Expression and Function of the c-myb Oncogene During Hematopoietic Differentiation

Kuehl, W. Michael; Bender, Timothy P.; Stafford, J; McClinton, D; Segal, Shoshana; Dmitrovsky, Ethan

doi:10.1007/978-3-642-74006-0_42

Cited by 21 publications

(19 citation statements)

References 14 publications

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“…Although all these changes have taken place, the failure to suppress c-myc expression still results in a block to differentiation. Experimental evidence that c-myc binds to DNA and may activate or suppress the expression of a variety of genes is highly suggestive (5,11,21,42 (23,24,36). Consistent with this notion, c-myb continued to be expressed when constitutive c-myc blocked chemically induced differentiation of mouse erythroleukemic cells (11,12).…”

Section: Resultsmentioning

confidence: 76%

Interleukin-6- and leukemia inhibitory factor-induced terminal differentiation of myeloid leukemia cells is blocked at an intermediate stage by constitutive c-myc.

Hoffman-Liebermann¹,

Liebermann²

1991

Mol. Cell. Biol.

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Interleukin-6 (IL-6) and leukemia inhibitory factor (LIF), two multifunctional cytokines, recently have been identified as physiological inducers of hematopoietic cell differentiation which also induce terminal differentiation and growth arrest of the myeloblastic leukemic M1 cell line. In this work, it is shown that c-myc exhibited a unique pattern of expression upon induction of M1 terminal differentiation by LIF or IL-6, with an early transient increase followed by a decrease to control levels by 12 h and no detectable c-myc mRNA by 1 day; in contrast, c-myb expression was rapidly suppressed, with no detectable c-myb mRNA by 12 h. Vectors containing the c-myc gene under control of the beta-actin gene promoter were transfected into M1 cells to obtain M1myc cell lines which constitutively synthesized c-myc. Deregulated and continued expression of c-myc blocked terminal differentiation induced by IL-6 or LIF at an intermediate stage in the progression from immature blasts to mature macrophages, precisely at the point in time when c-myc is normally suppressed, leading to intermediate-stage myeloid cells which continued to proliferate in the absence of c-myb expression.

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Section: Resultsmentioning

confidence: 76%

Interleukin-6- and leukemia inhibitory factor-induced terminal differentiation of myeloid leukemia cells is blocked at an intermediate stage by constitutive c-myc.

Hoffman-Liebermann¹,

Liebermann²

1991

Mol. Cell. Biol.

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“…Expression of these genes is cell cycleregulated, and inhibition of their expression with antisense at ASPET Journals on May 9, 2018 jpet.aspetjournals.org oligonucleotides has been found to affect cell cycle progression, cell division, and/or differentiation (Raschella et al, 1992). Inhibition of c-myb expression by compounds inducing differentiation has been widely studied in leukemic cells (Kuehl et al, 1988) and c-myb down-regulation accompanied the cessation of growth and the onset of differentiation markers (Yen et al, 1992). Our results also indicate that PPAR ligands induce the monocytic differentiation of HL-60 cells, …”

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor Ligands Affect Growth-Related Gene Expression in Human Leukemic Cells

Laurora¹,

Pizzimenti²,

Briatore³

et al. 2003

J Pharmacol Exp Ther

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Peroxisome proliferator-activated receptors (PPARs) are ligandactivated nuclear receptors. Three subtypes of PPARs (␣, ␤, and ␥) have been identified in different tissues. PPAR␣ and PPAR␥ ligands inhibit cell proliferation and induce differentiation in several human cell models. We demonstrated that both PPAR␣ (clofibrate and ciprofibrate) and PPAR␥ ligands (troglitazone and 15 deoxyprostaglandin J2, 15d-PGJ2) inhibited growth, induced the onset of monocytic-like differentiation, and increased the proportion of G 0 /G 1 cells in the HL-60 leukemic cell line. Moreover, 3 days after the treatment with 2.5 M 15d-PGJ2, an increase in sub-G 0 /G 1 population occurred, compatible with an induction of programmed cell death. To clarify the mechanisms involved in HL-60 growth inhibition due to the effects of PPAR ligands, we investigated their action on the expression of some genes involved in the control of cell proliferation, differentiation, and cell cycle progression such as c-myc, c-myb, and cyclin D1 and D2. Clofibrate (50 M), ciprofibrate (50 M), and 15d-PGJ2 (2.5 M) inhibited c-myb and cyclin D2 expression, whereas they did not affect c-myc and cyclin D1 expression. Only troglitazone (5 M) decreased c-myc mRNA and protein levels, besides decreasing c-myb and cyclin D2. The down-regulations of c-myb and cyclin D2 expression represent the first evidence of the inhibitory effect exerted by PPAR ligands on these genes. Moreover, the inhibition of c-myc expression by troglitazone may depend on a PPAR-independent mechanism.

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“…c-myb is highly expressed in immature hematopoietic cells and is down-regulated during terminal dierentiation of these cells (Westin et al, 1982;Gonda and Metcalf, 1984). Furthermore, cytokine or chemically induced dierentiation of myeloid cells or erythroid leukemia cells is accompanied by down-regulation of c-myb (Westin et al, 1982;Gonda and Metcalf, 1984;Kuehl et al, 1988;Ramsay et al, 1986). Similarly, dierentiation of a neuroblastoma cell line by retinoic acid was also associated with down-regulation of c-myb (Thiele et al, 1988).…”

Section: Myb In Dierentiationmentioning

confidence: 99%

The myb gene family in cell growth, differentiation and apoptosis

1999

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The myb gene family consists of three members, named A, B and c-myb which encode nuclear proteins that function as transcriptional transactivators. Proteins encoded by these three genes exhibit a tripartate structure with an N-terminal DNA-binding domain, a central transactivation domain and a C-terminal regulatory domain. These proteins exhibit highest homology in their DNA binding domains and appear to bind DNA with overlapping sequence speci®cities. Transactivation by myb gene family varies considerably depending on cell type and promoter context suggesting a dependence on interaction with other cell type speci®c co-factors. While the C-terminal domains of A-Myb and c-Myb proteins exert a negative regulatory eect on their transcriptional transactivation function, the C-terminal domain of BMyb appears to function as a positive regulator of this activity. One or more of these proteins interact with other transcription factors such as Ets-2, CEBP and NF-M. In addition, expression of these genes is cell cycleregulated and inhibition of their expression with antisense oligonucleotides has been found to aect cell cycleprogression, cell division and/or dierentiation. Members of the myb gene family exhibit dierent temporal and spatial expression patterns suggesting a distinctive function for each of these genes. Gene knockout experiments show that these genes play an essential role in development. Loss of c-myb function results in embryonic lethality due to failure of fetal hepatic hematopoiesis. A-myb null mutant mice, on the other hand are viable but exhibit growth abnormalities, and defects in spermatogenesis and female breast development. While the role of c-myb in oncogenesis is well established, future experiments are likely to provide further clues regarding the role of A-myb and B-myb in tumorigenesis.

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Expression and Function of the c-myb Oncogene During Hematopoietic Differentiation

Cited by 21 publications

References 14 publications

Interleukin-6- and leukemia inhibitory factor-induced terminal differentiation of myeloid leukemia cells is blocked at an intermediate stage by constitutive c-myc.

Interleukin-6- and leukemia inhibitory factor-induced terminal differentiation of myeloid leukemia cells is blocked at an intermediate stage by constitutive c-myc.

Peroxisome Proliferator-Activated Receptor Ligands Affect Growth-Related Gene Expression in Human Leukemic Cells

The myb gene family in cell growth, differentiation and apoptosis

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