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PubMedDate not supplied

Transformation-related cellular protein p53: increased level in untransformed rat cells following treatment with the tumorpromoter, tetradecanoylphorbol-acetate.

12-O-Tetradecanoylphorbol-13-acetate (TPA, 100 ng ml-1), a tumor promoting phorbol ester, is able to induce enhanced levels of the transformation-associated cellular antigen p53 in normal rat 2 cells which had not been previously initiated by a carcinogen. p53 was estimated in ethanol-fixed treated cells on microtiter plates with ELISA using the monoclonal antibody Pab 1620 [EMBO J. 7, 1485, (1984)]. Induction of p53 was confirmed by immunoblotting. This effect of TPA is an additional phenotypic characteristic of tumor cells which can be induced by TPA in untransformed rodent cells.

Animals↗
PubMed1983

Tachyphylaxis in 12-0-tetradecanoylphorbol acetate- and arachidonic acid-induced ear edema.

12-0-Tetradecanoylphorbol acetate (TPA) applied to mouse ears rapidly induces an edema which is maximal by 6 hr but has substantially waned by 24 hr. (This is in contrast to many inflammatory agents that cause a prolonged edema lasting many days.) Reapplication of TPA at 16-24 hr will not provoke a second edematous response although increased erythema is evident. Arachidonic acid (AA) applied to mouse ears (4 mg) provokes an even more rapid edema which is maximal at 1 hr and has substantially waned by 6 hr. Reapplication of AA at 3-24 hr also will not provoke a second edematous response although, again, increased erythema does result. Pretreatment of ears with AA results in inhibition of the edema response to subsequent application of TPA, and TPA pretreatment moderately inhibits a subsequent response to AA. TPA-induced edema can be delayed by agents such as naproxen, an inhibitor of AA cyclooxygenase. In contrast, AA-induced edema is inhibited only by agents, such as phenidone, that inhibit both cyclooxygenase and lipoxygenase. The data suggest that the edemas result from interaction of the products of the cyclooxygenase and lipoxygenase pathways of AA metabolism. The lack of secondary edema response appears to be related to the inability of TPA or AA to reinduce vascular permeability. The effect is specific to AA and TPA; responses to xylene or anthralin are unaffected by TPA or AA pretreatment. It is postulated that the tachyphylactic effects observed involve lipoxygenase metabolites of AA.

Animals↗
PubMed1986

The effect of tetradecanoylphorbol acetate on calcium-ion mobilization, protein phosphorylation and cytoskeletal assembly induced by thrombin or arachidonate.

Tetradecanoylphorbol acetate (TPA) activates primarily only the protein kinase C pathway not the calcium ion-dependent pathway in platelets. The net effect of this split activation is that only the pseudopodal cytoskeleton assembles, not the contractile cytoskeleton needed for rapid secretion. In this study, platelets were first activated with TPA, then activated secondarily with either thrombin or arachidonate and the subsequent dense body secretion, calcium-ion mobilization, protein phosphorylation and cytoskeletal assembly compared to these same processes in control platelets activated solely with either thrombin or arachidonate. Secretion was reduced as the length of time between the primary and secondary activation was increased; but at a 2-3 min interval, where the activation by TPA was essentially complete, the reduction in the total radiolabeled serotonin secreted was small. Furthermore, nearly normal cytosolic calcium-ion increases, phosphorylation of myosin light chain and contractile cytoskeletal development were induced by thrombin or arachidonate after this interval. Prior treatment of the platelets with 100 microM acetylsalicylate to block the cyclooxygenase-dependent pathway caused minor reduction in dense-body secretion induced by TPA or thrombin or the combination of both, but otherwise the relative results were comparable to the untreated platelets. Therefore, short-term prior activation of gel-filtered platelets with TPA, even at concentrations in excess of 100-times that required to saturate protein kinase C, does not prevent normal activation of the calcium ion dependent processes through either the cyclooxygenase-dependent or -independent pathway. Longer-term preincubations with TPA differentially inhibit the secretion response induced by thrombin and arachidonate.

Arachidonic Acid↗
PubMed2000

Effect of kanglemycin C on lymphocyte proliferation induced by tetradecanoylphorbol acetate and ionomycin.

AIM: To compare the suppressions of kanglemycin C (Kan) with that of cyclosporine (Cyc) on lymphocyte proliferations induced by tetradecanoylphorbol acetate (TPA) with ionomycin (IM), and concanavalin A (Con A). METHODS: Cell proliferation was quantified with 3-(4, 5-dimetyl-thiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) or [3H]thymidine ([3H]TdR) incorporating method. Calcineurin (CN) activity was measured with molybdate dye colorimetry. RESULTS: Kan (8, 40, 80, and 400 nmol.L-1) strongly suppressed splenocyte proliferation induced by TPA and IM, and the suppressive effect of Kan gradually decreased along with the increasing concentrations of TPA (1-100 micrograms.L-1) and IM (125-500 micrograms.L-1). But, the suppression of Cyc on the splenocyte proliferation induced by TPA was mild. Cyc suppressed CN activity of mouse splenocytes stimulated by Con A stronger than Kan. Moreover, Kan and Cyc strongly suppressed spleen enriched T-cell proliferation induced by Con A and TPA + IM, and the suppression of Kan on proliferation was partly attenuated by exogenous IL-2. CONCLUSION: Kan competitively suppressed the proliferation induced by TPA and IM, and Cyc mainly suppressed IM part of the proliferation induced by TPA and IM.

Animals↗
PubMed1998

Arachidonic acid (AA) and tetradecanoylphorbol acetate (TPA) exert systemic effects when applied topically in the mouse.

We studied the systemic actions of topically applied arachidonic acid (AA) and tetradecanoylphorbol acetate (TPA) in the mouse. AA or TPA-induced ear edema, increases in vascular permeability, eicosanoid levels, neutrophil and mononuclear influx were determined in both phlogogen-treated and contralateral vehicle-treated ear of each mouse and were compared with vehicle-treated ears from control mice. Edema and vascular permeability increases appeared only in AA- or TPA-applied ears. Moreover, in contralateral ears from AA-treated mice an increase in 6-keto-PGF1 alpha and LTB4 was found. Only LTB4 increased in the contralateral ear after TPA. Contralateral ears from AA- or TPA-treated mice also showed a significant increase in MPO levels. The increased levels of 6-keto-PGF1 alpha but not those of LTB4 in contralateral ears were reduced by indomethacin applied simultaneously with the phlogogen. AA also increased plasma and serum levels of LTB4, but not those of 6-keto-PGF1 alpha. In contrast, TPA increased plasma and serum levels of 6-keto-PGF1 alpha and LTB4. The results show that both AA and TPA applied topically exert systemic effects.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

The extinction of erythroid genes after tetradecanoylphorbol acetate treatment of erythroleukemic cells correlates with down-regulation of the tissue-specific factors NF-E1 and NF-E2.

We have studied the elements involved in the tetradecanoylphorbol acetate (TPA)-mediated extinction of erythroid-specific genes. We show that transcription driven by a -714/+78-base pair DNA fragment of the erythroid promoter of the human porphobilinogen deaminase gene is down-regulated upon TPA treatment of erythroleukemic cells. Examination of the DNA binding activity of trans-acting factors involved in the expression of the porphobilinogen deaminase erythroid promoter showed (i) a constitutive expression of the CACC binding proteins and (ii) a decrease in DNA binding activity of two tissue-specific factors, NF-E1 and NF-E2. Kinetics experiments indicated that NF-E2 was down-regulated after 1 h of TPA treatment whereas NF-E1 was down-regulated at the protein and mRNA levels only after 5 h of TPA treatment. These results suggest that different pathways, acting via different transcription factors, are involved in the TPA-mediated extinction of erythroid-specific genes.

Base Sequence↗
PubMed1997

Differential effects of 1,25-dihydroxyvitamin D3 and tetradecanoylphorbol acetate on cell cycle and apoptosis of MCF-7 cells and a vitamin D3-resistant variant.

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3), the active form of vitamin D3, and tetradecanoylphorbol acetate (TPA) are potent negative growth regulators of breast cancer cells. In this study, we compared the mechanism of action of these two compounds in MCF-7 cells and a vitamin D3-resistant variant (MCF-7D3Res). In parental MCF-7 cells, 1,25-(OH)2D3 induced morphological and biochemical markers of apoptosis (chromatin and nuclear matrix condensation and DNA fragmentation), whereas TPA induced growth arrest without apoptosis. Both 1,25-(OH)2D3 and TPA independently up-regulated the vitamin D receptor, p21, and the hypophosphorylated form of retinoblastoma (Rb) protein. The growth regulatory effects of 1,25-(OH)2D3 and TPA did not correlate with induction of p53 protein expression. When both compounds were added simultaneously, synergistic effects on MCF-7 cell number were observed, and cell cycle regulatory proteins were down-regulated. The MCF-7D3Res cells, which are not sensitive to 1,25-(OH)2D3, were growth inhibited by TPA, and TPA partially sensitized MCF-7D3Res cells to the growth inhibitory effects of 1,25-(OH)2D3. In MCF-7D3Res cells, 1,25-(OH)2D3 treatment had minimal effects on p21 or Rb protein expression, whereas TPA down-regulated Rb protein and transiently up-regulated p21. These studies indicate dissociation between the pathways triggered by 1,25-(OH)2D3 and TPA, which mediate growth regulation in MCF-7 cells. Because both compounds induce growth arrest, but only 1,25-(OH)2D3 mediates apoptosis, we conclude that cell cycle arrest is not sufficient to trigger cell death of MCF-7 cells, and that 1,25-(OH)2D3 generates distinct signals which lead to induction of apoptosis in breast cancer cells.

Apoptosis↗
PubMed1997

Inhibition of harringtonine-induced apoptosis by tetradecanoylphorbol acetate in human leukemia HL-60 cells.

AIM: To study the changes of the apoptosis induced by camptothecin (Cam) or harringtonine (Har) in human leukemia HL-60 cells after the cells were preincubated with tetradecanoylphorbol acetate (TA). METHODS: Chromatin condensation observation, flow cytometry, DNA agarose gel electrophoresis, and Dot blot hybridization. RESULTS: After the HL-60 cells were preincubated with TA 200 nmol.L-1 for 6 h, the apoptosis induced by Har 0.1 mg.L-1 for 3 h was drastically inhibited, and the apoptosis by Cam 0.2 mg.L-1 for 3 h was partly inhibited. On the other hand, the expression level of c-myc gene in HL-60 cells decreased apparently after the preincubation of TA. CONCLUSION: TA preincubation inhibited the apoptosis induced by Har obviously or by Cam partly in human leukemia HL-60 cells, and the expression of c-myc gene decreased drastically in the preincubated cells, which might result in the inhibition of apoptosis.

Antineoplastic Agents, Phytogenic↗
PubMed1997

Effect of topically applied cyclosporin A on arachidonic acid (AA)- and tetradecanoylphorbol acetate (TPA)-induced dermal inflammation in mouse ear.

Topical cyclosporin A (CsA) was compared with dexamethasone, indomethacin and phenidone in edema, increases in vascular permeability, eicosanoids and cell-influx induced by arachidonic acid (AA) and tetradecanoylphorbol acetate (TPA) in mouse ears. CsA ED(50) on AA-edema (7.7 micrograms/ear) was similar to dexamethasone and lower than indomethacin and phenidone. CsA ED(50) in TPA edema (21 micrograms/ear) was higher than dexamethasone and lower than indomethacin or phenidone. All drugs equally reduce the AA-induced increase in vascular permeability, but CsA and dexamethasone had more activity on TPA. AA-increase in vascular 6-keto-PGF1 alpha was reduced by dexamethasone, indomethacin and phenidone but not by CsA; only phenidone reduced LTB4. TPA-increase in 6-keto-PGF1 alpha was reduced by CsA and indomethacin while CsA, dexamethasone and phenidone decreased LTB4. CsA, indomethacin and phenidone, but not dexamethasone, suppressed AA-neutrophil influx. In TPA-ears all drugs produced similar reduction in neutrophil influx. CsA was shown to be a good topical anti-inflammatory drug.

Acetylglucosaminidase↗
PubMed1984

Incidence of radiation lymphomas in C57BL/6 mice is not promoted after intraperitoneal treatment with the phorbol ester tetradecanoylphorbol acetate.

Female C57BL/6 mice, given 4 X-ray irradiations each with 1.7 Gy, according to H.S. Kaplan and M.S. Brown (J. Natl. Cancer Inst., 13 (1952) 185-192) developed lethal lymphomas in more than 90%, 270 days after irradiation. Intraperitoneal application of tetradecanoylphorbol acetate (TPA), 30 ng/g, twice weekly for 240 days had no influence on survival of the animals and incidence of the malignant lymphomas.

Animals↗
PubMed1991

Tumor necrosis factor-alpha, transforming growth factor-beta, and tetradecanoylphorbol acetate: competence factors for ML-1 human myeloblastic leukemia cell differentiation.

ML-1 human myeloblastic leukemia cells, suspended in RPMI-1640 medium, differentiated to monocyte or macrophage-like cells when either tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), or tetradecanoylphorbol acetate (TPA) was added prior to or simultaneously with fetal bovine serum (FBS). When FBS was applied first, and followed, after washing, by the cytokines or by TPA, maturation did not occur. A 77 kDa glycoprotein (DF77), isolated from human leukocyte-conditioned medium and present in FBS, was capable of replacing FBS for induction of differentiation. Thus, in this cell system, TNF-alpha, TGF-beta, and TPA acted as competence factors, whereas DF77 acted as the progression signal. Optimal competence was established after exposure of the cells to TPA or to either of the cytokines for approximately 2 or 30 min, respectively. After removal of the factors, competence was retained for approximately 3 hr before it declined. These results demonstrate that the initiation of ML-1 human myeloblastic leukemia cell differentiation relied upon the sequential and ordered input of competence and progression signals.

Cell Differentiation↗
PubMed1989

Cyclic AMP inhibits chemotactic-peptide-induced but not Ca2+-ionophore- or tetradecanoylphorbol-acetate-induced enzyme secretion in guinea pig neutrophils.

cAMP-increasing agents such as prostaglandin El, dibutyryl cAMP and 8-bromo-cAMP inhibited N-acetyl-beta-D-glucosaminidase secretion induced by the chemotactic peptide formylmethionyl-leucyl-phenylalanine in guinea pig neutrophils. However, they could not inhibit but rather potentiated the secretion significantly when secretion was induced by the Ca2+ ionophore A23187. Similarly, these agents did not inhibit tetradecanoylphorbol acetate (TPA)-induced secretion. Moreover, the secretion induced by combined treatment with Ca2+ ionophore A23187 and TPA was hardly blocked by cAMP-increasing agents. These results strongly suggest that cAMP inhibits the secretion through suppression of a signal transduction from receptor activation to events such as Ca2+ mobilization and protein kinase C activation, probably of the inositol phospholipid metabolism.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1992

A comparison of the effects of concanavalin-A and tetradecanoylphorbol acetate on the modulation of parathyroid function by extracellular calcium and neomycin in dispersed bovine parathyroid cells.

Ca2+ and other polyvalent cations as well as polycations, such as neomycin, produce similar effects on intracellular second messengers and PTH release in dispersed bovine parathyroid cells, but it is unclear whether all of these agents share the same mechanism of action. The lectin Concanavalin-A (Con-A) and the activator of protein kinase-C tetradecanoylphorbol acetate (TPA) blunt the effects of elevated extracellular calcium (Ca2+) concentrations on several aspects of parathyroid function, including PTH release, the cytosolic calcium concentration, and the accumulation of cAMP and inositol phosphates. In the present studies we used these two agents as well as pertussis toxin as probes to investigate further whether neomycin acts on parathyroid cells through the same receptor-like mechanism used by extracellular Ca2+ to regulate parathyroid function. Con-A and TPA both enhanced PTH release by about 2-fold at 0.5-1 x 10(-4) M neomycin, concentrations that inhibited PTH release to an extent (40-50%) similar to that seen with high (1.5-2 mM) Ca2+. Con-A also reduced the inhibition of agonist-stimulated cAMP accumulation by the same concentrations of neomycin. Conversely, Con-A and TPA produced 70-80% decreases in the cytosolic calcium concentration transient and the accumulation of inositol phosphates stimulated by neomycin. The effects of these two agents on neomycin-regulated parathyroid function were similar in magnitude to their actions on the modulation of these same parameters by extracellular Ca2+. Pertussis toxin, however, which we have previously shown to block the inhibitory effects of high Ca2+ and neomycin on cAMP accumulation, had no effect on the inhibition of PTH release by these two agents. These results provide further indirect evidence that polyvalent cations and polycations act on the parathyroid cell through related pathways, which probably involve cell surface moieties containing carbohydrate(s).

Animals↗
PubMed1989

Induction of protein kinase C translocation and cell differentiation in ML-1 human myeloblastic leukemic cells by tumor necrosis factor-alpha, transforming growth factor-beta, or tetradecanoylphorbol acetate.

Tumor necrosis factor-alpha and transforming growth factor-beta, like 12-O-tetradecanoylphorbol 13-acetate, induce differentiation of ML-1 human myeloblastic leukemia cells along the monocyte path. As measured at 5 min following exposure of the cells to either of these agents, extensive translocation of protein kinase C from the cytosolic to the membrane fraction occurred. A correlation was observed to exist between protein kinase C translocation, cell differentiation, and cessation of cell growth induced by transforming growth factor-beta and tumor necrosis factor-alpha.

Cell Differentiation↗
PubMed1993

Comparative evaluation of arachidonic acid (AA)- and tetradecanoylphorbol acetate (TPA)-induced dermal inflammation.

The effects of topical application of arachidonic acid (AA) or phorbol ester, tetradecanoylphorbol 13-acetate (TPA), on edema response, vascular permeability, MPO, NAG, and generation of eicosanoids were studied in two murine models of cutaneous inflammation. AA produced a short-lived edema response with a rapid onset that was associated with marked increases in levels of prostaglandins (PGE2, 6-keto-PGF1 alpha, PGF2 alpha), thromboxane B2 (TxB2) and leukotriene B4 (LTB4), with smaller increases in levels of LTC4. TPA produced a longer-lasting edema that was associated with marked influx of neutrophils and predominant formation of LTB4 along with significant changes in levels of TxB2. Circulating T lymphocytes have no apparent role in the acute inflammatory responses induced by either agent. Arachidonic acid-induced vascular permeability preceded the edema response and neutrophil influx, whereas TPA-induced vascular permeability paralleled the edema response and influx of neutrophils. Mast cells appear to be important in the complete expression of inflammatory response, i.e., edema, cellular influx, and vascular permeability induced by either AA or TPA, as these responses were blunted in mast cell-deficient mice. Inhibitors of CO or 5-LO attenuated inflammatory responses in both models. The LTB4 receptor antagonist, SC-41930, inhibited the inflammatory response to TPA but had little effect on that initiated by AA. This suggests that LTB4 is an important mediator in the phorbol ester-induced inflammatory response, whereas peptidoleukotrienes and prostaglandins regulate vascular permeability responses in the arachidonate model.

Acetylglucosaminidase↗
PubMed1999

Transcriptional activation of the human manganese superoxide dismutase gene mediated by tetradecanoylphorbol acetate.

Transcriptional activation of human manganese superoxide dismutase (MnSOD) mRNA induced by a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), was examined to identify the responsive transcriptional regulator. The effect of various deletions and mutations within the 5'-flanking region of the human MnSOD gene promoter was evaluated using the luciferase reporter system in A549 human lung carcinoma cells. Deletion of a region between -1292 and -1202 nucleotides upstream of the transcription start site abolished TPA-responsive induction, whereas deletion of the putative binding sequence for NF-kappaB or AP-1 did not. The region between -1292 and -1202 contains a cAMP-responsive element-like sequence, TGACGTCT, which we identified as the manganese superoxide dismutase TPA-responsive element, MSTRE. Site-specific mutation of the MSTRE abolished the TPA-responsive induction, validating the critical role of this sequence. We detected specific MSTRE activity from nuclear extracts and demonstrated by antibody supershift assay that this activity is closely related to CREB-1/ATF-1. TPA treatment rapidly induced phosphorylation of the CREB-1/ATF-1-like factor via the protein kinase C pathway. These results led us to conclude that the human MnSOD gene having the promoter construct used in this study is induced by TPA via activation of a CREB-1/ATF-1-like factor and not via either NF-kappaB or AP-1. In addition, we found that this induction was blocked by inhibitors of flavoproteins and NADPH oxidases, indicating involvement of enhanced generation of superoxide radical anion as an upstream signal.

Activating Transcription Factor 1↗
PubMed1996

A variant CD30 protein lacking extracellular and transmembrane domains is induced in HL-60 by tetradecanoylphorbol acetate and is expressed in alveolar macrophages.

We identified and cloned cDNAs for two novel CD30 mRNAs of 2.3 kb that are induced by 12-O-tetradecanoylphorbol 13-acetate (TPA) in the human myeloid leukemia cell line HL-60. These transcripts were transcribed from the intronic region just upstream of the exon coding for the transmembrane domain of the CD30 protein. The shorter cDNA had a deletion of 54 nucleotides corresponding to the 3' region of the transmembrane domain of the CD30 and which was probably caused by alternative splicing. Translation of these transcripts appeared to start from the internal methionine codon at nucleotide position 289 that corresponds to that of 1612 in the CD30 cDNA, and encode a protein of 132 amino acid residues which corresponds exactly to the C-terminal cytoplasmic domain of CD30 protein. The calculated molecular mass of this variant CD30 (CD30v) protein was 14,087. Thus, the predicted CD30v protein retains most of the cytoplasmic region, but lacks the extracellular and transmembrane domains. Northern blots detected the expression of CD30v transcripts only in the lung and the TPA-stimulated HL-60 cell line. Translation of this mRNA in vitro produced a protein of 25 kD. Immunoblotting analysis with HCD30C1, a rabbit polyclonal antibody raised against the cytoplasmic domain of CD30 protein, detected proteins with an apparent Mr 25 kD expressed in TPA-stimulated HL-60 and COS-7 cells that were transfected with both types of CD30v cDNAs. Constitutive phosphorylation of the CD30v protein was demonstrated by in vitro labeling with [32P]. Immunohistochemical studies demonstrated CD30v protein was in alveolar macrophages. Cotransfection experiments using a kappa B-site-dependent reporter construct showed that CD30v can transactivate gene expression through activation of NF kappa B, as was noted on the authentic CD30 protein. Overexpression of the CD30v induced differentiation of HL-60 cells as evidenced by an increased NBT reduction activity. These observations provided new insights into the molecular heterogeneity and biological function of CD30 in myeloid cells.

Animals↗
PubMed1990

Proliferative potential of murine peritoneal mast cells after degranulation induced by compound 48/80, substance P, tetradecanoylphorbol acetate, or calcium ionophore A23187.

Proliferative potential of degranulated mast cells was investigated. Mast cells were collected from the peritoneal cavity of mice, and degranulation was induced by compound 48/80, substance P, 12-O-tetradecanoylphorbol 13-acetate (TPA), or calcium ionophore A23187. The potentiality of colony formation in methylcellulose was not reduced by treatment of various concentrations of compound 48/80, substance P and TPA. When degranulation was induced by compound 48/80, substance P or TPA, proportion of highly degranulated mast cells containing less than five granules was rather small. In contrast, considerable proportion of highly degranulated mast cells was obtained after the treatment with the low concentration (0.1 microgram/ml) of A23187. These highly degranulated mast cells, which were individually picked up by the micromanipulator, proliferated not only in methylcellulose but also in the skin of mast cell-deficient WBB6F1-W/Wv mice. Inasmuch as we have already shown the proliferation of IgE-sensitized and Ag-stimulated mast cells, degranulated mast cells appear to retain the proliferative potential in general.

Animals↗