Receptor Tyrosine Kinases Inhibit Bone Morphogenetic Protein-Smad Responsive Promoter Activity and Differentiation of Murine MC3T3-E1 Osteoblast-like Cells

Nakayama, Konosuke; Tamura, Yasuhiro; Suzawa, Miyuki; Harada, Satoru; Fukumoto, Seiji; Kato, Mitsuyasu; Miyazono, Kohei; Rodan, Gideon A.; Takeuchi, Yasuhiro; Fujita, Toshiro

doi:10.1359/jbmr.2003.18.5.827

Cited by 80 publications

(55 citation statements)

References 59 publications

(79 reference statements)

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“…Epidermal growth factor (EGF)-induced receptor tyrosine kinase activation suppresses BMP-2-induced differentiation of osteoblasts by interfering with Smad-1 activity (Nakayama et al, 2003). Integrin activation of focal adhesion kinase (FAK) induces Ras and the downstream Erk in ostoeblasts.…”

Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein 2 stimulation of tumor growth involves the activation of Smad-1/5

2005

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Morphogenetic protein 2 (BMP-2) is normally expressed in the embryo promoting the development of several organs. Aberrant expression of BMP-2 occurs in approximately 98% of lung carcinomas, however, its role in regulating tumor growth is poorly understood. We show that BMP-2 induces Id-1 expression in lung cancer cell lines through its activation of Smad-1/5, which is dependent on cell culture conditions. A549 cells in DMEM/5% FCS BMP-2 activated Smad-1/5 and caused a transient increase in proliferation. In serum-free medium, BMP-2 induced significantly less Smad-1/5 activation and Id-1 expression, and produced significant growth inhibition. The affect of BMP-2 on tumor growth in vivo was substantially more significant. Recombinant BMP-2 coinjected with A549 cells, into nude mice increased proliferation and produced an increase in Id-1 expression. Forced expression of BMP-2 in A549 cells significantly enhanced tumor growth in the lungs following intravenous injection but not of subcutaneous tumors. Tumors in the lung were found to have an activated Smad-1/5 and expressed Id-1. Subcutaneous tumors expressed less activated Smad-1/5 and Id-1 than that of controls. Human lung carcinomas were also found to express an activated Smad-1/5 and Id-1. We provide evidence that BMP-2 promotes tumor growth. This paper highlights that cell culture experiments may not reveal the full biological affects of BMP-2, and its activity varies depending of the local environment.

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Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein 2 stimulation of tumor growth involves the activation of Smad-1/5

2005

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“…However, we and others (56) did not observe inhibition of nuclear translocation of Smads in the presence of receptor tyrosine kinase signaling. Also, Nakayama et al (57) show that receptor tyrosine kinase signaling can suppress the transactivating properties of a Gal4-Smad1 chimeric protein that is constitutively nuclear. Furthermore, we found that the BMP-dependent gene expression was not generally suppressed as might be expected if nuclear translocation of Smads was absent.…”

Section: Discussionmentioning

confidence: 99%

FGF18 Represses Noggin Expression and Is Induced by Calcineurin

Reinhold

Abe

Kapadia

et al. 2004

Journal of Biological Chemistry

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“…The relationship between the TGFb/ BMP antigrowth and Ras/MAP-K progrowth signalling pathways remains unclear, but there is recent evidence of crosstalk between them (Kretzschmar et al, 1997;Yue et al, 1999;Wach et al, 2001). While BMP-2 stimulation of osteoblasts leads to activation of Ras (Nakayama et al, 2003), in Xenopus, BMP-4-stimulated erythroid differentiation is inhibited by dominant-negative activation of the Ras pathway (Xu et al, 1996). SMAD7, one of the inhibitory SMADs of the BMP/TGFb signalling pathway, has been shown to cooperate with oncogenic Ras to escape growth arrest (Liu et al, 2003).…”

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confidence: 99%

Interaction between the bone morphogenetic proteins and Ras/MAP-kinase signalling pathways in lung cancer

et al. 2005

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Bone morphogenetic proteins (BMPs) are an integral component of the TGFb superfamily, responsible for regulation of cell proliferation, differentiation, migration and programmed cell death in a variety of cell types. The BMPs transduce their signals directly through the SMAD family of proteins but they also have been reported to interact with the MAPK and Erk pathways. Inactivation of the BMP pathway genes has been implicated as important in several cancers. Recent work has shown that BMP3b is epigenetically inactivated in cancer and suggests that BMP6 can be epigenetically inactivated. We investigated whether BMP6 is epigenetically inactivated in cell lines and whether BMP3b and BMP6 are epigenetically inactivated in non-small-cell lung cancer (NSCLC). We also studied the relationship between BMP methylation and k-ras mutation. Here, we demonstrate that the BMP3b and BMP6 genes are common targets of epigenetic inactivation in NSCLC, and that they are significantly more likely to be concurrently inactivated (P ¼ 0.009). Furthermore, this coinactivation of BMP3b and BMP6 is significantly associated with mutation of k-ras codon 12 in lung cancer (P ¼ 0.003); those with a k-ras mutation were six times more likely to have concurrent methylation of these BMP loci. Hence, these data suggest that concurrent inactivation of the BMP and activation of the Ras signalling pathways are important in lung carcinogenesis.

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Receptor Tyrosine Kinases Inhibit Bone Morphogenetic Protein-Smad Responsive Promoter Activity and Differentiation of Murine MC3T3-E1 Osteoblast-like Cells

Cited by 80 publications

References 59 publications

Bone morphogenetic protein 2 stimulation of tumor growth involves the activation of Smad-1/5

Bone morphogenetic protein 2 stimulation of tumor growth involves the activation of Smad-1/5

FGF18 Represses Noggin Expression and Is Induced by Calcineurin

Interaction between the bone morphogenetic proteins and Ras/MAP-kinase signalling pathways in lung cancer

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