Biology of BMP signalling and cancer

Blanco-Calvo, Moisés; Fernández, Victoria Bolós; Villaamil, Vanessa Medina; Gallego, Guadalupe Aparicio; Prado, S. Díaz; Pulido, Enrique Grande

doi:10.1007/s12094-009-0328-8

Cited by 61 publications

(51 citation statements)

References 27 publications

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“…Among the MYCresponsive genes, we searched for candidate drivers of MYC-dependent tumorigenesis in MB. The results suggested the possible relevance of bone morphogenetic proteins (BMPs), which are cytokines of the family of the transforming growth factor-b (Blanco Calvo et al, 2009). BMPs can be activated, both in a paracrine and autocrine way, to promote recruitment of cell surface serine/threonine kinase receptors, thus triggering activation of SMAD transcription factors (Miyazono et al, 2005(Miyazono et al, , 2010.…”

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Bone morphogenetic protein-7 is a MYC target with prosurvival functions in childhood medulloblastoma

et al. 2011

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Medulloblastoma (MB) is the most common malignant brain tumor in children. It is known that overexpression and/or amplification of the MYC oncogene is associated with poor clinical outcome, but the molecular mechanisms and the MYC downstream effectors in MB remain still elusive. Besides contributing to elucidate how progression of MB takes place, most importantly, the identification of novel MYC-target genes will suggest novel candidates for targeted therapy in MB. A group of 209 MYC-responsive genes was obtained from a complementary DNA microarray analysis of a MB-derived cell line, following MYC overexpression and silencing. Among the MYC-responsive genes, we identified the members of the bone morphogenetic protein (BMP) signaling pathway, which have a crucial role during the development of the cerebellum. In particular, the gene BMP7 was identified as a direct target of MYC. A positive correlation between MYC and BMP7 expression was documented by analyzing two distinct sets of primary MB samples. Functional studies in vitro using a small-molecule inhibitor of the BMP/SMAD signaling pathway reproduced the effect of the small interfering RNA-mediated silencing of BMP7. Both approaches led to a block of proliferation in a panel of MB cells and to inhibition of SMAD phosphorylation. Altogether, our findings indicate that high MYC levels drive BMP7 overexpression, promoting cell survival in MB cells. This observation suggests the potential relevance of targeting the BMP/SMAD pathway as a novel therapeutic approach for the treatment of childhood MB.

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Bone morphogenetic protein-7 is a MYC target with prosurvival functions in childhood medulloblastoma

et al. 2011

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“…One of the pathways that is crucial for embryonic development and whose dysregulation is also implicated in human disease is the bone morphogenetic protein (BMP) signalling pathway (Blanco Calvo et al, 2009;Wu and Hill, 2009;Lowery and de Caestecker, 2010). BMPs are members of the TGFβ superfamily of ligands.…”

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A BMP regulatory network controls ectodermal cell fate decisions at the neural plate border

2013

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SUMMARYDuring ectodermal patterning the neural crest and preplacodal ectoderm are specified in adjacent domains at the neural plate border. BMP signalling is required for specification of both tissues, but how it is spatially and temporally regulated to achieve this is not understood. Here, using a transgenic zebrafish BMP reporter line in conjunction with double-fluorescent in situ hybridisation, we show that, at the beginning of neurulation, the ventral-to-dorsal gradient of BMP activity evolves into two distinct domains at the neural plate border: one coinciding with the neural crest and the other abutting the epidermis. In between is a region devoid of BMP activity, which is specified as the preplacodal ectoderm. We identify the ligands required for these domains of BMP activity. We show that the BMP-interacting protein Crossveinless 2 is expressed in the BMP activity domains and is under the control of BMP signalling. We establish that Crossveinless 2 functions at this time in a positive-feedback loop to locally enhance BMP activity, and show that it is required for neural crest fate. We further demonstrate that the Distal-less transcription factors Dlx3b and Dlx4b, which are expressed in the preplacodal ectoderm, are required for the expression of a cell-autonomous BMP inhibitor, Bambi-b, which can explain the specific absence of BMP activity in the preplacodal ectoderm. Taken together, our data define a BMP regulatory network that controls cell fate decisions at the neural plate border.

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“…Dysregulation of BMP signaling is also implicated in disease states including cancer (1). The canonical signaling pathway stimulated by BMP receptor engagement is the phosphorylation of the SMADs (mothers against decapentaplegic homologs), SMAD1, SMAD5, and SMAD9, which facilitates active transport of these mediators from the cytoplasm to the nucleus, where they bind and activate cellular promoters.…”

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“…Using this signaling mechanism, the phenotypic outcome of BMP receptor engagement is controlled by the level of activation of other signaling pathways and SMAD binding cofactors. While activation of BMP signaling appears to contribute to some cancer types, it inhibits other cancer types by promoting growth arrest and differentiation and by inducing senescence (1). In immune cells, BMP signaling has been shown by multiple groups to inhibit lymphocyte activation, maturation, and growth (2,6,13,18,19,37).…”

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MicroRNA miR-155 Inhibits Bone Morphogenetic Protein (BMP) Signaling and BMP-Mediated Epstein-Barr Virus Reactivation

Yin¹,

Wang²,

Fewell³

et al. 2010

J Virol

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Despite the limited genetic content of microRNAs, their pervasive role in controlling normal and pathology-associated cellular processes has become firmly established in recent years. The importance of microRNA dysregulation in cancer is well appreciated, and a number of oncomirs and tumor suppressor microRNAs have been identified (15). As a member of the oncomir class of microRNAs, miR-155 is implicated in lymphomagenesis and a wide array of nonlymphoid tumors including breast, colon, and lung (7,16,24,39,42,43). Despite strong evidence implicating miR-155 in cancer etiology, the mechanisms through which miR-155 supports the tumor phenotype are unclear, possibly due to limited knowledge of how predicted targets may be involved in the phenotypic properties of cancer. On the other hand, miR-155's roles in normal immune cell development and the adaptive immune response are much better understood (33, 41). These studies have demonstrated a critical role for miR-155 in immune cell activation and maturation. This evidence and other work (8, 40) have identified critical miR-155 targets whose downregulation is required for these processes.The Epstein-Barr virus (EBV) is a human DNA tumor virus that contributes to lymphoid and epithelial cell malignancies. As a herpesvirus, a unique aspect of the EBV infection cycle is the ability to exist in either a lytic replicative state or in a latent state in which no virus is produced. Depending in part on cell background, EBV utilizes multiple forms of latency gene expression programs. True latency and type I latency are defined by the expression of no protein coding genes or by expression of the episomal replication factor EBNA1 only. Type II latency is defined by the expression of EBNA1 and the latent membrane proteins, LMP1 and/or LMP2, and is the predominant form observed in epithelial tissues. Type III latency refers to expression of the full repertoire of latency genes, which are highly tumorigenic and are capable of growth-transforming naïve resting B cells. While this form of latency is not well tolerated in immunocompetent individuals except during early stages of infection (prior to the development of adaptive immunity to these proteins), type III latency-associated lymphoid malignancies are common in immunocompromised individuals. Expression of type III latency genes in B cells mimics antigen-dependent B-cell activation, and accompanying this activation is a substantial induction of miR-155 expression (17,20,23,29,44). While it is reasonable to assume that induction of miR-155 by the type III latency program plays a role in EBV-mediated B-cell activation and oncogenesis, little is known regarding the role of miR-155 in the virus life cycle or its tumorpromoting activities.Originally identified as cytokines critically involved in the regulation of osteogenic differentiation, bone morphogenetic proteins (BMPs) are now appreciated as having critical functions in a vast number of developmental processes. Dysregulation of BMP signaling is also implicated in disease states ...

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Biology of BMP signalling and cancer

Cited by 61 publications

References 27 publications

Bone morphogenetic protein-7 is a MYC target with prosurvival functions in childhood medulloblastoma

Bone morphogenetic protein-7 is a MYC target with prosurvival functions in childhood medulloblastoma

A BMP regulatory network controls ectodermal cell fate decisions at the neural plate border

MicroRNA miR-155 Inhibits Bone Morphogenetic Protein (BMP) Signaling and BMP-Mediated Epstein-Barr Virus Reactivation

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