Ectopic expression of A-<i>myb</i>in transgenic mice causes follicular hyperplasia and enhanced B lymphocyte proliferation

DeRocco, Susan E.; Iozzo, Renato V.; Ma, Xiaoping; Schwarting, Roland; Peterson, David; Calabretta, Bruno

doi:10.1073/pnas.94.7.3240

Cited by 26 publications

(17 citation statements)

References 20 publications

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“…Our method using a library of mES cells that are transgenic for a defined set of full-length ORFs is expected to be a powerful and facile approach for assessing protein function. Although human factors were introduced into mouse cells, there is considerable precedent for human proteins that function normally when introduced into mice or mouse cells (e.g., interleukin-6 receptor, A-myb) (Touw et al 1992;DeRocco et al 1997). Consistent with this shared function, our results with the human OCT-2.4 clone were identical to those obtained with the mouse Oct-2.4 gene.…”

Section: Using Mes Cells To Identify Functions Of Human Orfssupporting

confidence: 80%

A high throughput embryonic stem cell screen identifies Oct-2 as a bifunctional regulator of neuronal differentiation

Theodorou

Dalembert²,

Heffelfinger³

et al. 2009

Genes Dev.

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Neuronal differentiation is a complex process that involves a plethora of regulatory steps. To identify transcription factors that influence neuronal differentiation we developed a high throughput screen using embryonic stem (ES) cells. Seven-hundred human transcription factor clones were stably introduced into mouse ES (mES) cells and screened for their ability to induce neuronal differentiation of mES cells. Twenty-four factors that are capable of inducing neuronal differentiation were identified, including four known effectors of neuronal differentiation, 11 factors with limited evidence of involvement in regulating neuronal differentiation, and nine novel factors. One transcription factor, Oct-2, was studied in detail and found to be a bifunctional regulator: It can either repress or induce neuronal differentiation, depending on the particular isoform. Ectopic expression experiments demonstrate that isoform Oct-2.4 represses neuronal differentiation, whereas Oct-2.2 activates neuron formation. Consistent with a role in neuronal differentiation, Oct-2.2 expression is induced during differentiation, and cells depleted of Oct-2 and its homolog Oct-1 have a reduced capacity to differentiate into neurons. Our results reveal a number of transcription factors potentially important for mammalian neuronal differentiation, and indicate that Oct-2 may serve as a binary switch to repress differentiation in precursor cells and induce neuronal differentiation later during neuronal development.[Keywords: Oct-2; neuronal; embryonic stem cell; differentiation; high throughput] Supplemental material is available at http://www.genesdev.org. Neuronal development and differentiation are complex processes that involve extracellular factors, local niche, and intracellular factors. Much is known about extracellular factors that mediate neural induction. For example, inhibition of bone morphogenetic protein (BMP) by chordin, noggin (Sasai et al. 1995;Zimmerman et al. 1996), and follistatin (Hemmati-Brivanlou et al. 1994;Fainsod et al. 1997) (Kageyama et al. 2008). In spite of the large number of transcription factors implicated in neuronal development and differentiation, few systematic studies of these regulators have been performed, and thus it is likely that many other transcription factors regulate neuronal differentiation.The complete sequencing of the human genome offers new approaches to systematically identify components important for neuronal differentiation. Gray et al. (2004) examined the expression of most mouse transcription factors using in situ hybridization, and found that at least 20% of known transcription factors have spatially restricted expression patterns in developing mouse brains. While this study provided a wealth of information on the potential involvement of factors in neurogenesis, it lacked any functional information. In principle, another approach that could be developed is to inactivate transcription factors on a large scale; however, for many Cold Spring Harbor Laboratory Press on May 11, 2018 -Publis...

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Section: Using Mes Cells To Identify Functions Of Human Orfssupporting

confidence: 80%

A high throughput embryonic stem cell screen identifies Oct-2 as a bifunctional regulator of neuronal differentiation

Theodorou

Dalembert²,

Heffelfinger³

et al. 2009

Genes Dev.

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“…These tissues contained a polyclonally expanded B lymphocyte population that expressed a germinal center-cell phenotype. Transgenic B lymphocytes also showed increased DNA synthesis in response to low dose mitogen stimulation, suggesting that A-myb may contribute to hyperplasia by increasing the rate of B cell proliferation (DeRocco et al, 1997). After a 9 month period, these transgenic mice developed abnormalities predominantly in hematopoietic cells, despite the fact that the transgene was expressed in broad ranges of tissues, demonstrating tissue-speci®city of the A-myb function.…”

Section: Myb As a Regulator Of Proliferationmentioning

confidence: 96%

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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“…Surprisingly, in contrast to its c-myb and A-myb relatives [38,39], no direct involvement of B-myb in tumorigenesis has been reported. This is surprising, given the facts that B-myb expression patterns and activities in promoting cell cycle progression and its ability to override cell cycle arrests make such a role plausible.…”

Section: Introductionmentioning

confidence: 99%

B-myb rescues ras-induced premature senescence, which requires its transactivation domain

2001

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B-myb, a ubiquitously expressed member of the myb gene family, is highly regulated throughout the cell cycle and appears to be required for cell cycle progression. In contrast to its relatives A-myb, c-myb, and v-myb, no transforming activity of B-myb has been reported thus far. We report here that B-myb can rescue senescence induced by an activated ras oncogene in rodent cells in vitro. We show that transformation by B-Myb involves its ability to activate transcription. Similar to other oncogenic transcription factors, such as c-Myc and E2F, we show that B-Myb also has repression activity. We demonstrate that the Cterminus of B-Myb can function as a repressor of transcription, that B-Myb interacts with the repressor molecules BS69 and NCoR and that the repression function, like the transactivation domain, contributes to B-myb transformation. q

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Ectopic expression of A-mybin transgenic mice causes follicular hyperplasia and enhanced B lymphocyte proliferation

Cited by 26 publications

References 20 publications

A high throughput embryonic stem cell screen identifies Oct-2 as a bifunctional regulator of neuronal differentiation

A high throughput embryonic stem cell screen identifies Oct-2 as a bifunctional regulator of neuronal differentiation

The myb gene family in cell growth, differentiation and apoptosis

B-myb rescues ras-induced premature senescence, which requires its transactivation domain

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