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Groot, E. de; Veltmaat, Jacqueline M.; Caricasole, Andrea; Defize, L. H. K.; Raaij, Adriana van den Eijnden-van

doi:10.1023/a:1007159031000

Cited by 20 publications

(9 citation statements)

References 38 publications

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“…Primer extension analyses confirmed that both ␣T3-1 and primary rat anterior pituitary cells preferentially utilize the "␣" transcription start site and to a lesser extent the "␤" and "␥" sites 4 previously identified from studies of granulosa, P19 and F9 embryonic carcinoma cells (35,36). An upstream fragment equivalent to Ϫ2864 to ϩ136, relative to the transcription start site of the rat follistatin gene, failed to confer activin inducibility onto the basic pGL2 luciferase reporter.…”

Section: Discussionsupporting

confidence: 68%

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A Smad-binding Element in Intron 1 Participates in Activin-dependent Regulation of the Follistatin Gene

Blount

Vaughan

Vale

et al. 2008

Journal of Biological Chemistry

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Activins are members of the evolutionarily conserved transforming growth factor-␤ (TGF-␤) 3 superfamily of factors implicated in the control of a wide array of cellular processes of embryonic and adult tissues (1-3). Activin A and activin B are homodimers of inhibin ␤A and ␤B subunits, respectively, with established roles in the control of many cell types including those throughout the reproductive axis (1, 4 -6). The inhibin ␤A and ␤B subunits are both expressed in the pituitary and activin B arising from gonadotropes is a critical component of the network of autocrine or paracrine factors of this tissue (7). By exerting control on FSH␤ expression, activin B is hypothesized to locally provide a positive signal for the differential production of FSH over LH and to thereby facilitate the cyclic fluctuations of these hormones during the estrus cycle (7,8). The actions of activins are strictly controlled by the concerted actions and the preferential usage of several extracellular modulators (9, 10). Of these, inhibin and follistatin have established roles in the regulation of pituitary gonadotropes (7).Follistatins are cysteine-rich glycoproteins that bind and bioneutralize activin with high affinity at a 2:1 molar ratio (11-13). They also bind and inactivate myostatin and some bone morphogenetic proteins with varying degrees of affinity (14). Structural studies of the follistatin-activin complex have elucidated the basis for this interaction and provided clues about the determinants of follistatin binding to other ligands (15,16). The follistatin gene comprising 6 exons produces two alternatively spliced mRNA transcripts and the corresponding proteins of 315 or 288 amino acids (FS315 or FS288) (17, 18). The two isoforms, FS315 and FS288, are differentially expressed in most tissues (19,20). The FS315 form is the predominant circulating form, whereas the shorter FS288 form lacking the C-terminal tail associates tightly with heparan sulfate chains of cell surface proteoglycans and is presumed to be the form that acts locally to modulate activin signaling (2,(21)(22)(23). This local function of follistatin is, in turn, controlled by the actions of activin. In cultured rat anterior pituitary cells, activin increases steadystate follistatin mRNA and secreted protein levels (24 -28). Given that inhibin antagonizes the activin-induced rise in pituitary follistatin, this pinpoints gonadotropes as the primary targets of this action of activin (28,29).Activin signals by sequentially binding to activin-specific Type II (ActRII or ActRIIB) then Type I (ALK4) serine/threonine kinase receptors to form a multimeric complex (3,30,31). In this complex, the Type II receptors trans-phosphorylate ALK4 and allow it to transiently interact and phosphorylate the downstream signaling proteins, Smad2 and Smad3, at their C-terminal SSXS motifs (31-33). The phosphorylated forms of Smad2 and Smad3 in turn translocate to the nucleus where they bind to DNA targets and regulate transcription in association with the common Smad4/DPC4 and other p...

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Section: Discussionsupporting

confidence: 68%

“…A luciferase reporter construct that incorporates the Ϫ757/ϩ136 fragment of the rat follistatin gene is activated by a combination of cAMP and TPA (35,36). In L␤T2 cells, the same fragment is a target of GnRH (37) but not of activin A in ␣T3-1 cells (38).…”

mentioning

confidence: 99%

A Smad-binding Element in Intron 1 Participates in Activin-dependent Regulation of the Follistatin Gene

Blount

Vaughan

Vale

et al. 2008

Journal of Biological Chemistry

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“…Based on a genetic epistasis experiment, Fst acts downstream of WNT4 [24]. Furthermore, expression of mouse Fst is dependent upon a consensus β-catenin LEF/TCF binding site in the promoter region [46], [47], and expression of Fst was lost in the β-catenin cKO ovary [18], placing Fst downstream of β-catenin. FST is known to bind activins with high affinity, therefore preventing activins from activating their receptors [48].…”

Section: Discussionmentioning

confidence: 99%

WNT4/β-Catenin Pathway Maintains Female Germ Cell Survival by Inhibiting Activin βB in the Mouse Fetal Ovary

2010

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Female germ cells are essential for organogenesis of the ovary; without them, ovarian follicles do not form and functional and structural characteristics of the ovary are lost. We and others showed previously that when either Wnt4 or β-catenin was inactivated in the fetal ovary, female germ cells underwent degeneration. In this study, we set out to understand whether these two factors belong to the same pathway and how they maintain female germ cell survival. We found that activation of β-catenin in somatic cells in the Wnt4 knockout ovary restored germ cell numbers, placing β-catenin downstream of WNT4. In the absence of Wnt4 or β-catenin, female germ cells entered meiosis properly; however, they underwent apoptosis afterwards. Activin βB (Inhbb), a subunit of activins, was upregulated in the Wnt4 and β-catenin knockout ovaries, suggesting that Inhbb could be the cause for the loss of female germ cells, which are positive for activin receptors. Indeed, removal of Inhbb in the Wnt4 knockout ovaries prevented female germ cells from undergoing degeneration. We conclude that WNT4 maintains female germ cell survival by inhibiting Inhbb expression via β-catenin in the somatic cells. Maintenance of female germ cells hinge upon a delicate balance between positive (WNT4 and β-catenin) and negative (activin βB) regulators derived from the somatic cells in the fetal ovary.

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“…Thus, EGR-1 may exert its suppressive eect on tumorigenicity via transcriptional regulation of the TGFb gene. Since growth regulation by TGFb is completely abrogated in cells expressing the adenoviral E1A proteins (de Groot et al, 1995), EGR-1 may not be able to exert its growth inhibitory eect. In analogy, prostate carcinomas express elevated levels of TGFb (Royuela et al, 1998), but prostate carcinoma cells are insensitive to growth inhibition by TGFb (Cipriano and Chen, 1998).…”

Section: Discussionmentioning

confidence: 99%

EGR-1 enhances tumor growth and modulates the effect of the Wilms' tumor 1 gene products on tumorigenicity

et al. 2000

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The Wilms' tumor 1 gene (WT1) encodes a transcription factor of the zinc-®nger family and is homozygously mutated or deleted in a subset of Wilms' tumors. Through alternative mRNA splicing, the gene is expressed as four main polypeptides that dier by a stretch of 17 amino acids just N-terminal of the four zinc-®ngers and three amino acids between zinc ®ngers 3 and 4. We have previously shown that expression of the WT1(7/7) isoform, lacking both inserts, increases the tumor growth rate of the adenovirus-transformed baby rat kidney (AdBRK) cell line 7C3H2, whereas expression of the WT1(7/+) isoform, lacking the 17aa insert, strongly suppresses the tumorigenic phenotype. In the present study we show that expression of these splice variants does not aect the tumorigenic potential of the similar AdBRK cell line, 7C1T1. In contrast to the 7C3H2 cell line, this AdBRK cell line expresses high endogenous levels of EGR-1 (early growth response-1) protein, a transcription factor structurally related to WT1. Ectopic expression of EGR-1 in the 7C3H2 AdBRK cells signi®cantly increases their in vivo growth rate and nulli®es the tumor suppressor activity of the WT1(7/+) protein. Furthermore, we ®nd that EGR-1 levels are elevated in some Wilms' tumors. These data are the ®rst to show that EGR-1 overexpression causes enhanced tumor growth and that WT1 and EGR-1 exert antagonizing eects on growth regulation in baby rat kidney cells, which might re¯ect the situation in some Wilms' tumors. Oncogene (2000) 19, 791 ± 800.

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Cited by 20 publications

References 38 publications

A Smad-binding Element in Intron 1 Participates in Activin-dependent Regulation of the Follistatin Gene

A Smad-binding Element in Intron 1 Participates in Activin-dependent Regulation of the Follistatin Gene

WNT4/β-Catenin Pathway Maintains Female Germ Cell Survival by Inhibiting Activin βB in the Mouse Fetal Ovary

EGR-1 enhances tumor growth and modulates the effect of the Wilms' tumor 1 gene products on tumorigenicity

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