Transcription Activation of FLRG and Follistatin by Activin A, Through Smad Proteins, Participates in a Negative Feedback Loop to Modulate Activin a Function
Oncogene (2002) 21, 2227 ± 2235 ã 2002 Nature Publishing Group All rights reserved 0950 ± 9232/02 $25.00 www.nature.com/onc Transcription activation of FLRG and follistatin by activin A, through Smad proteins, participates in a negative feedback loop to modulate activin A function Laurent Bartholin1,3,Ve ronique Maguer-Satta1,3, Sandrine Hayette1,2, Sylvie Martel1, MyleÁ ne Gadoux2, Laura Corbo1, Jean-Pierre Magaud1,2 and Ruth Rimokh*,1 1INSERM U453, Centre LeÂon BeÂrard, 69373 Lyon, France; 2Laboratoire de CytogeÂneÂtique MoleÂculaire, HoÃpital Edouard Herriot, 69437 Lyon, France Signaling of TGFb family members such as activin is location (Hayette et al., 1998). FLRG is a secreted tightly regulated by soluble binding proteins. Follistatin glycoprotein which is highly homologous to follistatin, binds to activin A with high anity, and prevents activin a protein known to bind to activin, a member of the binding to its own receptors, thereby blocking its transforming growth factor b (TGFb) superfamily signaling. We previously identi®ed FLRG gene from a (Nakamura et al., 1990). Activin and follistatin B-cell leukemia carrying a t(11;19)(q13;p13) transloca- proteins were originally isolated from ovarian ¯uid as tion. We and others have already shown that FLRG, a result of their ability to stimulate and inhibit, which is highly homologous to follistatin, may be respectively, the secretion of follicle-stimulating hor- involved in the regulation of the activin function through mone from the pituitary gland (Phillips and de Kretser, its binding to activin. In this study, we found that, like 1998). Further studies have revealed that activin, a follistatin, FLRG protein inhibited activin A signaling as secreted protein produced by a variety of tissues, has demonstrated by the use of a transcriptional reporter important endocrine and paracrine roles.
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