Dissociation of hemoglobin accumulation and commitment during murine erythroleukemia cell differentiation by treatment with imidazole

Gusella, James F.; Tsiftsoglou, Asterios S.; Volloch, Vladimir; Weil, Susan C.; Neumann, Jeffrey R.; Housman, David E.

doi:10.1002/jcp.1041130127

Cited by 28 publications

(25 citation statements)

References 32 publications

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“…13,25 Several studies have indicated that the coordination of these programs is not obligatory. In this study we found that, although Bcl-X L antisense transcripts affect MEL cells in their ability to synthesize hemoglobin with DMSO, they have no effect on the proliferative aspect of the erythroid differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have indicated that the coordination of both programs is not obligatory. 25 That is why we examined the effect of Bcl-2 and Bcl-X L on loss of proliferative potential cell in DMSO-treated MEL cells. To study the loss of proliferative potential after DMSO induction, cells were cultured in suspension and diluted every 2 days.…”

Section: Transfection With Antisense Bcl-x L Induces Premature Apoptomentioning

confidence: 99%

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Bcl-XL is required for heme synthesis during the chemical induction of erythroid differentiation of murine erythroleukemia cells independently of its antiapoptotic function

Hafid-Medheb

Augery-Bourget

Minatchy

et al. 2003

Blood

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Bcl-XL is essential for the survival and normal maturation of erythroid cells, especially at the late stage of erythroid differentiation. It remains unclear whether Bcl-XL serves only as a survival factor for erythroid cells or if it can induce a signal for differentiation. We have previously shown that dimethyl sulfoxide (DMSO) induction of erythroid differentiation in murine erythroleukemia (MEL) cells correlates with delay of apoptosis and specific induction of Bcl-XL. In this study, we investigate the contribution of Bcl-2 and Bcl-XL to survival and erythroid differentiation by generating stable MEL transfectants expressing these antiapoptotic regulators. Overexpression of Bcl-2 completely prevented apoptosis of MEL cells before and after DMSO induction, whereas overexpression of Bcl-XL only delayed it. Overexpression of Bcl-2 or Bcl-XL neither induced spontaneous erythroid differentiation nor accelerated DMSO-induced differentiation. Inhibition of Bcl-XL by antisense transcripts accelerated apoptosis in DMSO-treated MEL cells and blocked the synthesis of hemoglobin without altering the growth arrest associated with terminal erythroid differentiation. An antisense oligonucleotide to Bcl-XL did not induce apoptosis in MEL cells overexpressing Bcl-2 but greatly decreased their hemoglobin synthesis when treated with DMSO, suggesting that Bcl-XL is necessary for erythroid differentiation independently of its antiapoptotic function. Importantly, Bcl-XL antisense transcripts prevented heme synthesis but not globin mRNA induction in DMSO-treated MEL cells. Furthermore, inhibition of hemoglobin synthesis by Bcl-XLantisense was reversed by addition of exogenous hemin. Finally, Bcl-XL localized to mitochondria during MEL erythroid differentiation, suggesting that it may mediate a critical mitochondrial transport function related to heme biosynthesis.

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Section: Discussionmentioning

confidence: 99%

Section: Transfection With Antisense Bcl-x L Induces Premature Apoptomentioning

confidence: 99%

Bcl-XL is required for heme synthesis during the chemical induction of erythroid differentiation of murine erythroleukemia cells independently of its antiapoptotic function

Hafid-Medheb

Augery-Bourget

Minatchy

et al. 2003

Blood

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“…HMBA and Me2SO are polar planar compounds that induce MELC to both terminal cell division and hemoglobin accumulation (11,19). Hemin induces MELC to accumulate globin mRNAs but does not cause commitment to terminal cell division (14,20,21). After 2 hr (62 hr after initiation of culture) with HMBA, Me2SO, hemin, or no addition, 56%, 27%, 11%, and 8% of MELC were committed.…”

Section: Effect Of Inducer Onmentioning

confidence: 99%

Inducer-mediated commitment of murine erythroleukemia cells to terminal cell division: the expression of commitment.

Murate¹,

Kaneda²,

Rifkind³

et al. 1984

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

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Murine erythroleukemia cells (MELC) are transformed cells that can be induced to differentiate by a variety of agents, such as hexamethylenebisacetamide (HMBA) and dimethyl sulfoxide. Dexamethasone suppresses HMBAmediated MELC differentiation, but MELC retain a memory for their exposure to HMBA since, on transfer from culture with HMBA and dexamethasone to medium without additions, a portion of the cells express characteristics of terminal differentiation. This study characterizes the steroid suppressed steps in the multi-step process of inducer-mediated MELC terminal differentiation. MELC in culture with HMBA and dexamethasone show low levels of commitment to terminal cell division; upon transfer to culture with inducer alone there is a rapid increase in the proportion of committed cells. The magnitude of this rapid or "step-up" expression of commitment increased with the length of prior culture with inducer and steroid. This step-up expression is not inhibited by actinomycin D or cordycepin but is blocked by cycloheximide. HMBA is required for step-up expression of commitment. In the absence of inducer, there is a rapid decay in the capacity for step-up expression. Thus, HMBA initiates a series of changes leading to the accumulation of factors-which may be mRNAs-whose expression is blocked by dexamethasone. Hemin, which induces MELC accumulation of globin mRNA but not commitment to terminal cell division, cannot, as does HMBA or dimethyl sulfoxide, cause step-up expression of commitment.Murine erythroleukemia cells (MELC) are virus-transformed erythroid precursor cells that appear to be blocked in a relatively early stage in the pathway of erythroid differentiation, probably corresponding to erythroid colony-forming unit CFU-e (1). MELC retain the capacity for self-renewal. When cultured with hexamethylenebisacetamide (HMBA) (2), dimethyl sulfoxide (Me2SO) (3), or any of several other agents (1), MELC are induced to express a pattern of terminal erythroid differentiation, including terminal cell division. In recent studies, we reported evidence that inducer-mediated MELC commitment to terminal cell differentiation is a multi-step process (4). Dexamethasone (4-10) and the tumor promoter phorbol 12-myristate 13-acetate (PMA) (11, 12) can suppress inducer-mediated MELC commitment to terminal cell division and hemoglobin accumulation. We have shown that there are inducer-mediated early changes in the multistep process of commitment that are not suppressed by dexamethasone or PMA (4, 11). MELC retain a "memory" for these early changes since expression of commitment to terminal cell division occurs rapidly upon removal of the steroid (4) or PMA (11). The expression of terminal cell division and hemoglobin accumulation are steps that are sensitive to suppression by the steroid or tumor promoter. The rate-limiting step in the inducer-mediated multi-step process is an early step and is not suppressed by steroid (4).The present studies were designed to characterize those steps of HMBA-mediated MELC commitment ...

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“…The benzidine reagent measures only heme biosynthesis, which under some conditions can be dissociated from terminal differentiation (15,16). We therefore asked whether pMbml-dhfr-transfected F-MEL clones also were inhibited in other differentiated functions.…”

mentioning

confidence: 99%

Constitutive expression of a c-myb cDNA blocks Friend murine erythroleukemia cell differentiation.

et al. 1988

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A full-length human c-myb cDNA clone has been isolated from a CCRF-CEM leukemia cell cDNA library. The plasmid vector contains simian virus 40-derived promotor, splice, and polyadenylation sequences as well as a transcription unit for a dihydrofolate reductase cDNA. We have introduced this construct into Friend erythroleukemia (F-MEL) cells and have isolated a number of clones which contain intact and transcriptionally active human c-myb sequences. F-MEL clones expressing the highest levels of the human c-myb mRNA differentiate poorly in response to dimethyl sulfoxide. Two clones which initially expressed low levels of human c-myb transcripts and which differentiated normally were subsequently inhibited in their ability to differentiate when grown in successively higher concentrations of methotrexate, due to amplification and enhanced expression of plasmid sequences. The inhibitory effect on F-MEL differentiation appeared to be independent of the early decline in c-myc transcripts which were normally regulated in all cases examined. Our results indicate that constitutive expression of a nontruncated human c-myb cDNA can exert profound effects on erythroid differentiation and argue for a causal role of c-myb in the F-MEL differentiation process.

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Dissociation of hemoglobin accumulation and commitment during murine erythroleukemia cell differentiation by treatment with imidazole

Cited by 28 publications

References 32 publications

Bcl-XL is required for heme synthesis during the chemical induction of erythroid differentiation of murine erythroleukemia cells independently of its antiapoptotic function

Bcl-XL is required for heme synthesis during the chemical induction of erythroid differentiation of murine erythroleukemia cells independently of its antiapoptotic function

Inducer-mediated commitment of murine erythroleukemia cells to terminal cell division: the expression of commitment.

Constitutive expression of a c-myb cDNA blocks Friend murine erythroleukemia cell differentiation.

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