Retroviral Insertional Mutagenesis in Murine Promonocytic Leukemias:c-myb and Mm/1

Wolff, Linda; Koller, Richard; Bies, Juraj; Nazarov, Viktor; Hoffman, Barbara; Amanullah, Arshad; Krall, Marianne; Mock, Beverly A.

doi:10.1007/978-3-642-85232-9_19

Cited by 11 publications

(14 citation statements)

References 23 publications

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“…The in¯uence of c-Myb may be indirect through, for example, transactivation of a repressor of the p15 INK4b promoter. One might speculate that c-Myb prevents a general growth arrest pathway from being turned on during di erentiation, even though c-Myb does not inhibit development of the monocytic phenotype itself as reported previously Wol et al, 1996).…”

Section: Discussionmentioning

confidence: 54%

Deregulated c-Myb expression in murine myeloid leukemias prevents the up-regulation of p15INK4b normally associated with differentiation

et al. 2001

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Section: Discussionmentioning

confidence: 54%

Deregulated c-Myb expression in murine myeloid leukemias prevents the up-regulation of p15INK4b normally associated with differentiation

et al. 2001

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“…Indeed, Gonda and coworkers have demonstrated, using an in vitro transformation assay in fetal liver cells, that cells infected with virus expressing a COOH-terminally truncated form of c-Myb showed a higher level of transformation when cultured at low densities than cells infected with viruses expressing wild-type c-Myb (Ferraro et al, 1995). Although experiments conducted in our laboratory did not uncover di erences in capacities of truncated forms of c-Myb and normal c-Myb to e ect proliferation or phenotypic maturation of granulocytic and monocytic cells, the high level of LTR driven expression of myb in these experiments may have masked the subtle e ects of COOH-terminal truncation (Bies et al, 1995;Wol et al, 1996). The high level of expression, as utilized in these di erentiation studies, mimics the promotor insertion mechanism of activation which has been observed in murine myeloid leukemias with virus integration sites at the 5' end of c-myb; for these leukemias we believe LTR promotor driven transcription to be the major activating event.…”

Section: Discussionmentioning

confidence: 86%

Oncogenic activation of c-Myb by carboxyl-terminal truncation leads to decreased proteolysis by the ubiquitin-26S proteasome pathway

Bies

Wolff

1997

Oncogene

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c-myb activation by insertional mutagenesis in murine myeloid leukemias can lead to amino (NH 2 )-terminal or carboxyl (COOH)-terminal truncation of its protein product. We observed that in these leukemias, the steady state level of the protein truncated at the COOH terminus was remarkably higher than that of the protein truncated at the NH 2 -terminus or full length wild-type protein. To examine the rate of proteolysis of di erent forms of Myb in a uniform cellular background, the proteins were constitutively expressed in the myeloblast cell line M1, using the retrovirus vector LXSN. In pulse chase experiments, using metabolically 35 S-labeled proteins, it was determined that COOH-terminal truncation of c-Myb by 248 aa (CT-c-Myb) substantially increases protein stability, resulting in a t 1/2 of about 140 min, as compared to 50 min for full length c-Myb (FL-c-Myb). In an investigation of the mechanism involved in the in vivo degradation of this short lived transcription factor, inhibitors of the lysosomal (chloroquine), proteasomal (ALLM, ALLN, lactacystin) and calpains (EGTA, E64d, BAPTA/AM) pathways were utilized. Results of this experiment identi®ed the 26S proteasome as a major pathway responsible for rapid breakdown of the protein in hematopoietic cells. Further experiments carried out in vitro demonstrated that c-Myb can be ubiquitinated, suggesting that this process may be involved in the targeting of wild-type c-Myb to degradation by the 26S proteasome. In addition, it was demonstrated that CT-cMyb was less e ciently ubiquitinated than wild-type protein indicating that defects in modi®cation account for its escape from rapid turnover. We speculate that the increased half-life of c-Myb resulting from truncation could contribute to its transforming potential.

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“…For example, the c-myb gene is a common target of retroviral insertion leading to leukemia formation in mouse models (24,41). Recently, two genetic abnormalities in the human c-myb gene in T-ALL patients were found, a duplication of the c-myb gene and a reciprocal translocation of c-myb and T-cell receptor beta loci, with both of these abnormalities leading to the overexpression of c-Myb (4,16).…”

Section: Discussionmentioning

confidence: 99%

Alternative RNA Splicing Produces Multiple Forms of c-Myb with Unique Transcriptional Activities

O'Rourke

Ness

2008

Molecular and Cellular Biology

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Retroviral Insertional Mutagenesis in Murine Promonocytic Leukemias:c-myb and Mm/1

Cited by 11 publications

References 23 publications

Deregulated c-Myb expression in murine myeloid leukemias prevents the up-regulation of p15INK4b normally associated with differentiation

Deregulated c-Myb expression in murine myeloid leukemias prevents the up-regulation of p15INK4b normally associated with differentiation

Oncogenic activation of c-Myb by carboxyl-terminal truncation leads to decreased proteolysis by the ubiquitin-26S proteasome pathway

Alternative RNA Splicing Produces Multiple Forms of c-Myb with Unique Transcriptional Activities

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