Bryostatin-1 and 1α,25-dihydroxyvitamin D3 synergistically stimulate the differentiation of NB4 acute promyelocytic leukemia cells

Song, Xiaojing; Norman, Anthony W.

doi:10.1038/sj.leu.2401261

Cited by 15 publications

(15 citation statements)

References 14 publications

(21 reference statements)

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“…NB4 cells have been characterized with respect to differentiation induced by bryostatin-1 (Ref. 17; also see Fig. 5 and Table I).…”

Section: Resultsmentioning

confidence: 99%

“…It has been used as a model for studying the mechanisms of cell differentiation, as it can be terminally differentiated into either mature neutrophilic granulocytes (14) or monocyte/macrophage-like cells (15) in response to various treatments. Among the treatments that have been shown to induce NB4 cells to differentiate into monocytes/ macrophage-like cells are 1␣,25-dihydroxyvitamin D 3 (16) and bryostatin-1 (17). Although the precise mechanisms involved in this differentiation are not yet fully understood, it is clear that a mitogen-activated protein kinase (MAPK) 1 pathway is involved (17,18).…”

mentioning

confidence: 99%

“…Among the treatments that have been shown to induce NB4 cells to differentiate into monocytes/ macrophage-like cells are 1␣,25-dihydroxyvitamin D 3 (16) and bryostatin-1 (17). Although the precise mechanisms involved in this differentiation are not yet fully understood, it is clear that a mitogen-activated protein kinase (MAPK) 1 pathway is involved (17,18). Interestingly, MAPK has been shown to phosphorylate the amino terminus of p53 in vitro (19).…”

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confidence: 99%

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Mitogen-activated Protein Kinase Is Involved in the Degradation of p53 Protein in the Bryostatin-1-induced Differentiation of the Acute Promyelocytic Leukemia NB4 Cell Line

Song

Sheppard

Norman

et al. 1999

Journal of Biological Chemistry

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Overexpression of mutant p53 has been reported to promote tumorigenicity in several cancers. However, despite its potential importance, the signals regulating mutant p53 protein expression are not known. Here we show that a form of p53 that is incapable of binding DNA is overexpressed in the acute promyelocytic leukemia NB4 cell line. Our results demonstrate that treatment of NB4 cells with bryostatin-1, which induces differentiation in this cell line, leads to hyperphosphorylation of this DNA binding-impaired form of p53 via mitogen-activated protein kinase. After this phosphorylation, the p53 protein is degraded by the ubiquitin/proteasome pathway. Furthermore, we show that inhibition of p53 hyperphosphorylation blocks p53 protein degradation and cell differentiation. In addition, inhibition of the ubiquitin/proteasome pathway also blocks p53 protein degradation and cell differentiation. These findings suggest a role for mitogen-activated protein kinase in the degradation of the DNA binding-impaired form of p53 protein and in the bryostatin-induced differentiation observed in this cell line. The implications of these results with respect to the functional significance of p53 phosphorylation and degradation in cell differentiation are discussed.

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“…NB4 cells have been characterized with respect to differentiation induced by bryostatin-1 (Ref. 17; also see Fig. 5 and Table I).…”

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Mitogen-activated Protein Kinase Is Involved in the Degradation of p53 Protein in the Bryostatin-1-induced Differentiation of the Acute Promyelocytic Leukemia NB4 Cell Line

Song

Sheppard

Norman

et al. 1999

Journal of Biological Chemistry

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“…However, APL cells differentiate in response to a variety of unrelated pharmacologic agents that do not signal through RARa, such as vitamin D, 42,43 phorbol esters, 44 bryostatin-1, 15,42 arsenic trioxide 15,45 and even typical cytotoxic anti-cancer agents (Figure 2). 18,46 The activity of such unrelated agents in APL suggests that a specific interaction between ATRA and PML-RARa may not be the total story underlying the sensitivity of APL to differentiation induction.…”

Section: Discussionmentioning

confidence: 99%

Induction of acute lymphocytic leukemia differentiation by maintenance therapy

et al. 2007

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Despite extensive study in many malignancies, maintenance therapy has clinically benefited only two diseases: acute lymphocytic leukemia (ALL) and acute promyelocytic leukemia (APL). ALL maintenance therapy utilizes low-dose 6-mercaptopurine (6MP) and methotrexate (MTX), while maintenance in APL primarily consists of all-trans-retinoic acid (ATRA). 6MP and MTX as used in ALL are also now usually added to maintenance ATRA for APL, based on data suggesting an improved disease-free survival. Although the mechanism of action of MTX and 6MP as maintenance is unknown, low-dose cytotoxic agents are potent inducers of differentiation in vitro. Thus, we studied whether maintenance therapy in ALL, like ATRA in APL, may be inducing terminal differentiation of ALL progenitors. The APL cell line NB4, the ALL cell lines REH and RS4;11, and patients' ALL blasts were incubated with ATRA, 6MP, and MTX in vitro. All three drugs inhibited the clonogenic growth of the APL and ALL cell lines without inducing immediate apoptosis, but associated with induction of phenotypic differentiation. The three drugs similarly upregulated lymphoid antigen expression, while decreasing CD34 expression, on patients' ALL blasts. These data suggest that induction of leukemia progenitor differentiation plays an important role in the mechanism of action of maintenance therapy in ALL.

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“…In an early investigation (Stone et al, 1988b), bryostatin, a nontumorigenic PKC agonist, was shown to induce monocytic maturation of HL60. In addition to its various therapeutic actions, bryostatin (brie¯y reviewed in Stone, 1997), cooperates with VD 3 to induce monocyte/macrophage maturation of NB4 cells (Song and Norman, 1999). The synergistic action of VD 3 and PKC may be due to a VDR-independent mechanism, since VD 3 at least its 6-s-cis locked stereoisomer (nuclear receptor-independent), likely acted through the signal transduction cascade of p42-MAP kinase (ERK 2 ) (Song and Norman, 1999).…”

Section: Signaling Cross-talk and Apl-cell Maturationmentioning

confidence: 99%

Orchestration of multiple arrays of signal cross-talk and combinatorial interactions for maturation and cell death: another vision of t(15;17) preleukemic blast and APL-cell maturation

et al. 2001

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Despite intensive molecular biology investigations over the past 10 years, and an important breakthrough on how PML ± RARa, the fusion protein resulting from t(15;17), can alter RARa and PML functions, no de®nitive views on how leukemia is generated and by what mechanism(s) the normal phenotype is restored, are yet available.`Resistances' to pharmacological levels of all-trans-retinoic acid (ATRA) have been observed in experimental in vivo and in vitro models. In this review, we emphasize the key role played by signal cross-talk for both normal and neoplastic hemopoiesis. After an overview of reported experimental data on APL-cell maturation and apoptosis, we apply our current knowledge on signaling pathways to underline those which might generate signal cross-talks. The design of biological models suitable to decipher the integration of signal cross-talks at the transcriptional level should be our ®rst priority today, to generate some realistic therapeutic approaches After`Ten Years of Molecular APL', we still know very little about how the disease develops and how eective medicines work. Oncogene (2001) 20, 7161 ± 7177.

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Bryostatin-1 and 1α,25-dihydroxyvitamin D3 synergistically stimulate the differentiation of NB4 acute promyelocytic leukemia cells

Cited by 15 publications

References 14 publications

Mitogen-activated Protein Kinase Is Involved in the Degradation of p53 Protein in the Bryostatin-1-induced Differentiation of the Acute Promyelocytic Leukemia NB4 Cell Line

Mitogen-activated Protein Kinase Is Involved in the Degradation of p53 Protein in the Bryostatin-1-induced Differentiation of the Acute Promyelocytic Leukemia NB4 Cell Line

Induction of acute lymphocytic leukemia differentiation by maintenance therapy

Orchestration of multiple arrays of signal cross-talk and combinatorial interactions for maturation and cell death: another vision of t(15;17) preleukemic blast and APL-cell maturation

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