Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism

Yu, Paul B.; Hong, Charles C.; Sachidanandan, Chetana; Babitt, Jodie L.; Deng, Donna Y.; Hoyng, Stefan A.; Lin, Herbert Y.; Bloch, Kenneth D.; Peterson, Randall T.

doi:10.1038/nchembio.2007.54

Cited by 933 publications

(943 citation statements)

References 51 publications

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“…A small molecule compound, DM, is reported to selectively decrease the level of SMAD1/5/8 phosphorylation by inhibiting the kinase activity of BMP type I receptor [11]. We confirmed this specific effect of DM on SMAD1/ 5/8 phosphorylation in Jurkat cells (Fig.…”

Section: Dm Inhibits Bmp-smad1/5/8 Signalling In Jurkat Cellssupporting

confidence: 81%

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Differential effects of inhibition of bone morphogenic protein (BMP) signalling on T‐cell activation and differentiation

et al. 2011

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Bone morphogenetic proteins (BMPs) are involved in patterning and cellular fate in various organs including the thymus. However, the redundancy of BMPs and their receptors have made it difficult to analyse their physiological roles. Here, we investigated the role of BMP signalling in peripheral CD4 1 T cells by analysing the effects of an inhibitor of BMP signalling, dorsomorphin. Dorsomorphin suppressed phosphorylation of SMAD1/5/8, suggesting that BMP signalling naturally occurs in T cells. At high doses, dorsomorphin suppressed proliferation of T cells in a dose-dependent manner, inducing G1 arrest. Also, dorsomorphin suppressed Th17 and induced Treg-cell differentiation, while preserving Th2 differentiation. Dorsomorphin efficiently suppressed IL-2 production even at low doses in mouse CD4 1 T cells, suggesting that the BMP-Smad signalling physiologically regulates IL-2 transcription in these cells. In addition, recombinant BMP2 induced a dosedependent multiphasic pattern of IL-2 production, while Noggin suppressed IL-2 production at higher doses in Jurkat cells. Notably, BMP signalling controlled the phosphorylation of RUNX1, revealing the molecular nature of its effect. Collectively, we describe multiple effects of dorsomorphin and Noggin on T-cell activation and differentiation, demonstrating a physiological role for BMP signalling in these processes.

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Section: Dm Inhibits Bmp-smad1/5/8 Signalling In Jurkat Cellssupporting

confidence: 81%

“…1). Thus, DM is a specific inhibitor of BMP-SMAD signalling in T cells, as the previous report showed using pulmonary artery smooth muscle cells [11].…”

Section: Dm Inhibits Bmp-smad1/5/8 Signalling In Jurkat Cellssupporting

confidence: 62%

Differential effects of inhibition of bone morphogenic protein (BMP) signalling on T‐cell activation and differentiation

et al. 2011

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“…In conclusion, although chemical inhibitors to the BMP type I receptors could be possible medicinal agents for FOP, 5,8 they further affect normal ALK2 receptor 7 and other BMP type I receptors, 9 as well as pathogenic (mutant) ALK2 receptors. Thus, the risk of adverse effects of the inhibitors cannot be excluded at present, and such problems remain to be solved.…”

Section: Resultsmentioning

confidence: 99%

Disease-causing allele-specific silencing against the ALK2 mutants, R206H and G356D, in fibrodysplasia ossificans progressiva

et al. 2011

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Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant congenital disorder characterized by progressive heterotopic bone formation. Currently, no definitive treatment exists for FOP. The activin receptor type IA / activin-like kinase 2 (ACVR1/ALK2) gene has been identified as the responsible gene for FOP, and disease-associated ALK2 mutations have been found. Chemical inhibitors to the pathogenic ALK2 receptors are considered possible medical agents for FOP, but their adverse effects on normal ALK2 and other receptors cannot be excluded. Here we describe another treatment strategy for FOP using allele-specific RNA interference (ASP-RNAi), and show modified small interfering RNAs (siRNAs) conferring allele-specific silencing against disease-causing ALK2 mutants found in FOP, without affecting normal ALK2 allele. Thus, the siRNAs presented here may become novel therapeutic agents for FOP, and their induced ASP-RNAi may pave the way for the achievement of radical treatment of FOP and/or for the relief of its severe symptoms.

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“…In addition to natural BMP antagonists, including noggin, Yu et al (2008) have recently developed dorsomorphin, a novel small-molecule inhibitor for BMP type I receptor kinases. Although the effects of BMP signaling on the progression of breast cancer bone metastases appear to be context-dependent, inhibition of BMP signaling offers a new potential therapeutic strategy for the treatment of metastases of breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway

et al. 2008

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Transforming growth factor (TGF)-b is known to promote tumor invasion and metastasis. Although bone morphogenetic proteins (BMPs), members of the TGF-b family, are expressed in a variety of human carcinoma cell lines, their roles in tumor progression have not been fully clarified. In this study, we sought to determine the roles of BMPs in the progression of breast cancer bone metastasis using human breast cancer samples and a mouse xenograft model. Immunohistochemical analysis of samples from breast cancer patients as well as a mouse xenograft model of MDA-231-D, highly metastatic human breast cancer cells, revealed phospho-Smad2 and phospho-Smad1/5/8 staining in the nuclei of cancer cells in primary tumor and/ or bone metastasis. Using a functional in vivo bioluminescence imaging system, we showed that TGF-b-and BMPinduced transcriptional pathways are active in bone metastatic lesions in vivo. In addition, both TGF-b3 and BMP-2 promoted the motility and invasiveness of the MDA-231-D cells in vitro. Moreover, expression of dominant-negative receptors for TGF-b and/or BMPs in the MDA-231-D cells inhibited invasiveness in vitro and bone metastasis in the xenograft model. These results suggest that BMPs as well as TGF-b promote invasion and bone metastasis of breast cancer.

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Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism

Cited by 933 publications

References 51 publications

Differential effects of inhibition of bone morphogenic protein (BMP) signalling on T‐cell activation and differentiation

Differential effects of inhibition of bone morphogenic protein (BMP) signalling on T‐cell activation and differentiation

Disease-causing allele-specific silencing against the ALK2 mutants, R206H and G356D, in fibrodysplasia ossificans progressiva

Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway

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