Induction of erythroid differentiation by dimethylsulfoxide in cells infected with Friend virus: relationship to the cell cycle.

Levy, Joseph; Terada, Masaaki; Rifkind, Richard A.; Marks, Paul A.

doi:10.1073/pnas.72.1.28

Cited by 90 publications

(28 citation statements)

References 23 publications

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“…The proposed model, that hypomethylation of specific sites allows gene expression, is also attractive in its consistency with two sets of observations: (a) that induction to differentiation requires the presence of inducer during DNA replication [62,63] since the only known mechanism by which DNA can become hypomethylated is through inhibition of methyl transfer during DNA synthesis [65]; (bj that administration of ethionine can be linked to a number of alterations of differentiated functions, i.e. morphological changes in the liver [5] and pancreas [64] of treated animals, rapid increases in a-fetoprotein [6] and progesterone [66] levels in serum and increases in the level of a number of liver enzymes [12,67].…”

Section: Discussionmentioning

confidence: 99%

Correlation between Hypomethylation of DNA and Expression of Globin Genes in Friend Erythroleukemia Cells

Christman

Price

Pedrinan

et al. 1977

European Journal of Biochemistry

202

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This report identifies L-ethionine as an inducer of differentiation in murine erythroleukemia cells. When Friend erythroleukemia cells are grown in the presence of 4 mM L-ethionine, globin mRNA accumulates and in 4-5 days, 25 -30 of the cells in the culture contain hemoglobin. Incubation of the cells with bromodeoxyuridine prevents both ethionine-induced accumulation of globin mRNA and er y thr oid differentiation.At the concentration where L-ethionine acts as an inducer of FL cell differentiation it inhibits methylation of DNA and tRNA in vivo but does not prevent macromolecular synthesis or cell division.To establish whether a link existed between inhibition of a specific methyltransferase and activation of globin synthesis in FL cells, we examined the degree of hypomethylation of DNA and tRNA from F L cells induced to differentiate with dimethylsulfoxide and butyrate.In contrast to the tRNA from ethionine-treated cells, tRNA from cells induced by butyrate or MezSO cannot be methylated in vitro using homologous enzymes.DNA isolated from cells exposed to any of the three inducers, however, was significantly hypomethylated when compared with DNA from uninduced cells. These data suggest that methylation of DNA may play a role in the regulation of gene expression.

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Section: Discussionmentioning

confidence: 99%

Correlation between Hypomethylation of DNA and Expression of Globin Genes in Friend Erythroleukemia Cells

Christman

Price

Pedrinan

et al. 1977

European Journal of Biochemistry

202

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“…The MEL cells are derived from murine erythroleukemia by infection of the Friend virus, causing Epo-independent polyclonal expansion through a constitutive activation of the Epo receptor (7). During the early hours after exposure to differentiation-inducing agents such as DMSO or hexamethylene bisacetamide (HMBA), MEL cells undergo alterations that commit them to cessation of growth and to development of the characteristics of differentiation (8,9).…”

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confidence: 99%

JNK-mediated turnover and stabilization of the transcription factor p45/NF-E2 during differentiation of murine erythroleukemia cells

Lee

Shyu

Hsu

et al. 2009

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

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Regulation of the homeostatic concentrations of specific sets of transcription factors is essential for correct programming of cell proliferation and differentiation. We have characterized the signal transduction pathways regulating the catabolisis of p45/NF-E2, a bZIP factor activating the erythroid and megakaryocytic gene transcription. Through use of different approaches including nano-scale proteomics, we show that activated-JNK, or Phospho-JNK (P-JNK), physically interacts with p45/NF-E2 and phosphorylates its Ser157 residue. This reaction leads to the poly-ubiquitination of p45/NF-E2 at one or more of six Lys residues, one of which being also a sumoylation site, and its degradation through the proteasome pathway. Significantly, this regulatory pathway of p45/NF-E2 by P-JNK exists only in uninduced murine erythroleukemia (MEL) cells but not in differentiated MEL cells in which JNK is inactivated on DMSO induction. Based on the above data and analysis of the chromatin-binding kinetics of p45/NF-E2 and the erythroid gene repressor Bach1 during the early phase of MEL differentiation, we suggest a model for the regulation of erythroid maturation. In the model, the posttranslational modifications and turnover of p45/NF-E2, as mediated by P-JNK, contribute to the control of its homeostatic concentration and consequently, its regulatory functions in the progression of erythroid differentiation and erythroid gene expression.egulation of erythroid differentiation is complex and occurs in multiple steps. Cytokines and nuclear hormones all play important roles in the maturation of erythroid cells. For example, it is known that signaling from the erythropoietin (Epo) receptor activates several pathways to promote cell proliferation, differentiation, and survival (1). Transcription factors such as GATA-1, EKLF, Bach1, and NF-E2 are also crucial for regulation of erythroid differentiation and maturation (2, 3). Among the many systems for studying the molecular mechanisms of erythroid differentiation is MEL (4-6). The MEL cells are derived from murine erythroleukemia by infection of the Friend virus, causing Epo-independent polyclonal expansion through a constitutive activation of the Epo receptor (7). During the early hours after exposure to differentiation-inducing agents such as DMSO or hexamethylene bisacetamide (HMBA), MEL cells undergo alterations that commit them to cessation of growth and to development of the characteristics of differentiation (8, 9).Multiple kinases are involved during MEL differentiation. For example, the inhibition of PI3 kinase reduces the GATA-1 binding to its DNA targets and thus, prevents MEL differentiation. On one hand, the PKC δ, and possibly PKC ε and PKC ζ as well, also plays a role in the HMBA-mediated differentiation of MEL, although their downstream targets are not clear yet (10). On the other hand, the MAPK families including p38, JNK, and ERK have been shown to be essential for Epo-dependent cell growth (11,12). This subfamily of the MAPK, including JNK and p38, could be activate...

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“…We have been particularly interested in whether inducers must enter the cell to affect differentiation and whether induction is a membrane-mediated process. Studies using labeled dimethyl sulfoxide (DMSO) (18), butyric acid (1), or actinomycin D (31) indicated that inducers accumulated intracellularly after a certain lag period. However, studies on membrane transport indicated that significant alterations in membrane function occur before the internalization of significant levels of inducer (3, 11, 15, 20; unpublished data).…”

mentioning

confidence: 99%

Induction and inhibition of Friend erythroleukemia cell differentiation by pyrimidine analogs: analysis of the requirement for intracellular accumulation and incorporation into DNA.

Bilello¹,

Gauri²,

Kühne³

et al. 1982

Mol. Cell. Biol.

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Alkyldeoxyuridines which differ from thymidine by a C5 substitution of straight or branched alkyl chains of two to six carbon atoms have been tested for their ability to be taken up, phosphorylated, and incorporated into DNA. Analysis of the uptake of 5-ethyl-2'-deoxyuridine and 5-propyl-2'-deoxyuridine (n-PrdU)-similar to both thymidine and 5-bromo-2'-deoxyuridine-indicates that transport is dependent upon a functional cellular thymidine kinase. All of the aforementioned pyrimidines with the exception of n-PrdU are phosphorylated to the triphosphate and incorporated into DNA. The homologs 5-iso-propyl-2'-deoxyuridine (iso-PrdU) and 5-hexyl-2'-deoxyuridine are neither transported into the cell, phosphorylated, nor incorporated into DNA. These analogs were tested (i) for their ability to induce in the absence of dimethyl sulfoxide and (ii) to determine whether they enhance or inhibit dimethyl sulfoxide-induced differentiation of Friend erythroleukemia cells. Inhibition of erythroid differentiation appears to require the incorporation of thymidine analogs into DNA, and thus only 5-ethyl-2'-deoxyuridine and 5-bromo-2'-deoxyuridine were effective in inhibiting dimethyl sulfoxide-induced differentiation. The observation that iso-PrdU, and to a lesser extent n-PrdU and 5-propyldeoxyuridine monophosphate, induce differentiation under conditions in which they are not detectable intracellularly is strong evidence that this class of inducer acts at the cell membrane.Friend erythroleukemia cells are a suitable model system to study control mechanisms involved in alterations in cellular gene expression which lead to phenotypical and biochemical changes characteristic of erythroid differentiation in vivo. This system is particularly advantageous because induced erythroid differentiation in Friend cells is a synchronous process which gives rise to a homogeneous, differentiated cell population (for review, see reference 21). Erythroid differentiation, which is induced in this system by a number of compounds of diverse chemical structure, is readily assessed by measurement of hemoglobin, which comprises 20 to 50% of the total cytoplasmic protein in induced cells. Changes in cell architecture and the synthesis of globin mRNA and other differentiationspecific proteins are observed after exposure to inducers. Our laboratory has been concerned with changes in gene expression in response to alterations in the cellular environment and with the characterization of early events in the induction of Friend cells (3, 15). We have been particularly interested in whether inducers must enter the cell to affect differentiation and whether induction is a membrane-mediated process. Studies using labeled dimethyl sulfoxide (DMSO) (18), butyric acid (1), or actinomycin D (31) indicated that inducers accumulated intracellularly after a certain lag period. However, studies on membrane transport indicated that significant alterations in membrane function occur before the internalization of significant levels of inducer (3, 11, 15, 20; unpublished d...

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Induction of erythroid differentiation by dimethylsulfoxide in cells infected with Friend virus: relationship to the cell cycle.

Cited by 90 publications

References 23 publications

Correlation between Hypomethylation of DNA and Expression of Globin Genes in Friend Erythroleukemia Cells

Correlation between Hypomethylation of DNA and Expression of Globin Genes in Friend Erythroleukemia Cells

JNK-mediated turnover and stabilization of the transcription factor p45/NF-E2 during differentiation of murine erythroleukemia cells

Induction and inhibition of Friend erythroleukemia cell differentiation by pyrimidine analogs: analysis of the requirement for intracellular accumulation and incorporation into DNA.

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