Identification and characterization of follistatin as a novel angiogenin‐binding protein

Gao, Xiangwei; Hu, Huajun; Zhu, Junqiao; Xu, Zhengping

doi:10.1016/j.febslet.2007.10.059

Cited by 34 publications

(32 citation statements)

References 23 publications

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“…Table I shows the expression profile of FST and its targeting ligands in various tissues and organs of the human body. In addition, FST may also have an interaction with other non-TGFβ family proteins, such as angiogenin, known as a pro-angiogenic factor (61), and α2-macroglobulin, known as a serum pan-protease inhibitor (62). However, further investigations are required to explain the functional value of the interplay between FST and these molecules.…”

Section: Abstract Follistatin (Fst) As a Single-chain Glycosylated mentioning

confidence: 99%

Clinical and Therapeutic Implications of Follistatin in Solid Tumours

Shi

Resaul

Owen

et al. 2016

CGP

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Abstract. Follistatin (FST) Follistatin (FST), which was first isolated from porcine and bovine follicular fluid (1, 2), was initially described as a protein involved in the regulation of the secretion of folliclestimulating hormone. This monomeric glycosylated polypeptide chain is encoded by a single gene located on the long arm chromosome 5q11.2 (3), which through alternative splicing may be transcribed into the mRNA precursors, FST317 and FST344. From these precursors, three major FST isoforms may be produced, namely FST288 (from pre-FST317), FST315 (from pre-FST344) and a third FST isoform, FST303, produced from the post-translational truncation of the FST315 C-terminus. These three main FST isoforms can also be glycosylated to yield six further FST isoforms that were previously identified in bovine (4) and porcine (5, 6) follicular fluid. At the core, all FST isoforms contain a 63 residue N-terminal domain and three follistatin domains, termed FSD1, FSD2 and FSD3. These domains comprise 73-77 amino acid residues and are characterised by an arrangement of 10 conserved cysteine residues (7). Both FST288 and FST315 are differentially expressed in human tissues (6-9). FST315 is the predominant isoform, whilst the FST288 isoform accounts for less than 5% of the encoded mRNA (10, 11). Some molecules such as activin, transforming growth factor-beta (TGFβ), forkhead domain transcription factor L2 (12, 13), gonadotropin-releasing hormone (14), zinc finger protein (GLI2) (15), dexamethasone (16), androgens (17), activators of winglessrelated integration site (WNT) signalling (18, 19) and 1,25-dihydroxyvitamin D (20) have been shown to regulate the transcription of the FST gene. In addition, down-regulation of FST gene expression by peroxisome proliferator-activated receptor gamma (PPARγ) or the transcription factor epiprofin (21, 22) has been shown.As an antagonist of TGFβ superfamily member activin, FST seems to primarily function in relation to the role that activin plays. Along with FST, activin acts as a pleiotropic growth factor system, which is involved in proliferation, differentiation, and apoptosis of a number of cell types (23-28). As such, the functions of the FST isoforms are therefore linked to their binding affinity for activin (6,10,11,(29)(30)(31)(32)(33)(34)(35)(36)(37). In fact, this critical binding and neutralisation of activin, either partial or complete, is based on the order of at least two of the FST cysteine domains and its Nterminal (38), conferring a difference in affinities for activin between the FST isoforms. The binding complex between activin and FST generally occurs in a 1:2 ratio, where the two FST molecules, connected C-terminus to N-425

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Section: Abstract Follistatin (Fst) As a Single-chain Glycosylated mentioning

confidence: 99%

Clinical and Therapeutic Implications of Follistatin in Solid Tumours

Shi

Resaul

Owen

et al. 2016

CGP

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“…However, follistatin had no benefit as surveillance biomarker for HCC development in patients with alcoholic and non-alcoholic liver disease (ALD and NAFLD) due to the already elevated levels in the underlying liver pathologies [131] . Whether or not, interaction of follistatin with TGF-β family members other than activins (myostatin, BMP, GDFs) or with angiogenin [132] plays a role in liver tumorigenesis remains to be explored.…”

Section: Follistatinmentioning

confidence: 99%

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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“…However, nuclear localization of FST has been observed in epithelial cells of breast tissue (37) and HeLa cells (20), suggesting a possible nuclear function of FST. In this study, we provide experimental evidence to support a nucleolar function of FST-inhibiting rRNA synthesis and promoting cancer cell survival.…”

Section: Discussionmentioning

confidence: 99%

“…Plasmid Construction-The construction of pECFP-FST, in which a FST gene lacking its signal sequence has been fused to the C terminus of the enhanced CFP gene, was described previously (20).…”

Section: Methodsmentioning

confidence: 99%

“…Recently, several reports have shown that FST regulates a variety of processes during tumor progression including angiogenesis (14), metastasis (15), and cell apoptosis (16). Although it is believed that FST exerts most of its functions through extracellularly inactivating TGF-␤-like molecules (17)(18)(19), we have recently identified the nuclear localization ability of this protein (20), suggesting a possible nuclear mechanism.…”

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confidence: 99%

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Nucleolar Follistatin Promotes Cancer Cell Survival under Glucose-deprived Conditions through Inhibiting Cellular rRNA Synthesis

Gao

Wei

Lai

et al. 2010

Journal of Biological Chemistry

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Solid tumor development is frequently accompanied by energy-deficient conditions such as glucose deprivation and hypoxia. Follistatin (FST), a secretory protein originally identified from ovarian follicular fluid, has been suggested to be involved in tumor development. However, whether it plays a role in cancer cell survival under energy-deprived conditions remains elusive. In this study, we demonstrated that glucose deprivation markedly enhanced the expression and nucleolar localization of FST in HeLa cells. The nucleolar localization of FST relied on its nuclear localization signal (NLS) comprising the residues 64 -87. Localization of FST to the nucleolus attenuated rRNA synthesis, a key process for cellular energy homeostasis and cell survival. Overexpression of FST delayed glucose deprivation-induced apoptosis, whereas down-regulation of FST exerted the opposite effect. These functions depended on the presence of an intact NLS because the NLS-deleted mutant of FST lost the rRNA inhibition effect and the cell protective effect. Altogether, we identified a novel nucleolar function of FST, which is of importance in the modulation of cancer cell survival in response to glucose deprivation.Solid tumors over a certain size are continuously exposed to glucose deficiency and hypoxia microenvironments because of the inadequate vascular supply. The cancer cells comprising these tumors thus have to limit energy expenditure to survive under such energy-deprived conditions (1, 2). An effective way is to reduce ribosome biogenesis, the most energy-consuming process in eukaryotic cells. As a matter of fact, the rate of cellular rRNA transcription is tightly regulated in response to metabolic changes (3-5).Transcription of rRNA is catalyzed by polymerase I. Energy deprivation activates AMP-activated protein kinase, which then inactivates the polymerase I-associated transcription factor TIF-IA and thereby impairs rRNA synthesis (6). Energy depletion also triggers heterochromatin formation and rRNA gene silencing by activating the nucleolar remodeling complex (7) or the energy-dependent nucleolar silencing complex (eNoSC) (8). Inhibition of rRNA transcription by eNoSC suppresses energy expenditure and protects cells from energy deprivation-induced apoptosis (8). Meanwhile, increased production of H ϩ under hypoxia promotes the interactions between VHL and rRNA gene (rDNA) to reduce rRNA synthesis (9). Overall, cells repress rRNA transcription through multiple pathways to preserve energy and survive under energy-deprived conditions. FST 3 was originally identified from ovarian follicular fluid, with a function to suppress follicle-stimulating hormone secretion (10, 11). Later, FST was found to be expressed in a variety of tissues and organisms, participating in various processes such as cell growth, development, differentiation, and secretion (12). FST-deficient mice exhibit numerous phenotypes, including musculoskeletal and cutaneous abnormalities, and die within hours of birth because of respiratory failure (13). Recently, s...

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Identification and characterization of follistatin as a novel angiogenin‐binding protein

Cited by 34 publications

References 23 publications

Clinical and Therapeutic Implications of Follistatin in Solid Tumours

Clinical and Therapeutic Implications of Follistatin in Solid Tumours

Activins and follistatins: Emerging roles in liver physiology and cancer

Nucleolar Follistatin Promotes Cancer Cell Survival under Glucose-deprived Conditions through Inhibiting Cellular rRNA Synthesis

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