B-myb antisense oligonucleotides inhibit proliferation of human hematopoietic cell lines

Arsura, Marcello; Introna, Martino; Passerini, F; Mantovani, Alberto; Golay, Joseé

doi:10.1182/blood.v79.10.2708.bloodjournal79102708

Cited by 37 publications

(21 citation statements)

References 25 publications

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“…Previous authors have reported that antisense B-myb induced apoptosis in cell lines representing neurobastoma and several haematopoietic lineages, including a B-cell line. 44,45 Our results, unlike earlier results on the survival of T cells 26 and myeloid cells, 25 revealed that antisense c-myb had little effect on the survival of REH cells. This suggests that B-Myb may play a more prominent role in B-cell survival.…”

Section: Discussioncontrasting

confidence: 95%

A transcriptional regulatory element in the coding sequence of the human Bcl‐2 gene

2004

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Summary We investigated the protein‐binding sites in a DNAse I hypersensitive site associated with bcl‐2 gene expression in human B cells. We mapped this hypersensitive site to the coding sequence of exon 2 of the bcl‐2 gene in the bcl‐2‐expressing REH B‐cell line. Electrophoretic mobility shift assays (EMSAs) with extracts from REH cells revealed three previously unrecognized B‐Myb‐binding sites in this sequence. The protein was identified as B‐Myb by using a specific antibody and EMSAs. Accordingly, the levels of B‐Myb and bcl‐2 proteins, and of Myb EMSA activity, were correlated over a wide range of cell lines, representing different stages of B‐cell development. Transfection of REH cells with antisense B‐myb down‐regulated EMSA activity and the level of bcl‐2, and led to the apoptosis of REH cells. Transfection of the bcl‐2‐non‐expressing RPMI 8226 cell line with a B‐Myb expression vector induced B‐Myb EMSA activity and the expression of bcl‐2. Reporter assays indicated that the HSS8 sequence containing the three B‐Myb sites may act as an enhancer when it is linked to the bcl‐2 gene promoter. Interaction of B‐Myb with HSS8 may enhance bcl‐2 gene expression by co‐operating with positive regulatory elements (e.g. previously identified B‐Myb response elements) or silencing negative response elements in the bcl‐2 gene promoter.

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Section: Discussioncontrasting

confidence: 95%

A transcriptional regulatory element in the coding sequence of the human Bcl‐2 gene

2004

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“…21 The phenotype of DREAM disruption thus closely resembles that of B-Myb over-expression. 22,23 These results support the idea of mandatory MMB complex formation when DREAM is unable to assemble and also suggest that B-Myb, when over-expressed, plays a causal role in disrupting DREAM. When DREAM is inactivated by genetic mutations in mice, abnormal binding of B-Myb to MuvB during the G1 phase of the cell cycle correlates with loss of DREAM target gene repression, leading to cell cycle deregulation.…”

Section: Introductionsupporting

confidence: 72%

The cell cycle gene regulatory DREAM complex is disrupted by high expression of oncogenic B-Myb

Iness

Felthousen

Ananthapadmanabhan

et al. 2017

Preprint

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The oncogene MYBL2 (encoding B-Myb) is a poor prognostic biomarker in many cancers. B-Myb interacts with the MuvB core of five proteins (LIN9, LIN37, LIN52, LIN53/RBBP4, and LIN54) to form the MMB (Myb-MuvB) complex and promotes expression of late cell cycle genes necessary for progression through mitosis. Both MYBL2 amplification and over-expression are associated with deregulation of the cell cycle and increased cell proliferation. Alternatively, by interacting with E2F4-DP1 and p130 or p107, the MuvB core becomes part of the DREAM complex (DP, RB-like, E2F, and MuvB). The DREAM complex opposes MMB by globally repressing cell cycle genes in G0/G1, maintaining the cell in a quiescent state. However, the specific mechanism by which B-Myb alters the cell cycle is not well understood. Our analysis of The Cancer Genome Atlas data revealed significant upregulation of DREAM and MMB target genes in breast and ovarian cancer with MYBL2 gain. Given that most of the DREAM target genes are not directly regulated by B-Myb, we investigated the effects of B-Myb on DREAM formation. We found that depletion of B-Myb results in increased DREAM formation in human cancer cells, while its overexpression inhibits DREAM formation in the non-transformed cells. Since the MuvB core subunit LIN52 is essential for assembly of both the DREAM and MMB complexes, we tested whether B-Myb disrupts DREAM by sequestering LIN52. Overexpression of LIN52 did not increase either DREAM or MMB formation, but instead increased the turnover rate of the endogenous LIN52 protein. Interestingly, co-expression of B-Myb increased the expression of both endogenous and overexpressed LIN52 while knockdown of B-Myb had an opposite effect. We found that regulation of LIN52 occurs at the protein level, and that activity of DYRK1A kinase, the enzyme that triggers DREAM complex formation by phosphorylating LIN52, is required for this regulation. These findings are the first to implicate B-Myb in the disassembly of the DREAM complex and offer insight into the underlying mechanisms of poor prognostic value of MYBL2 amplification in cancer. We conclude that B-Myb mediates its oncogenic effects not only by increasing mitotic gene expression by the MMB complex, but also by broad disruption of cell cycle gene regulatory programs through compromised DREAM formation.

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“…Although the exact function of B-Myb is unknown, it is very likely that it acts as a transcription factor. The strict cell cycle regulation of B-myb expression, and its importance for cell growth (Arsura et al, 1992;Sala and Calabretta, 1992), suggest that B-Myb may control entry into S phase, perhaps by targeting transcription of genes required for DNA synthesis (Sala and Calabretta, 1992). Expression of E7 can induce DNA synthesis in serum starved rodent cells (Sato et al, 1989;Banks et al, 1990a), and the ability to interact with pRb and p107 is necessary and may be sufficient for this activity (Banks et al, 1990b).…”

Section: Discussionmentioning

confidence: 99%

“…Disappearance of the GO/GI complex correlated with induction of B-myb transcription, suggesting that repression of promoter activity at this stage of the cell cycle is imposed by binding of this complex to the B-myb E2F site. Since B-myb expression is necessary for cell growth (Arsura et al, 1992;Sala and Calabretta, 1992), it is possible that B-Myb represents an important regulator of proliferation with a role in controlling entry into DNA synthesis.…”

Section: Introductionmentioning

confidence: 99%

HPV16 E7 oncoprotein deregulates B-myb expression: correlation with targeting of p107/E2F complexes.

et al. 1994

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HPV16 is a human tumour virus encoding two principal oncoproteins, E6 and E7. Expression of E7 can induce DNA synthesis in quiescent cells and this property coincides with its ability to bind to the cell proteins pRb and p107. As these cell proteins are regulators of the transcription factor E2F, we have investigated whether the interaction with E7 could result in induction of cell cycle regulated genes. We show that B‐myb, whose induction at the G1/S boundary is regulated by release from E2F mediated transcriptional repression, is a target for transcriptional activation by E7 and is the first E7 responsive cell gene to be identified. E7 transactivation leads to both inappropriate transcription of B‐myb during G1 and constitutive over‐expression in cycling cells. B‐Myb plays an essential role in cell cycle progression, and activation by E7 is likely to contribute to the mitogenic activity of the viral oncoprotein. Regulation of the B‐myb promoter in NIH3T3 cells correlates with binding of distinct p107‐containing complexes at the E2F binding site, and analysis of E7 mutants confirms that B‐myb transcription in these cells is regulated through interactions with p107 rather than pRb. These results provide the first example of a potentially specific role for p107 in the regulation of the cell cycle.

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B-myb antisense oligonucleotides inhibit proliferation of human hematopoietic cell lines

Cited by 37 publications

References 25 publications

A transcriptional regulatory element in the coding sequence of the human Bcl‐2 gene

A transcriptional regulatory element in the coding sequence of the human Bcl‐2 gene

The cell cycle gene regulatory DREAM complex is disrupted by high expression of oncogenic B-Myb

HPV16 E7 oncoprotein deregulates B-myb expression: correlation with targeting of p107/E2F complexes.

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