Regulation of Cell Proliferation, Apoptosis, and Carcinogenesis by Activin

Chen, Ye-Guang; Lui, Hannah M.; Lin, Shi-Lung; Lee, Jeffery M.; Ying, Shao‐Yao

doi:10.1177/153537020222700201

Cited by 206 publications

(171 citation statements)

References 172 publications

(186 reference statements)

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“…(14)(15)(16)(17) Subsequent studies have demonstrated that activins are expressed in diverse tissues and play important roles in embryology, wound healing, and tissue homeostasis. (18)(19)(20)(21)(22) Activins signal by binding either the activin receptor type IIA (ActRIIA) or the activin receptor type IIB, which recruits the type I receptor, activin-like kinase 4 (Alk4), leading to phosphorylation of cytoplasmic Smads 2/3. This complex associates with Smad 4 and translocates to the nucleus to regulate gene transcription.…”

Section: J Jbmrmentioning

confidence: 99%

Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo

Chantry

Heath

Mulivor

et al. 2010

Journal of Bone and Mineral Research

135

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Cancers that grow in bone, such as myeloma and breast cancer metastases, cause devastating osteolytic bone destruction. These cancers hijack bone remodeling by stimulating osteoclastic bone resorption and suppressing bone formation. Currently, treatment is targeted primarily at blocking bone resorption, but this approach has achieved only limited success. Stimulating osteoblastic bone formation to promote repair is a novel alternative approach. We show that a soluble activin receptor type IIA fusion protein (ActRIIA.muFc) stimulates osteoblastogenesis ( p < .01), promotes bone formation ( p < .01) and increases bone mass in vivo ( p < .001). We show that the development of osteolytic bone lesions in mice bearing murine myeloma cells is caused by both increased resorption ( p < .05) and suppression of bone formation ( p < .01). ActRIIA.muFc treatment stimulates osteoblastogenesis ( p < .01), prevents myeloma-induced suppression of bone formation ( p < .05), blocks the development of osteolytic bone lesions ( p < .05), and increases survival ( p < .05). We also show, in a murine model of breast cancer bone metastasis, that ActRIIA.muFc again prevents bone destruction ( p < .001) and inhibits bone metastases ( p < .05). These findings show that stimulating osteoblastic bone formation with ActRIIA.muFc blocks the formation of osteolytic bone lesions and bone metastases in models of myeloma and breast cancer and paves the way for new approaches to treating this debilitating aspect of cancer. ß

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Section: J Jbmrmentioning

confidence: 99%

Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo

Chantry

Heath

Mulivor

et al. 2010

Journal of Bone and Mineral Research

135

View full text Add to dashboard Cite

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“…Whereas apoptoticacting TGF-βs are well described in ontogenetic cell death and in the nervous system (Böttner et al 2000;Duenker and Krieglstein 2000Duenker et al 2002a, b;Krieglstein et al 2000;Sanchez-Capelo 2005;Schuster and Krieglstein 2002;Unsicker and Strelau 2000), apoptoticacting Activins have so far only been described in nonneural and adult systems (W. Chen et al 2000;Y.G. Chen et al 2002Y.G.…”

Section: Discussionmentioning

confidence: 99%

“…In neural systems, activins have been shown to promote survival rather than apoptosis (W. Chen et al 2000; Y.G. Chen et al 2002Chen et al , 2006. TGF-βs are also involved in developmental and neuronal apoptosis and cooperate with other secreted cytokines such as BMPs or TNF-α (Böttner et al 2000;Duenker and Krieglstein 2000Duenker et al 2002a, b;Franke et al 2006;Sanchez-Capelo 2005;Schuster et al 2003;Schuster and Krieglstein 2002;Unsicker and Strelau 2000).…”

Section: Introductionmentioning

confidence: 99%

TGF-β superfamily members, ActivinA and TGF-β1, induce apoptosis in oligodendrocytes by different pathways

et al. 2008

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Activins and transforming growth factor (TGF)-βs, members of the TGF-β superfamily, affect numerous physiological processes, including apoptosis, in a variety of organs and tissues. Apoptotic functions of TGF-βs, in contrast to those of the activins, are well documented in the developing and adult nervous system. TGF-βs operate in a contextdependent manner and cooperate with other cytokines in the regulation of apoptosis. In this study, we show, for the first time, an apoptotic function of ActivinA in the nervous system, i.e. in oligodendroglial progenitor cells. Using the oligodendroglial cell line OLI-neu, we show that ActivinA acts autonomously, without cooperating with TGF-β. In contrast to the mechanism of TGF-β-mediated apoptosis involving Bcl-xl down-regulation, Bcl-xl in ActivinA-induced apoptosis is classically sequestered by the BH3-only protein Puma.Puma expression is controlled by the transcription factor p53 as demonstrated by experiments with the p53 inhibitor Pifithrin-α. Furthermore, in the apoptotic TGF-β pathway, caspase-3 is activated, whereas in the apoptotic ActivinA pathway, apoptosis-inducing factor is released to trigger DNA fragmentation. These data suggest that TGF-β and ActivinA induce apoptosis in oligodendrocytes by different apoptotic pathways.

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“…Activin A modulates cell differentiation and proliferation by effecting a broad range of cellular targets (Chen et al, 2002). In order to identify which molecular pathways may be involved in signaling by SEL1L, we investigated the endogenous expression level of activin A and DPC4/SMAD4, two genes induced by TGF-b.…”

Section: Transcription and Western Blot Analysis Of Suit-2-sel1l Clonmentioning

confidence: 99%

SEL1L expression in pancreatic adenocarcinoma parallels SMAD4 expression and delays tumor growth in vitro and in vivo

et al. 2003

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Recent data suggest that SEL1L may play an important role in pancreatic carcinoma, similar to breast cancer, where the expression of SEL1L has been associated with a reduction in both proliferative activity in vitro and clinical tumor aggressiveness. To investigate this possibility, we examined the expression of Sel1L in a series of primary pancreatic carcinomas by immunohistochemistry and characterized the effects of Sel1L overexpression both in vitro and in vivo. In 74 pancreatic cancers analysed, 36% lacked Sel1L expression, although there was no significant correlation between the expression of Sel1L and any clinicopathologic parameter, including survival. However, immunohistochemical reactivity for Sel1L and Dpc4/ Smad4 was concordant in 69% of cases (v 2 test Po0.004). Overexpression of SEL1L in stably transfected pancreatic cancer cells caused both a decrease in clonogenicity and anchorage-independent growth as well as a significant increase in the levels of activin A and SMAD4. When implanted in nude mice, Suit-2-SEL1L-overexpressing clones displayed a considerably reduced rate of tumor growth. Thus, it can be hypothesized that Sel1L plays an important function in the growth and aggressiveness of pancreatic carcinoma. Moreover, our data provide evidence that SEL1L has an impact on the expression of genes involved in regulation of cellular growth, possibly through the TGF-b signaling pathway.

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Regulation of Cell Proliferation, Apoptosis, and Carcinogenesis by Activin

Cited by 206 publications

References 172 publications

Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo

Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo

TGF-β superfamily members, ActivinA and TGF-β1, induce apoptosis in oligodendrocytes by different pathways

SEL1L expression in pancreatic adenocarcinoma parallels SMAD4 expression and delays tumor growth in vitro and in vivo

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