Bone morphogenetic proteins-2 and -4 attenuate apoptosis in a cerebellar primitive neuroectodermal tumor cell line

Iantosca, Mark; McPherson, Clifton E.; Ho, Shih Yieh; Maxwell, Gerald D.

doi:10.1002/(sici)1097-4547(19990501)56:3<248::aid-jnr4>3.0.co;2-u

Cited by 36 publications

(8 citation statements)

References 81 publications

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“…For the first 120 h, the growth rate of the 4D6 cells (μ max : 0.013 h −1 ) is similar to that of the CHOsus cells (μ max : 0.015 h −1 ). Afterward, the viability of the CHOsus cultures declines, while that of the 4D6 cultures remains at nearly 80 % for another 72 h. Several groups have reported an anti-apoptotic effect of BMP proteins on mammalian cells [36][37][38]. A similar effect may be operative here.…”

Section: Production Of Human Bmp2 In Stably Transfected Cho Cellssupporting

confidence: 56%

Comparison of cell‐based versus cell‐free mammalian systems for the production of a recombinant human bone morphogenic growth factor

Jérôme

Thoring

Salzig

et al. 2017

Engineering in Life Sciences

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The human bone morphogenetic protein-2 (hBMP2) is a glycoprotein, which induces de novo bone formation. Here, recombinant production in stably transfected Chinese Hamster Ovary (CHO) cells is compared to transient expression in Human Embryo Kidney (HEK) cells and cell-free synthesis in CHO cell lysates containing microsomal structures as sites of post-translational processing. In case of the stably transfected cells, growth rates and viabilities were similar to those of the parent cells, while entry into the death phase of the culture was delayed. The maximum achievable rhBMP2 concentration in these cultures was 153 pg/mL. Up to 280 ng/mL could be produced in the transient expression system. In both cases the rhBMP-2 was found to interact with the producer cells, which presumably contributed to the low yields. In the cell-free system, hBMP2 yields could be increased to almost 40 μg/mL, reached within three hours. The cell-free system thus approached productivities for the active (renatured) protein previously only recorded for bacterial hosts, while assuring comprehensive post-translational processing

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Section: Production Of Human Bmp2 In Stably Transfected Cho Cellssupporting

confidence: 56%

Comparison of cell‐based versus cell‐free mammalian systems for the production of a recombinant human bone morphogenic growth factor

Jérôme

Thoring

Salzig

et al. 2017

Engineering in Life Sciences

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“…Additional investigations on the role of other BMP family members will emphasize the relevance of the whole pathway in the development of MB. They will also help to shed lights on the emerging recent data showing opposite effects of BMPs, such as BMP2 and BMP4, to whom either anti-apoptotic (Iantosca et al, 1999) or anti-proliferative properties (Zhao et al, 2008) were assigned.…”

Section: Discussionmentioning

confidence: 96%

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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“…Previous studies have described that BMPs are able to promote cell survival in the CNS (Iantosca et al, 1999;Izumi et al, 2001;Wang et al, 2001;Gratacos et al, 2002;Yabe et al, 2002;Chang et al, 2003). Before studying the eventual effect of BMP-6 on survival of cultured CGCs under proapoptotic conditions, we analyzed the expression of BMP receptors and Smad proteins at different days in vitro (DIV).…”

Section: Bmp-6 Protects Against K5-induced Apoptosis In Mature Cgcsmentioning

confidence: 99%

Bone Morphogenetic Protein-6 Promotes Cerebellar Granule Neurons Survival by Activation of the MEK/ERK/CREB Pathway

Barneda-Zahonero

Miñano-Molina

Badiola

et al. 2009

MBoC

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Bone morphogenetic proteins (BMPs) have been implicated in the generation and postnatal differentiation of cerebellar granule cells (CGCs). Here, we examined the eventual role of BMPs on the survival of these neurons. Lack of depolarization causes CGC death by apoptosis in vivo, a phenomenon that is mimicked in vitro by deprivation of high potassium in cultured CGCs. We have found that BMP-6, but not BMP-7, is able to block low potassium-mediated apoptosis in CGCs. The neuroprotective effect of BMP-6 is not accompanied by an increase of Smad translocation to the nucleus, suggesting that the canonical pathway is not involved. By contrast, activation of the MEK/ERK/CREB pathway by BMP-6 is necessary for its neuroprotective effect, which involves inhibition of caspase activity and an increase in Bcl-2 protein levels. Other pathways involved in the regulation of CGC survival, such as the c-Jun terminal kinase and the phosphatidylinositol 3-kinase (PI3K)-Akt/PKB, were not affected by BMP-6. Moreover, failure of BMP-7 to activate the MEK/ ERK/CREB pathway could explain its inability to protect CGCs from low potassium-mediated apoptosis. Thus, this study demonstrates that BMP-6 acting through the noncanonical MEK/ERK/CREB pathway plays a crucial role on CGC survival. INTRODUCTIONCerebellar granule cells (CGCs) are generated in the external granule layer and migrate to the internal granule layer (Ryder and Cepko, 1994). During their postnatal migration, CGCs require excitatory inputs for proper differentiation and development. Otherwise, CGCs die by apoptosis (Burgoyne and Cambray-Deakin, 1988;Wood et al., 1993). This situation can be mimicked in vitro in primary cultures of CGCs. These neurons undergo spontaneous apoptosis when they grow in the presence of low potassium concentration (5 mM KCl [K5]). By contrast, if they grow in the presence of high potassium concentrations (25 mM KCl [K25]) or N-methyl-d-aspartate (NMDA), they develop and survive (Gallo et al., 1987;Xifro et al., 2005).BMPs have been described to have an important role during differentiation of CGCs. For instance, BMP-2 and -4 are able to prevent Shh-induced proliferation, thereby allowing granule neuron differentiation (Rios et al., 2004). Expression of granule cell markers such as math1 or Zic has been reported to be controlled by BMPs (Aruga et al., 1994;Ben Arie et al., 1997). Accordingly, Alder et al. (1999) have demonstrated that exposure of neural cells to BMPs induces CGC phenotype, whereas CGC differentiation is greatly impaired in BMP receptors conditional knockout mice (Qin et al., 2006). Moreover, Smad 1 and BMP-4 expression and protein levels peak during CGC differentiation and migration toward the internal granule cell layer (IGL; Angley et al., 2003). Besides its role in CGC differentiation, several reports have suggested that BMPs have an antiapoptotic effect in many cell types (Izumi et al., 2001;Wang et al., 2001;Harvey et al., 2004), which opens the possibility that they could be also involved on regulation of CGC survival (Yabe et...

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Bone morphogenetic proteins-2 and -4 attenuate apoptosis in a cerebellar primitive neuroectodermal tumor cell line

Cited by 36 publications

References 81 publications

Comparison of cell‐based versus cell‐free mammalian systems for the production of a recombinant human bone morphogenic growth factor

Comparison of cell‐based versus cell‐free mammalian systems for the production of a recombinant human bone morphogenic growth factor

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

Bone Morphogenetic Protein-6 Promotes Cerebellar Granule Neurons Survival by Activation of the MEK/ERK/CREB Pathway

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