The effect of tumor-promoting phorbol diesters on terminal differentiation of cells in culture

Abrahm, Janet L.; Rovera, Giovanni

doi:10.1007/bf00225849

Cited by 31 publications

(7 citation statements)

References 60 publications

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“…Furthermore, it is noteworthy that at least one of these lines (HL-60) is induced to undergo both differentiation and growth arrest in response to phorbol esters (21).…”

Section: Resultsmentioning

confidence: 99%

Lamin B is rapidly phosphorylated in lymphocytes after activation of protein kinase C.

Hornbeck

Huang

Paul

1988

Proc. Natl. Acad. Sci. U.S.A.

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Lamin B was shown to be a major substrate of cellular phosphorylation in the response of lymphocytes to phorbol esters. Lamins A and C, which were not observed in lymphocytes, were also substrates of phorbol-stimulated phosphorylation in those cell types that express them. Lamin B phosphopeptides labeled with 32p in intact cells treated with phorbol 12-myristate 13-acetate were compared to those produced by in vitro phosphorylation with protein kinase M, cAMP-dependent protein kinase, and Ca2 + /calmodulindependent protein kinase II. The phosphopeptides labeled by in vivo stimulation with phorbol esters are very similar to those phosphorylated in vitro by protein kinase M, a catalytic domain of protein kinase C. Phorbol treatment of interphase cells significantly reduces the amount of detergent-insoluble lamin B, suggesting that phosphorylation of lamin may alter the architecture of the nuclear lamina. In addition, we have shown that treatment of a B-cell line with antibodies to IgM induces a modest increase in lamin B phosphorylation. These results strongly suggest that ligands that are known to activate protein kinase C at the cell surface or in the cytosol also lead to the activation of a nuclear kinase activity with a protein kinase C-type specificity.Protein kinase C (PKC) plays a crucial role in signal transduction in many cell types (1). Physiologically, PKC is activated by diacylglycerol, a lipophilic second messenger generated by receptor-coupled phosphodiesterase (2). PKC has also been identified as the major cellular receptor for tumor-promoting phorbol esters, which activate PKC in a manner similar to diacylglycerol (3). Phorbol esters, when added to intact cells, rapidly partition into hydrophobic environments throughout the plasma membrane and cytoplasm (4), where they specifically bind and activate PKC (5,6). This cytoplasmic activation of PKC influences nuclear events, including the rapid transcription of specific sets of genes (7-10). The mechanisms through which these nuclear events are achieved are unknown. Because neither PKC nor phorbol esters apparently enter the nucleus (1, 4), it has been postulated that the influence of phorbol esters upon transcription may result from indirect events, such as the phosphorylation of cytoplasmic proteins (4). Alternatively, protein kinase M (PKM), a proteolytic fragment of PKC that is known to be generated after phorbol treatment, may be translocated into nuclei to cause phosphorylation of nuclear proteins. In this study, we show that a nuclear protein, lamin B, is one of the principal lymphocytic proteins to be rapidly phosphorylated after treatment of intact cells with phorbol 12-myristate 13-acetate (PMA). Lamin B, one of the three lamins that constitute the nuclear lamina in most adult mammalian cells (11,12), is the only lamin we observe in lymphocytes. The in vitro pattern of phosphorylation of purified lamin B by PKM, which has the same specificity as intact PKC (13)

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“…Furthermore, it is noteworthy that at least one of these lines (HL-60) is induced to undergo both differentiation and growth arrest in response to phorbol esters (21).…”

Section: Resultsmentioning

confidence: 99%

Lamin B is rapidly phosphorylated in lymphocytes after activation of protein kinase C.

Hornbeck

Huang

Paul

1988

Proc. Natl. Acad. Sci. U.S.A.

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“…Synergism between these agents in secretory events [l] and in some long-term signalling events such as lymphocyte activation [2] indicates that the affected pathways often act in concert to elicit a full biological response. Although phorbol esters influence terminal differentiation in many cell types [3], synergism with Ca*+ ionophores has not been observed. As a result, the role of phosphoinositide turnover in such processes is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Ca²⁺ and phorbol ester synergistically induce HL‐60 differentiation

Tyers

Harley

1986

FEBS Letters

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Exposure of HL-60 cells to subthreshold concentrations of TPA caused monocytic differentiation only when cells were cotreated with the Ca2+ ionophore A23187. Phorbol ester dose-response curves for growth arrest and enzymatic markers of differentiation were shifted to lower concentrations when the ionophore was present. Expression of a monocyte/granulocyte cell surface antigen also occurred only when cells were treated with both agents. Similar effects were seen with other active but not inactive phorboi esters and with another Caz+ ionophore. The Ca2+ component of phosphoinositide-based signalling may thus play a role in HL-60 differentiation. Synergism Phorbol esterCa2+ ionophore Differentiation (HL-60 cell)

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“…HL60 cells are a human promyelocytic leukemic cell line that, when treated with tumor-promoting phorbol diesters, differentiate into functional monocyte-like cells (10). Treatment of HL60 cells with phorbol esters induces a rapid de-cline in surface transferrin-receptor numbers (7).…”

Section: Introductionmentioning

confidence: 99%

Association of phorbol ester-induced hyperphosphorylation and reversible regulation of transferrin membrane receptors in HL60 cells.

May¹,

Jacobs²,

Cuatrecasas³

1984

Proc. Natl. Acad. Sci. U.S.A.

208

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Phorbol diesters are tumor-promoting agents that cause differentiation of HL60 human leukemic cells and concomitantly alter surface transferrin-receptor expression [Rovera, G., Ferreo, D., Pagliardi, G. L., Vartikar, J., Pessano, S., Bottero, L., Abraham, S. & Lebman, D. (1982) Ann. N.Y. Acad. Sci. 397,[211][212][213][214][215][216][217][218][219][220]. Transferrin-receptor regulation is shown here to result from a rapid and reversible internalization process that is temporally associated with reversible increased phosphorylation (hyperphosphorylation) of the transferrin receptor. Such a reversible mechanism involving regulation of these surface proteins could result in the rapid generation of an early signal for HL60 cellular differentiation.Transferrin is a necessary component of virtually all serumfree tissue culture media (1), and for some cells it acts as a requisite growth factor (2, 3). Recently, the transferrin receptor has been identified and partially characterized (4, 5). It is a 180-kilodalton phosphorylated glycoprotein in its nonreduced homodimeric form (4-6). It is present in large amounts on the surface of rapidly proliferating cells of both malignant and normal origin (4), and it drastically diminishes when cells are induced to terminally differentiate (7-9).HL60 cells are a human promyelocytic leukemic cell line that, when treated with tumor-promoting phorbol diesters, differentiate into functional monocyte-like cells (10). Treatment of HL60 cells with phorbol esters induces a rapid decline in surface transferrin-receptor numbers (7). This decline occurs relatively rapidly and it precedes both biochemical and morphological events associated with differentiation. Thus, the phorbol ester-induced loss of surface transferrin receptors in HL60 cells represents a unique system to study initial events related to induction of differentiation from the standpoint of changes occurring in a specific membrane receptor that has been universally associated with cellular proliferation.We report here that, at early times, the decrease in sur-

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The effect of tumor-promoting phorbol diesters on terminal differentiation of cells in culture

Cited by 31 publications

References 60 publications

Lamin B is rapidly phosphorylated in lymphocytes after activation of protein kinase C.

Lamin B is rapidly phosphorylated in lymphocytes after activation of protein kinase C.

Ca²⁺ and phorbol ester synergistically induce HL‐60 differentiation

Association of phorbol ester-induced hyperphosphorylation and reversible regulation of transferrin membrane receptors in HL60 cells.

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The effect of tumor-promoting phorbol diesters on terminal differentiation of cells in culture

Cited by 31 publications

References 60 publications

Lamin B is rapidly phosphorylated in lymphocytes after activation of protein kinase C.

Lamin B is rapidly phosphorylated in lymphocytes after activation of protein kinase C.

Ca2+ and phorbol ester synergistically induce HL‐60 differentiation

Association of phorbol ester-induced hyperphosphorylation and reversible regulation of transferrin membrane receptors in HL60 cells.

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Ca²⁺ and phorbol ester synergistically induce HL‐60 differentiation