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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms by which transforming growth factor beta (TGF-beta) and related ligands regulate transcription remain poorly understood. The winged-helix (WH) transcription factor fork head activin signal transducer 1 (FAST-1) was identified as a mediator of activin signaling in Xenopus embryos (X. Chen, M. J. Rubock, and M. Whitman, Nature 383:691-696, 1996). We have cloned a novel WH gene from the mouse which shares many properties with FAST-1. We find that this gene, which we call FAST-2, is able to mediate transcriptional activation by TGF-beta. FAST-2 also interacts directly with Smad2, a cytoplasmic protein which is translocated to the nucleus in response to TGF-beta, and forms a multimeric complex with Smad2 and Smad4 on the activin response element, a high-affinity binding site for FAST-1. Analysis of the sequences of FAST-1 and FAST-2 reveals substantial protein sequence divergence compared to known vertebrate orthologs in the WH family. This suggests that FAST-2 represents a new WH gene related to FAST-1, which functions to mediate TGF-beta signals in mammals. We have also examined the structure of the FAST-2 gene and find that it overlaps with a kinesin motor protein gene. The genes are transcribed in opposite orientations, and their transcripts overlap in the 3' untranslated region.
Mol Cell Biol 1999 Jan
PMID:FAST-2 is a mammalian winged-helix protein which mediates transforming growth factor beta signals. 985 66

Activins and other members of the transforming growth factor-beta-like superfamily of growth factors transduce their signals by interacting with two types of receptor serine/threonine kinases. The Smad proteins, a new family of intracellular mediators are involved in the signaling pathways of these receptors, but the initial stages of their activation as well as their specific functions remain to be defined. We report here that the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. This complex formation is rapid but also transient. Indeed, soon after their association with the activin receptor, Smad2 and Smad3 are released into the cytoplasm where they interact with the common partner Smad4. These Smad complexes then mediate activin-induced transcription. Finally, we show that the inhibitory Smad7 can prevent the association of the two pathway-specific Smads with the activin receptor complex, thereby blocking the activin signal.
Mol Endocrinol 1999 Jan
PMID:Roles of pathway-specific and inhibitory Smads in activin receptor signaling. 989 9

Recent studies have revealed that islet cells differentiate from the epithelial cells of primitive pancreatic ducts during embryogenesis, and can regenerate in response to the loss of islet cells even in adult pancreas. The ability of islet cells to regenerate raises the possibility that impaired and decreased islets of diabetic patients can be restored. In this review, factors regulating islet development including differentiation factors (Shh, activin, follistatin, and TGF alpha), transcriptional factors (PDX1, Isl1, Pax4, Pax6, Nkx2.2, Nkx6.1, BETA2, and HNF), growth factors (the EGF family, HGF, IGF-I, IGF-II, Reg, INGAP, PDGF, FGF, VEGF, and NGF), hormones (insulin, the GH family, PTHrP, TRH, and gastrin), and cell adhesion molecules (N-CAM and cadherins) are described after a short introduction and an outline of pancreatic development.
Int J Mol Med 1999 Mar
PMID:Development of pancreatic islets (review). 1002 48

Activin, and its binding protein, follistatin, are up-regulated by mediators of inflammation, and recent studies have demonstrated that activin A can block the activity of the key inflammatory cytokine, interleukin-6 (IL-6). These findings thereby implicate activin and follistatin in the control of the inflammatory cascade. In this study, interactions between interleukin-1beta (IL-1beta), IL-6 and activin were examined the human liver cell line, HepG2, for their effect on cell proliferation and the production of the acute phase proteins, haptoglobin and alpha1-acid glycoprotein (alpha1-AGP). IL-1beta and activin A, but not IL-6, inhibited the proliferation of HepG2 cells. Activin A together with IL-1beta caused a greater inhibition of proliferation than either factor alone, and the inhibitory effects of activin A were blocked by the addition of follistatin to the cultures. Activin A alone inhibited the production of haptoglobin but did not affect alpha1-AGP concentrations. However, activin A suppressed the stimulatory effects of IL-6 on the production of both haptoglobin and alpha1-AGP. Production of follistatin by HepG2 cells was stimulated by activin A, but was inhibited by both IL-1beta and IL-6, indicating a complex regulatory loop is operable to modulate the effects of activin A during inflammation. Taken together, these data suggest that activin A interacts with IL-1beta and IL-6 to regulate and coordinate the production of acute phase proteins during an inflammatory episode.
Mol Cell Endocrinol 1999 Feb 25
PMID:Activin A regulates growth and acute phase proteins in the human liver cell line, HepG2. 1022 78

We have produced a transgenic (TG) mouse model expressing the Simian Virus 40 T-antigen (Tag) gene, driven by a 6-kb fragment of the mouse inhibin-alpha subunit promoter (inh-alpha). The mice develop gonadal tumors with 100% penetrance by the age of 5-8 months, of granulosa cell origin in the ovary, and of Leydig cell origin in the testis. In the present study, we characterized the hormonal regulation of proliferation of two immortalized cell lines, BLT-1, originating from a Leydig cell tumor, and NT-1, originating from a granulosa cell tumor. [3H]-thymidine incorporation in both types of cells was stimulated by activin (> or = 10-30 microg/l), while inhibin had no effect. Transforming growth factor (TGF)-beta, at > or = 0.01 microg/l, stimulated proliferation of the granulosa tumor cells, but no effect was found on the Leydig tumor cells. Progesterone inhibited the proliferation of both cell lines, although the granulosa tumor cells were clearly less sensitive than the Leydig cells to this effect ( > or = 3 micromol/l vs. > 10 nmol/l, respectively). hCG had no effect on the Leydig tumor cell DNA synthesis whereas at high concentration (100 microg/l) it stimulated that of the granulosa cells. We also investigated in BLT-1 and NT-1 cells whether the proliferative changes were related to concomitant changes in Tag expression. In BLT-1 cells, this was stimulated by activin, progesterone and hCG, even though the latter substance did not affect cell proliferation. In contrast, TGF-beta inhibited Tag expression. In NT-1 cells, the expression of Tag was stimulated by activin, while hCG had no effect. In contrast, it was reduced by progesterone, inhibin and TGF-beta. In conclusion, our results indicate that the granulosa and Leydig tumor cells, despite similar mechanism of immortalization, respond differently to several mitotic stimuli. The responses in the level of Tag expression in these cells did not always correlate with the changes observed in cell proliferation, indicating the independence of these two phenomena.
Mol Cell Endocrinol 1999 Mar 25
PMID:Hormonal regulation of proliferation of granulosa and Leydig cell lines derived from gonadal tumors of transgenic mice expressing the inhibin-alpha subunit promoter/simian virus 40 T-antigen fusion gene. 1037 13

FSH is required to maintain FSH and LH/hCG receptors at elevated steady-state levels after receptor induction. Although this function of FSH is mediated by cAMP, how cAMP level is related to the maintenance of gonadotropin receptors is unknown. To investigate cAMP's effect on changes in the levels of FSH receptor mRNAs in rat granulosa cells, total RNA from cells was prepared and analyzed by Northern blots. Incubation with 8-Br-cAMP for 24 h produced a dose-related increase in FSH receptor mRNA in granulosa cells of DES-primed immature rats. On the other hand, 8-Br-cAMP, washed at 24 h, exerted inverse dose-related effects on FSH receptor mRNA levels at 96 h. The addition of 1 mM cAMP resulted in higher levels of FSH receptor mRNA than that induced by 0.2 mM cAMP at 24 h, while 0.2 mM cAMP is as effective as 1-2 mM cAMP for the induction of FSH receptor mRNA at 96 h. To further analyze cAMP's role in the production of activin in granulosa cells, we measured activin levels in the culture medium after the addition of 8-Br-cAMP. The levels of activin A were suppressed by the addition of 8-Br-cAMP in a dose-dependent manner. In addition, the procedure by which 8-Br-cAMP was removed after 24 h incubation showed that the level of activin in the medium increased after medium change. With regard to the actions of activin A on gonadotropin receptors, our laboratory has demonstrated that activin A increases the levels of FSH receptor mRNAs. Therefore, cAMP has a negative effect on FSH receptor expression by suppressing the activin level. Since follistatin production is up-regulated by cAMP in this system, we examined the effect of follistatin on FSH receptor mRNA level, which is induced by activin and FSH. Cotreatment with follistatin (0-100 ng/ml) and activin (50 ng/ml) in the presence of FSH (30 ng/ml) caused a significant reduction in FSH receptor mRNA levels induced by activin. Based on these observations, it is possible that cAMP has both stimulatory and inhibitory effects on the expression of gonadotropin receptors, and the overall influence of cAMP on their expression might be determined by the integration of such opposing effects.
Mol Cell Endocrinol 1999 Mar 25
PMID:Control of FSH receptor mRNA expression in rat granulosa cells by 3',5'-cyclic adenosine monophosphate, activin, and follistatin. 1037 19

Activins were originally isolated based on their ability to stimulate follicle-stimulating hormone secretion but later they have been shown to regulate a number of different cellular functions such as nerve cell survival, mesoderm induction during early embryogenesis as well as hematopoiesis. We studied the regulation of activin A, a homodimer of betaA-subunits, mRNA and protein in K562 erythroleukemia cells, which are known to be induced toward the erythroid lineage in response to activin or TGF-beta or toward the megakaryocytic lineage by the phorbol ester protein kinase C activator 12-O-tetradecanoylphorbol-13-acetate (TPA). Here we show by Northern blot analysis as well as by Western and ligand blotting that TPA strongly promotes activin betaA-subunit mRNA and activin A protein expression in K562 cells in time- and concentration dependent manner. In contrast, neither activin A nor TGF-beta induced betaA-subunit mRNA expression during erythroid differentiation in K562 cells. Interestingly, whereas activin type II receptors are not regulated during K562 cell differentiation (Hilden et al. (1994) Blood 83, 2163-2170), we now show that the activin type I and IB receptor mRNAs are clearly induced by TPA but not by activin or TGF-beta. We also show that the inducing effect of TPA on expression of activin betaA-subunit mRNA is potentiated by the protein kinase A activator 8-bromo-cAMP. We conclude that activin A and its type I receptors appear to be co-ordinately up-regulated during megakaryocytic differentiation of K562 cells.
Mol Cell Endocrinol 1999 Jul 20
PMID:Co-ordinate expression of activin A and its type I receptor mRNAs during phorbol ester-induced differentiation of human K562 erythroleukemia cells. 1045 61

A full-length cDNA encoding for activin type IIB receptor (ActRIIB) was cloned from zebrafish embryos. It encodes a protein with 509 amino acids consisting of a signal peptide, an extracellular ligand binding domain, a single transmembrane region, and an intracellular kinase domain with predicted serine/threonine specificity. The extracellular domain shows 74-91% sequence identity to human, bovine, mouse, rat, chicken, Xenopus and goldfish activin type IIB receptors, while the transmembrane region and the kinase domain show 67-78% and 82-88% identity to these known activin IIB receptors, respectively. In adult zebrafish, ActRIIB mRNA was detected by RT-PCR in the gonads, as well as in non-reproductive tissues, including the brain, heart and muscle. In situ hybridization on ovarian sections further localized ActRIIB mRNA to cytoplasm of oocytes at different stages of development. Using whole-mount in situ hybridization, ActRIIB mRNA was found to be expressed at all stages of embryogenesis examined, including the sphere, shield, tail bud, and 6-7 somite. These results provide the first evidence that ActRIIB mRNA is widely distributed in fish embryonic and adult tissues. Cloning of zebrafish ActRIIB demonstrates that this receptor is highly conserved during vertebrate evolution and provides a basis for further studies on the role of activin in reproduction and development in lower vertebrates.
Mol Cell Endocrinol 1999 Jul 20
PMID:Cloning of zebrafish activin type IIB receptor (ActRIIB) cDNA and mRNA expression of ActRIIB in embryos and adult tissues. 1045 65

We have cloned a full-length cDNA coding for activin betaA subunit from a goldfish brain and pituitary cDNA library, which represents the first for activin betaA in fish. Sequence analysis of goldfish activin betaA shows that this peptide is highly conserved across vertebrates. The mature region of goldfish activin betaA shares 81% amino acid identity with that of humans. Messenger RNA of goldfish activin betaA is expressed in a variety of tissues including ovary, testis, brain and liver, suggesting a wide range of physiological roles for activin A in the goldfish. The identity of the cloned goldfish activin betaA was confirmed by expressing the protein in the Chinese hamster ovary (CHO) cells followed by detection of the specific activin activity in the culture medium using erythroid differentiation factor (EDF) assay with F5-5 cells. Stable CHO cell lines producing high level of recombinant goldfish activin A were established and characterized.
Mol Cell Endocrinol 1999 Aug 20
PMID:Cloning and characterization of goldfish activin betaA subunit. 1050 99

Activin uptake into Xenopus oocytes was studied by several complementary methods. Immunocytochemistry of adult ovary localized activin and follistatin in the cytoplasm of vitellogenic oocytes and surrounding follicle cells. Surface plasmon resonance analysis of protein interaction kinetics indicated that while follistatin or a complex of activin-follistatin bound to yolk vitellogenin, activin alone did not. Radioactive tracer analysis measured specific incorporation of activin by viable oocytes in vitro. Together, the results suggest that vitellogenic oocytes can import activins from follicle cells and that follistatin may act as a chaperone for binding activin to vitellogenin in yolk platelets.
Cell Mol Biol (Noisy-le-grand) 1999 Jul
PMID:Activin incorporation into vitellogenic oocytes of Xenopus laevis. 1051 87


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