Phorbol esters, but not the hormonal form of vitamin D, induce changes in protein kinase C during differentiation of human histiocytic lymphoma cell line (U-937)

Mezzetti, Gabriele; Gp, Bagnara; Monti, Maria Giuseppina; Casolo, L. Pernecco; Bonsi, Laura; Brunelli, M. A.

doi:10.1016/0024-3205(87)90105-6

Cited by 8 publications

(5 citation statements)

References 9 publications

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“…These observations further support the possibility that calcitriol alters expression of phorbol inducible genes by amplifying the PKC signal transduction pathway. Contrary to this argument, there is limited evidence that amplification of PKC activity is not required for induction of cell differentiation [39,40]. We therefore questioned whether calcitriol altered cellular PKC activity under conditions known to modulate expression of uPA and PAI-2 proteins.…”

Section: Discussionmentioning

confidence: 92%

Calcitriol-mediated modulation of urokinase-type plasminogen activator and plasminogen activator inhibitor-2

Kole

Gyetko

Simpson

et al. 1991

Biochemical Pharmacology

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Calcitriol-induced differentiation of U937 mononuclear phagocytes is known to have divergent effects on the synthesis of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-2 (PAI-2). In this study, we sought to determine whether calcitriol affects the expression of these proteins by modulating intermediate signal transduction involving intracellular calcium and protein kinase C (PKC). U937 cells were stimulated with calcitriol (50 nM) for 6-72 hr, inducing a transient increase in specific binding of [3H]phorbol dibutyrate ([3H]PDBu), seen only after 24 hr. Staurosporine (2 nM), a PKC inhibitor, had no effect on calcitriol-induced secretion of plasminogen activator (PA) activity. However, staurosporine significantly (P less than 0.05) inhibited the ability of calcitriol to enhance phorbol myristate acetate (PMA)-induced secretion of PA inhibitor activity, indicating that this priming effect of calcitriol requires expression of PKC. The calcium ionophore A23187 (0.1 microM) induced a modest increase in secreted PA inhibitor activity, in contrast to the secretion of PA activity which is consistently seen in response to calcitriol. Northern blot analysis demonstrated that A23187 induced an increase in PAI-2 mRNA and a marked reduction in uPA mRNA, while calcitriol induced opposite changes in both mRNA species. We conclude that calcitriol modulates uPA and PAI-2 expression by multiple mechanisms that are both PKC dependent and PKC independent. Our studies also demonstrated that increased intracellular calcium alters the synthesis of both uPA and PAI-2 in a manner which favors expression of PA inhibitor activity.

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Section: Discussionmentioning

confidence: 92%

Calcitriol-mediated modulation of urokinase-type plasminogen activator and plasminogen activator inhibitor-2

Kole

Gyetko

Simpson

et al. 1991

Biochemical Pharmacology

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“…Protein kinase C may be involved in the response of the Y-1 adrenal cells to TPA. Evidence has accumulated that phorbol esters act a t least partly by stimulating the calcium-activated phospholipid-dependent protein kinase C (Mezzetti et al, 1987;Roos et al, 1986;Kleine et al, 1986;Shoji et al, 1987;Nishizuka,1984;Kikkawa et al, 1983;Castagna et al, 1982). Further studies demonstrating the time-and dose-dependent effect of TPA on CAMP-dependent protein kinase and kinase C will aid in the elucidation of the mechanism of TPA action.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the ability of the adrenal cortical tumor cells to elaborate steroids was demonstrated following ACTH stimulation of cultures in the presence or absence of TPA. One possible mechanism by which phorbol esters mediate their effects is by stimulating protein kinase C (Castagna et al, 1982;Mezzetti et al, 1987). Whether TPA acts solely through protein kinase C, however, or whether other mechanisms are possible, remains controversial.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the morphological, growth, and steroidogenic effect of TPA on mouse Y‐1 adrenal cortical tumor cells in culture

Murray

Polizotto

1988

Am. J. Anat.

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The tumor-promoting agent 12-0-tetradecanoyl-phorbol-13-acetate (TPA) caused a time- and dose-dependent morphological change in Y-1 adrenocortical tumor cells. The morphological alteration was apparent 2 hr following addition of 1 microgram/ml TPA to cell cultures and became more striking with longer treatment times. Smaller doses of TPA took a longer time to produce an effect. Cultures grown in the presence of TPA exhibited more rounding and piling up of cells than similar cultures maintained in medium lacking TPA. These TPA-stimulated morphological changes were reversible, and after 24 hr in TPA-free media, the cultured cells began to flatten. After 96 hr in TPA-free media they resembled the control cultures. The reversibility of the morphological change was also dose dependent: cells treated with 1 microgram/ml TPA took a longer time to resume the typical control morphology than did cultures treated with 0.01 microgram/ml TPA. In addition, TPA treatment resulted in a decrease in cell growth rate, an increase in steroid production, and an increase in the localization of free catalytic units of cAMP-dependent protein kinase in the cytoplasm. The steroidogenic effect of ACTH on the cell population was inhibited in cultures maintained in TPA. The results of this study indicate that TPA induces morphological changes in the Y-1 adrenocortical tumor cell population while increasing steroidogenesis and the activation of cAMP-dependent protein kinase and decreasing cell growth rate.

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“…TPA is thought to bring about changes in the cell by activating PKC (Mezzetti et al, 1987;Kleine et al, 1986;Roos et al, 1986;Shoji et al, 1987;Nishizuka, 1984;Kikkawa et al, 1984;Castagna et al, 1982). A number of studies have demonstrated that the phenothiazine drug TFP is an inhibitor of PKC (Mori et al, 1980;Wise et al, 1982;Schatzman et al, 1981).…”

Section: T -mentioning

confidence: 94%

“…The mechanism by which tumor promoters are able, in some cell types, to alter cell-cell communication is poorly understood. Evidence has accumulated that phorbol esters, which are potent tumor promoters, act at least partly by stimulating the calcium-activated phospholipid-dependent protein kinase C (PKC) (Mezzetti et al, 1987;Kleine et al, 1986;Roos et al, 1986;Shoji et al, 1987;Nishizuka, 1984; Kikkawa et al, 1984;Castagna et al, 1982). PKC has been shown to be involved in the signal transduction pathways of many growth factors and agents that promote transformation and oncogenesis in cells (Nishizuka, 1988).…”

mentioning

confidence: 95%

Regulation of the 12‐o‐tetradecanoyl‐phorbol‐13‐acetate‐induced inhibition of intercellular communication

et al. 1993

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Effects of the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and protein kinase C (PKC) inhibitors on cell-cell communication were studied in a normal rat liver cell line, clone 9. Communication was observed and quantitated with microspectofluorometric and image analysis techniques following scrape-loading of the cells with lucifer yellow. Lucifer yellow migrated as far as ten cells away from the scraped edge in control populations. Two minute TPA (25-50 micrograms/ml) treatment inhibited dye movement such that the dye remained mainly in the cells at the cut edge. The TPA-induced inhibition of cell-cell communication could be partially blocked by 15 min treatment of the cell populations with the PKC inhibitors trifluoperazine (30 micrograms/ml), staurosporine (2 x 10(-8) or 2 x 10(-6) M), sangivamycin (15 or 200 microM), or a PKC inhibitor peptide (20 micrograms/ml) scraped in at the same time as lucifer yellow. Normal communication was observed in cultures treated only with PKC inhibitors. Lower concentrations of TPA (50 ng/ml-1 micrograms/ml) used for 2 min did not inhibit dye communication. Our results demonstrate the phorbol ester-induced interruption of cell-cell communication. The inhibition of PKC by inhibitors eliminates the effect of TPA on communication. Our data are consistent with a role of PKC in the control of junctional communication.

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Phorbol esters, but not the hormonal form of vitamin D, induce changes in protein kinase C during differentiation of human histiocytic lymphoma cell line (U-937)

Cited by 8 publications

References 9 publications

Calcitriol-mediated modulation of urokinase-type plasminogen activator and plasminogen activator inhibitor-2

Calcitriol-mediated modulation of urokinase-type plasminogen activator and plasminogen activator inhibitor-2

Characterization of the morphological, growth, and steroidogenic effect of TPA on mouse Y‐1 adrenal cortical tumor cells in culture

Regulation of the 12‐o‐tetradecanoyl‐phorbol‐13‐acetate‐induced inhibition of intercellular communication

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