lipid hydrolysis and translocation of protein kinase C α (PKCα) to the nucleus. Here we have transfected freshly prepared GM-CFC with a constitutively activated form of PKCα, namely PKAC, in which the regulatory domain has been truncated. Greater than 95% of the transfected cells showed over a twofold increase in PKCα expression with the protein being located primarily within the nucleus. The expression of PKAC caused macrophage development even in the presence of stimuli that normally promote only neutrophilic development. Thus, M-CSF–stimulated translocation of PKCα to the nucleus is a signal associated with macrophage development in primary mammalian hematopoietic progenitor cells, and this signal can be mimicked by ectopic PKAC, which is also expressed in the nucleus.

scholarly journals The macrocyclic lactone protein kinase C activator, bryostatin 1, either alone, or in conjunction with recombinant murine granulocyte- macrophage colony-stimulating factor, protects Balb/c and C3H/HeN mice from the lethal in vivo effects of ionizing radiation

Blood ◽  
1994 ◽  
Vol 83 (3) ◽  
pp. 663-667 ◽  
Author(s):  
S Grant ◽  
R Traylor ◽  
GR Pettit ◽  
PS Lin
Keyword(s):  
Protein Kinase C ◽  
Single Dose ◽  
Macrocyclic Lactone ◽  
Colony Stimulating Factor ◽  
Bryostatin 1 ◽  
Kinase C ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract We have examined the in vivo radioprotective effects of the macrocyclic lactone protein kinase C (PK-C) activator, bryostatin 1, administered either alone or in conjunction with recombinant murine granulocyte- macrophage colony-stimulating factor (rmGM-CSF), in Balb/c and C3H/HeN mice subjected to lethal total body irradiation (TBI). When administered alone on a divided dose schedule (24 hours and 30 minutes before TBI), rmGM-CSF (20 micrograms/kg) was ineffective in increasing survival in either strain. However, in Balb/c mice, bryostatin 1 alone (1 microgram) permitted the long-term survival (60 days) of 70% of the animals following TBI, and 80% when administered in conjunction with rmGM-CSF. Bryostatin 1 administered alone according to this schedule exerted minimal radioprotective effects in C3H/HeN mice, but, when combined with a subeffective dose of rmGM-CSF, allowed 50% of the animals to survive. Treatment of Balb/c mice with bryostatin 1 administered as a single dose 4 hours before TBI resulted in a 20% survival rate, and 45% when administered with rmGM-CSF; corresponding values for the C3H/HeN strain were 60% and 40%, respectively. Lastly, the survival rates of Balb/c mice treated with bryostatin 1 administered as a single dose 4 hours following TBI was 20%, and 25% with rmGM-CSF; corresponding values were 50% and 25% for C3H/HeN mice. These findings indicate that the PK-C activator bryostatin 1 exhibits intrinsic in vivo radioprotective effects in lethally irradiated Balb/c and C3H/HeN mice, and may, under some circumstances, augment the radioprotective capacity of rmGM-CSF. They also underscore the critical role that strain differences and scheduling considerations play in determining the in vivo radioprotective capacity of bryostatin 1, as well as its interactions with rmGM-CSF.

scholarly journals Flt3 Ligand Synergizes With Granulocyte-Macrophage Colony-Stimulating Factor or Granulocyte Colony-Stimulating Factor to Mobilize Hematopoietic Progenitor Cells Into the Peripheral Blood of Mice

Blood ◽  
1997 ◽  
Vol 90 (9) ◽  
pp. 3781-3788 ◽  
Author(s):  
Kenneth Brasel ◽  
Hilary J. McKenna ◽  
Keith Charrier ◽  
Phillip J. Morrissey ◽  
Douglas E. Williams ◽  
...  
Keyword(s):  
Growth Factors ◽  
Peripheral Blood ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Flt3 Ligand ◽  
Gm Csf ◽  
Colony Forming Unit ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Peripheral blood progenitor cells (PBPC) are increasingly being used in the clinic as a replacement for bone marrow (BM) in the transplantation setting. We investigated the capacity of several different growth factors, including human flt3 ligand (FL), alone and in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF ) or granulocyte colony-stimulating factor (G-CSF ), to mobilize colony forming cells (CFU) into the peripheral blood (PB) of mice. Mice were injected subcutaneously (SC) with growth factors daily for up to 10 days. Comparing the single agents, we found that FL alone was superior to GM-CSF or G-CSF in mobilizing CFU into the PB. FL synergized with both GM-CSF or G-CSF to mobilize more CFU, and in a shorter period of time, than did any single agent. Administration of FL plus G-CSF for 6 days resulted in a 1,423-fold and 2,717-fold increase of colony-forming unit–granulocyte-macrophage (CFU-GM) and colony-forming unit granulocyte, erythroid, monocyte, megakaryocyte (CFU-GEMM) in PB, respectively, when compared with control mice. We also followed the kinetics of CFU numerical changes in the BM of mice treated with growth factors. While GM-CSF and G-CSF alone had little effect on BM CFU over time, FL alone increased CFU-GM and CFU-GEMM threefold and fivefold, respectively. Addition of GM-CSF or G-CSF to FL did not increase CFU in BM over levels seen with FL alone. However, after the initial increase in BM CFU after FL plus G-CSF treatment for 3 days, BM CFU returned to control levels after 5 days treatment, and CFU-GM were significantly reduced (65%) after 7 days treatment, when compared with control mice. Finally, we found that transplantation of FL or FL plus G-CSF–mobilized PB cells protected lethally irradiated mice and resulted in long-term multilineage hematopoietic reconstitution.

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