Activin C Antagonizes Activin A in Vitro and Overexpression Leads to Pathologies in Vivo

Gold, Elspeth; Jetly, Niti M.; O'Bryan, Moira K; Meachem, Sarah J; Srinivasan, Deepa; Behuria, Supreeti; Sanchez-Partida, L. G.; Woodruff, Teresa K.; Hedwards, Shelley; Wang, Hong; McDougall, H.; Casey, Victoria; Niranjan, Birunthi; Patella, Shane; Risbridger, Gail P.

doi:10.2353/ajpath.2009.080296

Cited by 68 publications

(69 citation statements)

References 46 publications

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“…Activin C does not activate activin A-responsive promoters and it was suggested that the beta C subunit down-regulates the levels of bioactive activin A via the formation of signaling-incompetent activin AC heterodimers in PC3 human prostate cancer cells [9,86] . In a recent study from the same group, it was shown that homodimeric activin C inhibited activin A-induced Smad2 phosphorylation and growth inhibition, and that activin beta C transgenic mice develop prostate, testis and liver pathologies suggestive of an activin A antagonistic effect [87] . In line with these observations, elevated beta C immunoreactivity was found in human prostate, testis and liver cancers [87] .…”

Section: Beta C and Beta Ementioning

confidence: 99%

“…In a recent study from the same group, it was shown that homodimeric activin C inhibited activin A-induced Smad2 phosphorylation and growth inhibition, and that activin beta C transgenic mice develop prostate, testis and liver pathologies suggestive of an activin A antagonistic effect [87] . In line with these observations, elevated beta C immunoreactivity was found in human prostate, testis and liver cancers [87] . Like beta C, also the beta E subunit is highly expressed in the liver, but has been detected at lower levels in several other tissues as well [7,11,88,89] .…”

Section: Beta C and Beta Ementioning

confidence: 99%

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Activins and follistatins: Emerging roles in liver physiology and cancer

Kreidl

Öztürk²,

Metzner³

et al. 2009

WJH

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Activins are secreted proteins belonging to the TGF-β family of signaling molecules. Activin signals are crucial for differentiation and regulation of cell proliferation and apoptosis in multiple tissues. Signal transduction by activins relies mainly on the Smad pathway, although the importance of crosstalk with additional pathways is increasingly being recognized. Activin signals are kept in balance by antagonists at multiple levels of the signaling cascade. Among these, follistatin and FLRG, two members of the emerging family of follistatin-like proteins, can bind secreted activins with high affinity, thereby blocking their access to cell surface-anchored activin receptors. In the liver, activin A is a major negative regulator of hepatocyte proliferation and can induce apoptosis. The functions of other activins expressed by hepatocytes have yet to be more clearly defined. Deregulated expression of activins and follistatin has been implicated in hepatic diseases including inflammation, fibrosis, liver failure and primary cancer. In particular, increased follistatin levels have been found in the circulation and in the tumor tissue of patients suffering from hepatocellular carcinoma as well as in animal models of liver cancer. It has been argued that up-regulation of follistatin protects neoplastic hepatocytes from activin-mediated growth inhibition and apoptosis. The use of follistatin as biomarker for liver tumor development is impeded, however, due to the presence of elevated follistatin levels already during preceding stages of liver disease. The current article summarizes our evolving understanding of the multi-faceted activities of activins and follistatins in liver physiology and cancer.

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Section: Beta C and Beta Ementioning

confidence: 99%

Section: Beta C and Beta Ementioning

confidence: 99%

Activins and follistatins: Emerging roles in liver physiology and cancer

Kreidl

Öztürk²,

Metzner³

et al. 2009

WJH

View full text Add to dashboard Cite

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“…The formation of homodimeric activin C (bC-bC), heterodimeric activins AC (bA-bC), BC (bB-bC), and CE (bC-bE), and inhibin C (a-b) has been demonstrated by ectopic expression of the respective subunits in different cell models (Mellor et al 2000;Ushiro et al 2006). Interestingly, activin C (bC-C) does not activate activin A (bA-bA)-responsive promoters, suggesting that the bC subunit regulates the levels of bioactive activin A (bA-bA) through the formation of signalingincompetent activin AC heterodimers (Mellor et al 2003;Butler et al 2005;Gold et al 2009). Therefore, the bC subunit might function as an antagonist of activin function and thereby regulate activin signaling (Mellor et al 2000(Mellor et al ,2003.…”

Section: Discussionmentioning

confidence: 99%

“…However, this subunit has been detected in cells from several other organs, including normal or malignant prostate and ovarian, testicular, endometrial, and pituitary tissues (Loveland et al 1996;Mellor et al 2000;Gold et al 2004Gold et al ,2009Kimmich et al in press). The inhibin bC gene was detected in placental tissue from uncomplicated term pregnancies and pregnancies with preeclampsia (Casagrandi et al 2003).…”

Section: Discussionmentioning

confidence: 99%

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Immunohistochemical Labeling of the Inhibin/Activin βC Subunit in Normal Human Placental Tissue and Chorionic Carcinoma Cell Lines

Weißenbacher

Brüning

Kimmich

et al. 2010

J Histochem Cytochem.

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(JM) S U M M A R Y Inhibins and activins are important regulators of the female reproductive system. A novel inhibin subunit, named bC, has been identified and demonstrated to be expressed in several human tissues. We demonstrate here that inhibin bC is expressed in human placenta. Expression of the inhibin bC subunit was demonstrated at the protein level by means of immunohistochemical evaluation and at the transcriptional level by an inhibin bC-specific RT-PCR analysis. Expression of inhibin bC was detected in the human chorionic carcinoma cell lines JEG and BeWo. Although the precise role of this novel inhibin subunit in human placenta development and homeostasis is unclear, analogies with other inhibin subunits and the strong expression of bC in normal human trophoblast cells and chorionic carcinoma cells suggest that bC may be involved in autocrine/paracrine signaling pathways, angiogenesis, decidualization, and tissue remodeling under normal and malignant conditions. Additionally, JEG and BeWo express bC and, therefore, can be used as a cell culture model for further functional analysis of this subunit in the human placenta. (J Histochem Cytochem 58:751-757, 2010)

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Differentiation of mouse embryonic stem cells into hepatocytes induced by a combination of cytokines and sodium butyrate

Zhou

Tan

et al. 2009

J of Cellular Biochemistry

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There is increasing evidence to suggest that embryonic stem cells (ESCs) are capable of differentiating into hepatocytes in vitro. In this study, we used a combination of cytokines and sodium butyrate in a novel three-step procedure to efficiently direct the differentiation of mouse ESCs into hepatocytes. Mouse ESCs were first differentiated into definitive endoderm cells by 3 days of treatment with Activin A. The definitive endoderm cells were then differentiated into hepatocytes by the addition of acidic fibroblast growth factor (aFGF) and sodium butyrate to the culture medium for 5 days. After 10 days of further in vitro maturation, the morphological and phenotypic markers of hepatocytes were characterized using immunohistochemistry, immunoblotting, and reverse transcription-polymerase chain reaction (RT-PCR). Furthermore, the cells were tested for functions associated with mature hepatocytes, including glycogen storage and indocyanine green uptake and release, and the ratio of hepatic differentiation was determined by counting the percentage of albumin-positive cells. In the presence of medium containing cytokines and sodium butyrate, numerous epithelial cells resembling hepatocytes were observed, and approximately 74% of the cells expressed the hepatic marker, albumin, after 18 days in culture. RT-PCR analysis and immunohistochemistry showed that these cells expressed adult liver cell markers, and had the abilities of glycogen storage and indocyanine green uptake and release. We have developed an efficient method for directing the differentiation of mouse ESCs into cells that exhibit the characteristics of mature hepatocytes. This technique will be useful for research into the molecular mechanisms underlying liver development, and could provide a source of hepatocytes for transplantation therapy and drug screening.

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Activin C Antagonizes Activin A in Vitro and Overexpression Leads to Pathologies in Vivo

Cited by 68 publications

References 46 publications

Activins and follistatins: Emerging roles in liver physiology and cancer

Activins and follistatins: Emerging roles in liver physiology and cancer

Immunohistochemical Labeling of the Inhibin/Activin βC Subunit in Normal Human Placental Tissue and Chorionic Carcinoma Cell Lines

Differentiation of mouse embryonic stem cells into hepatocytes induced by a combination of cytokines and sodium butyrate

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