Differentiation of Mouse Erythroleukemia Cells Is Blocked by Late Up-Regulation of a c-<i>myb</i> Transgene

McClinton, D; Stafford, J; Brents, Leslie A.; Bender, Timothy P.; Kuehl, W. Michael

doi:10.1128/mcb.10.2.705-710.1990

Cited by 13 publications

(1 citation statement)

References 23 publications

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“…Its level of expression decreases dramatically upon spontaneous or chemically induced differentiation of these cells (Westin et al ., 1982; Gonda and Metcalf, 1984; Duprey and Boettinger, 1985). Furthermore, constitutive expression of exogenous c‐Myb in erythroid leukemia cells blocked their differentiation (McClinton et al ., 1990), which suggested that down‐regulation of c‐Myb is a critical step for the progression of differentiation. The AMV v‐myb oncogene blocks differentiation which results in transformation of immature macrophage precursors (Baluda and Reddy, 1994).…”

Section: Introductionmentioning

confidence: 99%

D-type cyclins repress transcriptional activation by the v-Myb but not the c-Myb DNA-binding domain

Ganter

Lipsick

1998

The EMBO Journal

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The v-Myb DNA-binding domain differs from that of c-Myb mainly by deletion of the first of three repeats. This truncation correlates with efficient oncogenic transformation and a decrease in DNA-binding activity. Here we demonstrate that the D-type cyclins, cyclin D1 and D2 in particular, specifically inhibit transcription when activated through the v-Myb DNA-binding domain, but not the c-Myb DNA-binding domain. Analysis of a cyclin D1 mutant and a dominant-negative CDK4 mutant implied that this repression is independent of complex formation with a CDK partner. Association of cyclin D1 and D2 with the Myb DNA-binding domain could be demonstrated. Increased levels of cyclin D1 and D2 resulted in a stabilization of the Myb proteins, but not in an alteration in binding of the Myb proteins to DNA. These results highlight an unexpected role for cyclin D as a CDK-independent repressor of transcriptional activation by v-Myb but not c-Myb. This differential effect of D-type cyclins on v-Myb and c-Myb might help to explain the mechanism underlying the oncogenic activity of v-Myb, which appears to be a stronger transcriptional activator following the TPA-induced differentiation of transformed monoblasts when cyclin D1 and D2 are down-regulated.

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Section: Introductionmentioning

confidence: 99%

D-type cyclins repress transcriptional activation by the v-Myb but not the c-Myb DNA-binding domain

Ganter

Lipsick

1998

The EMBO Journal

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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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Transcriptional elongation of c-myb is regulated by NF-κB (p50/RelB)

Suhasini

Pilz

1999

Oncogene

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High levels of c-myb expression are necessary for the proliferation of hematopoietic precursor cells whereas down-regulation of c-myb is required for terminal di erentiation; this down-regulation occurs through a conditional block to transcriptional elongation in intron I. We previously observed that cAMP analogs prevented the late down-regulation of c-myb during hexamethylene bisacetamide (HMBA)-induced di erentiation of murine erythroleukemia (MEL) cells and blocked di erentiation; this correlated with the induction of NF-kB (p50/RelB) complexes which were shown to bind to NF-kB recognition sites¯anking the transcriptional pause site of c-myb. We now selected stably-transfected MEL cells which overexpressed p50, RelB or both at levels similar to those induced by cAMP to determine whether these NF-kB proteins regulate c-myb expression in intact cells. We demonstrate that transcriptionally active NF-kB (p50/RelB) complexes, but not p50 or RelB alone, prevented the early and late down-regulation of c-myb mRNA and increased c-myb transcriptional elongation in HMBA-induced MEL cells. The increase in c-myb expression was su cient to block erythroid di erentiation and allow continuous proliferation of cells in the presence of HMBA. Steady-state c-myb mRNA levels in untreated cells were not a ected by overexpression of NF-kB, suggesting that p50/RelB speci®cally modulated the e ciency of transcriptional attenuation during MEL cell di erentiation.

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Differentiation of Mouse Erythroleukemia Cells Is Blocked by Late Up-Regulation of a c-myb Transgene

Cited by 13 publications

References 23 publications

D-type cyclins repress transcriptional activation by the v-Myb but not the c-Myb DNA-binding domain

D-type cyclins repress transcriptional activation by the v-Myb but not the c-Myb DNA-binding domain

The myb gene family in cell growth, differentiation and apoptosis

Transcriptional elongation of c-myb is regulated by NF-κB (p50/RelB)

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