Bone morphogenetic protein-5, -6 and -7 inhibit growth and induce apoptosis in human myeloma cells

Rø, Torstein Baade; Holt, Randi Utne; Brenne, Anne-Tove; Hjorth‐Hansen, Henrik; Waage, Anders; Hjertner, Øyvind; Sundan, Anders; Børset, Magne

doi:10.1038/sj.onc.1207386

Cited by 107 publications

(43 citation statements)

References 39 publications

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“…BMP-induced phosphorylation of R-Smad has been associated with various functional effects depending on the cellular systems. In normal and malignant B lineage cells, BMP have previously been shown to inhibit proliferation via R-Smad phosphorylation [16][17][18]28]. In our study we detected a rapid phosphorylation of Smad1/5/8 in both peripheral CD4 + T cells as well as in Jurkat TAg cells in response to BMP-6, although the level of pSmad1/5/8 was higher in the latter.…”

Section: Discussionsupporting

confidence: 45%

“…We have recently demonstrated the inhibitory effect of BMP-6 on immature as well as mature cells of B cell origin [16,17]. Similar effects were demonstrated for BMP-2, BMP-4, BMP-6 and BMP-7 in human myeloma cells [18,19]. Several studies have shown that BMP signalling may play a role in thymocyte differentiation.…”

Section: Discussionmentioning

confidence: 58%

“…1C). Since BMP-6 mainly utilizes the Alk-2 and BMPRII receptors, these data show that BMP-6 signalling is feasible in T cells [18].…”

Section: Resultsmentioning

confidence: 73%

“…However, we recently showed that BMP-6 inhibits growth of human B progenitors and mature B cells [16,17]. In multiple myeloma cells, BMP-2, BMP-4, BMP-6 and BMP-7 have been shown to have antiproliferative and proapoptotic effects [18,19]. Interestingly, BMP-2 and BMP-4 were shown to inhibit early thymocyte differentiation [20], whereas transgenic expression of the BMP antagonist Noggin implicated that BMP signalling was required for normal thymus development [21].…”

Section: Introductionmentioning

confidence: 99%

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Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

et al. 2007

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Bone morphogenetic proteins (BMP) are multifunctional cytokines that belong to the TGF-b superfamily. BMP have been shown to regulate haematopoietic stem cells, B lymphopoiesis and early thymocyte differentiation. In the present study we explored the role of BMP-6 in Jurkat TAg cells. BMP-6 rapidly induced phosphorylation of Smad1/5/8, p38 and ERK1/2, followed by a potent up-regulation of ID1, ID2 and ID3. ID1 and ID3 were also induced at the protein level. Genome-wide expression profiling of cells treated with BMP-6 compared to medium confirmed that ID1-ID3 were target genes of BMP-6 together with Noggin and Smad6. Furthermore, several genes involved in transcriptional regulation were also identified, including NFKBIA, HEY1, DLX2, KLF10 and early growth response 1. Stimulation with BMP-6 exerted an antiproliferative effect that was counteracted by inhibitor of DNA binding (Id)1 siRNA, indicating that Id1 is an important downstream mediator in Jurkat TAg cells. A subset of CD4 + T cells were found to express the BMP receptors Alk-2 and Alk-3 (type I), in addition to BMPRII (type II). BMP-6 also induced phosphorylation of Smad1/5/8, followed by transcriptional increase in ID1-ID3 mRNA expression. However, we did not observe significant changes in Id protein expression in CD4 + T cells. Altogether, the data indicate a role for BMP-6 in human T lineage cells.

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Section: Discussionsupporting

confidence: 45%

Section: Discussionmentioning

confidence: 58%

“…1C). Since BMP-6 mainly utilizes the Alk-2 and BMPRII receptors, these data show that BMP-6 signalling is feasible in T cells [18].…”

Section: Resultsmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

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Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

et al. 2007

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“…BMP-2 or -4 and retinoic acid induce apoptosis of pluripotent P19 embryonic carcinoma cells, whereas either BMP or retinoic acid alone shows little effect (Glozak and Rogers, 2001). As shown in previous reports, treatment with BMP-4 inhibits proliferation and induces apoptosis in some multiple myeloma cell lines and in freshly harvested myeloma cells (Hjertner et al, 2001;Baade Ro et al, 2004), though the mechanism remains unclear.…”

Section: Introductionmentioning

confidence: 79%

Execution of BMP-4-induced apoptosis by p53-dependent ER dysfunction in myeloma and B-cell hybridoma cells

et al. 2006

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Bone morphogenic protein (BMP)-4 inhibits proliferation and induces the apoptosis of myeloma cells. However, little is known about the molecular mechanisms of how BMP-4 executes this apoptosis. In this report, we investigated the roles of p53 and the endoplasmic reticulum (ER) in BMP-4-induced apoptosis of mouse hybridoma HS-72 cells. We found that 3 ng/ml of BMP-4 is sufficient to induce the expression of proapoptotic proteins, puma and bax, in a p53-dependent mechanism, and facilitate Ca 2 þ release from the ER to the cytosol, resulting in the activation of caspase-12 and ER dysfunction. Similarly to HS-72 cells, multiple myeloma cells with wild-type p53 genes show much higher sensitivity to BMP-4-induced apoptosis than cells without wild-type p53 genes, suggesting that wild-type p53 status is required for dysfunction of the ER during BMP-4-induced apoptosis in ER-enriched cells, such as hybridoma and myeloma cells. These findings demonstrate that the presence of wild-type p53 genes and enrichment of the ER determines the sensitivity to effective apoptosis by BMP-4, and suggest that ER stress-inducing agents would be valuable in the treatment of multiple myeloma.

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Osseous metaplasia in diffuse large B‐cell lymphoma of the kidney

2007

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A 57-year-old female with a history of diffuse large B-cell lymphoma (DLBCL) presented with a renal mass. Microscopic analysis of the nephrectomy specimen revealed DLBCL, confirmed by immunohistochemical analysis (CD45, CD20, CD3, pan-keratin) and polymerase chain reaction (PCR). Multiple spicules of metaplastic bone were identified within the tumor mass, but not within the uninvolved kidney parenchyma. No evidence of bone or dystrophic calcification was detected on the pre-nephrectomy computerized tomography (CT) scan. To our knowledge, this is the first incidence of osseous metaplasia occurring within DLBCL. The pathogenesis of osseous metaplasia is briefly discussed. Am. J. Hematol. 82:321-324, 2007. V V C 2006 Wiley-Liss, Inc.

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Bone morphogenetic protein-5, -6 and -7 inhibit growth and induce apoptosis in human myeloma cells

Cited by 107 publications

References 39 publications

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

Execution of BMP-4-induced apoptosis by p53-dependent ER dysfunction in myeloma and B-cell hybridoma cells

Osseous metaplasia in diffuse large B‐cell lymphoma of the kidney

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