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PubMed2006

Post-transcriptional control of Cited2 by transforming growth factor beta. Regulation via Smads and Cited2 coding region.

Cited2 is a transcription factor without typical DNA binding domains. Cited2 interacts with cAMP-responsive element-binding protein-binding protein (CBP)/p300, TFAP2, Lhx2, and nuclear receptors, such as peroxisome proliferator-activated receptor and estrogen receptor to function as a transcriptional modulator. Overexpression of Cited2 in Rat1 cells leads to tumor formation in nude mice, suggesting that Cited2 is a transforming gene. Through microarray analysis, Cited2 was found to be down-regulated by transforming growth factor beta1 (TGF-beta) in various cell lines. In this study, we confirmed that both mRNA and protein levels of Cited2 are down-regulated in MDA-MB-231 breast cancer cells. Overexpression of Smad7 or knockdown of Smad4 in MDA-MB-231 cells showed that the Smad pathway is involved in the down-regulation of Cited2. Based on nuclear run-on analysis and Cited2 promoter/reporter assay, Cited2 transcription was not affected by TGF-beta, supporting that down-regulation of Cited2 by TGF-beta is most likely through post-transcriptional regulation. By using transcriptional inhibitors, we demonstrated that the turnover of Cited2 transcripts appears to be accelerated during TGF-beta stimulation. Pharmacologic inhibition of translation with cycloheximide attenuated Cited2 down-regulation by TGF-beta. We examined the expression of recombinant Cited2 gene introduced into MDA-MB-231 cells by stable transfection, and we found that mRNA containing the Cited2 protein-coding region controlled by a heterologous promoter indeed responds to TGF-beta-mediated down-regulation. Study from Cited2 deletion mutants showed that the C-terminal conserved region of Cited2 coding sequence is essential for the down-regulation. This is the first demonstration that TGF-beta-mediated down-regulation of Cited2 is post-transcriptional, through the Smad pathway, and requires the presence of its coding sequence.

Cell Line, Tumor↗
PubMed2006

The NH2-terminal propeptide of type I procollagen acts intracellularly to modulate cell function.

The function of the NH(2)-terminal propeptide of type I procollagen (N-propeptide) is poorly understood. We now show that a recombinant trimeric N-propeptide interacts with transforming growth factor-beta1 and BMP2 and exhibits functional effects in stably transfected cells. The synthesis of N-propeptide by COS-7 cells results in an increase in phosphorylation of Akt and Smad3 and is associated with a marked reduction in type I procollagen synthesis and impairment in adhesion. In C2C12 cells, N-propeptide inhibits the osteoblastic differentiation induced by BMP2. Our data suggest that these effects are mediated by the interaction of N-propeptide with an intracellular receptor in the secretory pathway, because they are not observed when recombinant N-propeptide is added to the culture medium of either COS-7 or C2C12 cells. Both the binding of N-propeptide to cytokines and its functional properties are entirely dependent on the exon 2-encoded globular domain, and a mutation that substitutes a serine for a highly conserved cysteine in exon 2 abolishes its function. Our findings suggest that N-propeptide performs an important feedback regulatory function and provides a rationale for the prominence of a homotrimeric form of type I procollagen (alpha1 trimer) during vertebrate development.

Animals↗
PubMed2006

Dephosphorylation of the linker regions of Smad1 and Smad2/3 by small C-terminal domain phosphatases has distinct outcomes for bone morphogenetic protein and transforming growth factor-beta pathways.

Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases. The activity of Smad1 in the BMP pathway and Smad2/3 in the TGFbeta pathway is restricted by pathway cross-talk and feedback through protein kinases, including MAPK, CDK2/4, p38MAPK, JNK, and others. These kinases phosphorylate Smads 1-3 at the region that links the N-terminal DNA-binding domain and the C-terminal transcriptional domain. Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. Here we provide evidence that SCP1-3 also dephosphorylate the linker regions of Smad1 and Smad2/3 in vitro, in mammalian cells and in Xenopus embryos. Overexpression of SCP 1, 2, or 3 decreased linker phosphorylation of Smads 1, 2 and 3. Moreover, RNA interference-mediated knockdown of SCP1/2 increased the BMP-dependent phosphorylation of the Smad1 linker region as well as the C terminus. In contrast, SCP1/2 knockdown increased the TGFbeta-dependent linker phosphorylation of Smad2/3 but not the C-terminal phosphorylation. Consequently, SCP1/2 knockdown inhibited TGFbeta transcriptional responses, but it enhanced BMP transcriptional responses. Thus, by dephosphorylating Smad2/3 at the linker (inhibitory) but not the C-terminal (activating) site, the SCPs enhance TGFbeta signaling, and by dephosphorylating Smad1 at both sites, the SCPs reset Smad1 to the basal unphosphorylated state.

Animals↗
PubMed1998

Spindle checkpoint protein Xmad1 recruits Xmad2 to unattached kinetochores.

The spindle checkpoint prevents the metaphase to anaphase transition in cells containing defects in the mitotic spindle or in chromosome attachment to the spindle. When the checkpoint protein Xmad2 is depleted from Xenopus egg extracts, adding Xmad2 to its endogenous concentration fails to restore the checkpoint, suggesting that other checkpoint component(s) were depleted from the extract through their association with Xmad2. Mass spectrometry provided peptide sequences from an 85-kD protein that coimmunoprecipitates with Xmad2 from egg extracts. This information was used to clone XMAD1, which encodes a homologue of the budding yeast (Saccharomyces cerevisiae) checkpoint protein Mad1. Xmad1 is essential for establishing and maintaining the spindle checkpoint in egg extracts. Like Xmad2, Xmad1 localizes to the nuclear envelope and the nucleus during interphase, and to those kinetochores that are not bound to spindle microtubules during mitosis. Adding an anti-Xmad1 antibody to egg extracts inactivates the checkpoint and prevents Xmad2 from localizing to unbound kinetochores. In the presence of excess Xmad2, neither chromosomes nor Xmad1 are required to activate the spindle checkpoint, suggesting that the physiological role of Xmad1 is to recruit Xmad2 to kinetochores that have not bound microtubules.

Animals↗
PubMed2000

Transforming growth factor beta(1) selectively inhibits the cyclic AMP-dependent proliferation of primary thyroid epithelial cells by preventing the association of cyclin D3-cdk4 with nuclear p27(kip1).

Dog thyroid epithelial cells in primary culture constitute a physiologically relevant model of positive control of DNA synthesis initiation and G0-S prereplicative phase progression by cAMP as a second messenger for thyrotropin (thyroid-stimulating hormone [TSH]). As previously shown in this system, the cAMP-dependent mitogenic pathway differs from growth factor cascades as it stimulates the accumulation of p27(kip1) but not cyclins D. Nevertheless, TSH induces the nuclear translocations and assembly of cyclin D3 and cdk4, which are essential in cAMP-dependent mitogenesis. Here we demonstrate that transforming growth factor beta(1) (TGFbeta(1)) selectively inhibits the cAMP-dependent cell cycle in mid-G1 and various cell cycle regulatory events, but it weakly affects the stimulation of DNA synthesis by epidermal growth factor (EGF), hepatocyte growth factor, serum, and phorbol esters. EGF+serum and TSH did not interfere importantly with TGFbeta receptor signaling, because they did not affect the TGFbeta-induced nuclear translocation of Smad 2 and 3. TGFbeta inhibited the phosphorylation of Rb, p107, and p130 induced by TSH, but it weakly affected the phosphorylation state of Rb-related proteins in EGF+serum-treated cells. TGFbeta did not inhibit c-myc expression. In TSH-stimulated cells, TGFbeta did not affect the expression of cyclin D3, cdk4, and p27(kip1), nor the induced formation of cyclin D3-cdk4 complexes, but it prevented the TSH-induced relocalization of p27(kip1) from cdk2 to cyclin D3-cdk4. It prevented the nuclear translocations of cdk4 and cyclin D3 without altering the assembly of cyclin D3-cdk4 complexes probably formed in the cytoplasm, where they were prevented from sequestering nuclear p27(kip1) away from cdk2. This study dissociates the assembly of cyclin D3-cdk4 complexes from their nuclear localization and association with p27(kip1). It provides a new mechanism of regulation of proliferation by TGFbeta, which points out the subcellular location of cyclin D-cdk4 complexes as a crucial factor integrating mitogenic and antimitogenic regulations in an epithelial cell in primary culture.

Animals↗
PubMed2003

Opposing functions of ZEB proteins in the regulation of the TGFbeta/BMP signaling pathway.

Binding of TGFbeta/BMP factors to their receptors leads to translocation of Smad proteins to the nucleus where they activate transcription of target genes. The two-handed zinc finger proteins encoded by Zfhx1a and Zfhx1b, ZEB-1/deltaEF1 and ZEB-2/SIP1, respectively, regulate gene expression and differentiation programs in a number of tissues. Here I demonstrate that ZEB proteins are also crucial regulators of TGFbeta/BMP signaling with opposing effects on this pathway. Both ZEB proteins bind to Smads, but while ZEB-1/deltaEF1 synergizes with Smad proteins to activate transcription, promote osteoblastic differentiation and induce cell growth arrest, the highly related ZEB-2/SIP1 protein has the opposite effect. Finally, the ability of TGFbeta to mediate transcription of TGFbeta-dependent genes and induce growth arrest depends on the presence of endogenous ZEB-1/deltaEF1 protein.

Animals↗
PubMed2001

Transgenic analysis of the Smad family of TGF-beta signal transducers in Drosophila melanogaster suggests new roles and new interactions between family members.

Smad signal transducers are required for transforming growth factor-beta-mediated developmental events in many organisms including humans. However, the roles of individual human Smad genes (hSmads) in development are largely unknown. Our hypothesis is that an hSmad performs developmental roles analogous to those of the most similar Drosophila Smad gene (dSmad). We expressed six hSmad and four dSmad transgenes in Drosophila melanogaster using the Gal4/UAS system and compared their phenotypes. Phylogenetically related human and Drosophila Smads induced similar phenotypes supporting the hypothesis. In contrast, two nearly identical hSmads generated distinct phenotypes. When expressed in wing imaginal disks, hSmad2 induced oversize wings while hSmad3 induced cell death. This observation suggests that a very small number of amino acid differences, between Smads in the same species, confer distinct developmental roles. Our observations also suggest new roles for the dSmads, Med and Dad, in dActivin signaling and potential interactions between these family members. Overall, the study demonstrates that transgenic methods in Drosophila can provide new information about non-Drosophila members of developmentally important multigene families.

Animals↗
PubMed1999

Signal transduction of the TGF-beta superfamily by Smad proteins.

Members of the TGF-beta superfamily regulate the growth and differentiation of various types of cells. Smads are recently identified proteins that mediate intracellular signaling of the TGF-beta superfamily. Smads are grouped into three classes depending on their structure and functions. R-Smads are phosphorylated by type I serine-threonine kinase receptors for TGF-beta superfamily members. R-Smads then associate with Co-Smads. Smad4 is the only vertebrate Co-Smad identified thus far, and is required for the signaling pathways of different ligands. The heteromeric Smad complex translocates into the nucleus, where it activates target genes. Anti-Smads inhibit signaling by R-Smads and Co-Smads. Smads bind to DNA directly or indirectly via other DNA binding proteins. R-Smads interact with transcriptional coactivators, and have intrinsic transactivation activity. Elucidation of the functions of Smads will provide the framework for research on TGF-beta superfamily signaling.

Animals↗
PubMed2004

The role of bone morphogenetic proteins BMP-2 and BMP-4 and their related postreceptor signaling system (Smads) in distraction osteogenesis of the mandible.

Distraction osteogenesis has become a widely used clinical approach in the treatment of craniofacial and orthopedic disorders. The exact biological mechanism of bone formation remains illusive, however. The aim of this study was to evaluate the role of bone morphogenetic protein-2, bone morphogenetic protein-4, and transforming growth factor-beta superfamily-related postreceptor signaling glycoproteins Smads 1 through 5 in distraction osteogenesis. Twelve sheep randomly divided into two groups were distracted to 24 mm at 1 or 4 mm/d using a submandibular osteotomy and an external distractor. After a 5-week fixation period, the mandibles were harvested. Employing immunohistochemical techniques, the sections were investigated for the previous antigens. Osteoblasts and periosteal lining cells were strongly positive. The matrix did not stain for the antigens investigated. Osteocytes demonstrated weak staining for the antigens. No significant difference between the groups was noted. In fracture healing, bone morphogenetic proteins 2 and 4 have been localized to the cambial layer of the periosteum, where healing occurs by intramembranous ossification. Their diffuse staining of the osteoblasts in the distracted region supports a similar role in distraction osteogenesis, where bone formation is predominantly through intramembranous ossification. Furthermore, bone morphogenetic proteins 2 and 4 have been demonstrated to promote mesenchymal cell conversion to osteoblasts. This is similar to the process observed in distraction osteogenesis. The presence of related Smads confirms postreceptor activity of these bone morphogenetic proteins in the process of distraction osteogenesis. This study supports induction of bone morphogenetic proteins 2 and 4, their related postreceptor signaling system (Smads), and intramembranous bone formation associated with mechanical strain in distraction osteogenesis.

Animals↗
PubMed1998

The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation.

The spindle assembly checkpoint mechanism delays anaphase initiation until all chromosomes are aligned at the metaphase plate. Activation of the anaphase-promoting complex (APC) by binding of CDC20 and CDH1 is required for exit from mitosis, and APC has been implicated as a target for the checkpoint intervention. We show that the human checkpoint protein hMAD2 prevents activation of APC by forming a hMAD2-CDC20-APC complex. When injected into Xenopus embryos, hMAD2 arrests cells at mitosis with an inactive APC. The recombinant hMAD2 protein exists in two-folded states: a tetramer and a monomer. Both the tetramer and the monomer bind to CDC20, but only the tetramer inhibits activation of APC and blocks cell cycle progression. Thus, hMAD2 binding is not sufficient for inhibition, and a change in hMAD2 structure may play a role in transducing the checkpoint signal. There are at least three different forms of mitotic APC that can be detected in vivo: an inactive hMAD2-CDC20-APC ternary complex present at metaphase, a CDC20-APC binary complex active in degrading specific substrates at anaphase, and a CDH1-APC complex active later in mitosis and in G1. We conclude that the checkpoint-mediated cell cycle arrest involves hMAD2 receiving an upstream signal to inhibit activation of APC.

Anaphase↗
PubMed1998

Determinants of specificity in TGF-beta signal transduction.

Signal transduction by the TGF-beta family involves sets of receptor serine/threonine kinases, Smad proteins that act as receptor substrates, and Smad-associated transcription factors that target specific genes. We have identified discrete structural elements that dictate the selective interactions between receptors and Smads and between Smads and transcription factors in the TGF-beta and BMP pathways. A cluster of four residues in the L45 loop of the type I receptor kinase domain, and a matching set of two residues in the L3 loop of the Smad carboxy-terminal domain establish the specificity of receptor-Smad interactions. A cluster of residues in the highly exposed alpha-helix 2 of the Smad carboxy-terminal domain specify the interaction with the DNA-binding factor Fast1 and, as a result, the gene responses mediated by the pathway. By establishing specific interactions, these determinants keep the TGF-beta and BMP pathways segregated from each other.

Activin Receptors, Type I↗
PubMed2004

Combining TGF-beta inhibition and angiotensin II blockade results in enhanced antifibrotic effect.

BACKGROUND: Although angiotensin II (Ang II) blockade is rapidly becoming standard antifibrotic therapy in renal diseases, current data suggest that Ang II blockade alone cannot stop fibrotic disease. New therapies, such as antibodies to transforming growth factor-beta (TGF-beta), or drug combinations will be required to further slow or halt disease progression. Here, using the anti-Thy1 model of glomerulonephritis, the maximally therapeutic dose of the TGF-beta neutralizing mouse monoclonal antibody (1D11) was determined and compared with the maximally effective dose of enalapril. Then, the effect of combining both treatments at maximal doses was determined. METHODS: After disease induction with the anti-Thy1 antibody, OX-7, increasing doses of 1D11 were given intraperitoneally (IP) on days 1, 3, and 5. Enalapril was administered in drinking water from day 1. The fibrotic response was assessed at day 6. RESULTS: 1D11 dose-dependently reduced fibrosis, with the 0.5 and 5 mg/kg doses showing maximal therapeutic effects, reducing period-acid Schiff (PAS) staining by 56% and 45%, respectively. Fibronectin and collagen I staining was reduced by 32% to 36%, respectively. Glomerular mRNA and production of fibronectin, plasminogen activator inhibitor-1 (PAI-1), TGF-beta1, and p-Smad2 protein were also reduced. The maximal therapeutic effects of 1D11 and enalapril alone were very similar. However, combination therapy led to further reduction in disease. Notably, matrix deposition was reduced by 80%. CONCLUSION: While 1D11 or enalapril at maximal doses reduce fibrosis equally, simultaneous blockade of Ang II and TGF-beta reduces fibrotic disease considerably more, offering hope that such drug combinations may confer a therapeutic advantage over angiotensin blockade alone.

Angiotensin II↗
PubMed2001

Cell-specific regulation of human aryl hydrocarbon receptor expression by transforming growth factor-beta(1).

Previous studies showed that TGF-beta down-regulates aryl hydrocarbon (AhR) expression in human lung carcinoma cells A549. Here we analyzed the molecular mechanisms by which TGF-beta modulates AhR expression. A 5799-nucleotide 5'-flanking region of human AhR gene was isolated. Transient transfection studies of full-length (hAhRP) and deletion promoter constructs indicate the requirement of a cis-regulatory element encompassing -1980 to -1892 for full constitutive activity. Basal hAhRP activity occurs in a cell-specific manner; human hepatoma HepG2 cells possess a 10-fold higher activity compared with A549 cells. TGF-beta exerts cell-specific effects on hAhRP activity. Treatment of cells with 100 pM TGF-beta leads to a 50% inhibition in A549 and a 3-fold induction in HepG2 cells. Deletion mutagenesis identified a TGF-beta-responsive sequence containing a functional conserved Smad-binding element. Transient overexpression of Smad 2, 3, and 4 indicates that these signal transducers modulate hAhRP activity. The down-regulation of AhR by TGF-beta is modulated by 5'-TG-3'-interacting factor (TGIF). Transient overexpression of TGIF in MDA-MB231 and HepG2 cells led to inhibition of hAhRP activity and a similar decrease of AhR mRNA expression. Our findings indicate that Smad proteins are involved in the cell-specific regulation of AhR expression by TGF-beta.

5' Untranslated Regions↗
PubMed2002

Decreased Smad 7 expression contributes to cardiac fibrosis in the infarcted rat heart.

We examined the role of the transforming growth factor (TGF)-beta(1) signaling inhibitor Smad 7 in cardiac fibrosis. TGF-beta(1) (10 ng/ml) was found to increase cytosolic Smad 7 expression in primary adult rat fibroblasts and induce rapid nuclear export of exogenous Smad 7 in COS-7 cells. Furthermore, overexpression of Smad 7 in primary adult fibroblasts was associated with suppressed collagen type I and III expression. We detected Smad 7, phosphorylated Smad 2, TGF-beta type I receptor (TbetaRI), and TGF-beta(1) proteins in postmyocardial infarct (MI) rat hearts. In 2 and 4 wk post-MI hearts, Smad 7 and TbetaRI expression were decreased in scar tissue, whereas TGF-beta(1) expression was increased in scar and viable tissue. In the 8 wk post-MI heart, Smad 7 expression was decreased in both scar tissue and myocardium remote to the infarct scar. Finally, we confirmed that these changes are paralleled by decreased expression of cytosolic phosphorylated receptor-regulated Smad 2 in 4-wk viable myocardium and in 2- and 4-wk infarct scar tissues. Taken together, our data imply that decreased inhibitory Smad 7 signal in cardiac fibroblasts may play a role in the pathogenesis of cardiac fibrosis in the post-MI heart.

Animals↗
PubMed2026

Novel association of NAV3 with dilated cardiomyopathy and its role in cardiac fibrosis.

A genome-wide association study (GWAS) identified neuron navigator 3 (NAV3) as a potential genetic determinant of myocardial recovery in dilated cardiomyopathy (DCM). This study aimed to understand its functional role in cardiac pathophysiology by leveraging omics approaches. Single-cell RNA-seq transcriptomic data from previously published adult human hearts indicate that NAV3 expression is highest in cardiac fibroblasts, suggesting its functional role in these cells. In vitro, stimulation of primary human ventricular cardiac fibroblasts with transforming growth factor β1 (TGF-β1) induced NAV3 expression in a dose and time-dependent manner. Small-interfering-RNA-mediated knockdown of NAV3 significantly attenuated TGF-β1-induced fibroblast activation, reducing the expression of α-smooth muscle actin (α-SMA), collagens, and fibronectin. RNA sequencing of NAV3-silenced fibroblasts, confirmed by Western blot, revealed upregulation of cell cycle regulators and downregulation of profibrotic markers, suggesting that NAV3 facilitates TGF-β1-induced cell cycle arrest and fibroblast-to-myofibroblast transition. Notably, NAV3 silencing did not alter canonical SMAD2/3 phosphorylation, implying a role for NAV3 in modulating fibrotic signaling through other pathways. Our findings provide functional and mechanistic insights into NAV3's novel role in cardiac fibrosis, showing that reduced NAV3 expression attenuates TGF-β1-mediated fibroblast activation by regulating cell cycle signaling. These results support further investigation of NAV3 as a potential modulator of cardiac fibrosis and myocardial recovery in DCM.NEW & NOTEWORTHY This study uncovers a previously unrecognized role for NAV3 in TGF-β1-driven cardiac fibroblast activation. We show that NAV3 facilitates profibrotic remodeling through noncanonical signaling and cell cycle arrest, independently of SMAD2/3. These findings position NAV3 as a novel regulator of fibroblast phenotype and a potential modulator of cardiac fibrosis.

Humans↗
PubMed2001

Human T-cell leukemia virus type I oncoprotein Tax represses Smad-dependent transforming growth factor beta signaling through interaction with CREB-binding protein/p300.

Human T-cell leukemia virus type I (HTLV-I) Tax is a potent transcriptional regulator that can activate or repress specific cellular genes and that has been proposed to contribute to leukemogenesis in adult T-cell leukemia. Previously, HTLV-I- infected T-cell clones were found to be resistant to growth inhibition by transforming growth factor (TGF)-beta. Here it is shown that Tax can perturb Smad-dependent TGF-beta signaling even though no direct interaction of Tax and Smad proteins could be detected. Importantly, a mutant Tax of CREB-binding protein (CBP)/p300 binding site, could not repress the Smad transactivation function, suggesting that the CBP/p300 binding domain of Tax is essential for the suppression of Smad function. Because both Tax and Smad are known to interact with CBP/p300 for the potentiation of their transcriptional activities, the effect of CBP/p300 on suppression of Smad-mediated transactivation by Tax was examined. Overexpression of CBP/p300 reversed Tax-mediated inhibition of Smad transactivation. Furthermore, Smad could repress Tax transcriptional activation, indicating reciprocal repression between Tax and Smad. These results suggest that Tax interferes with the recruitment of CBP/p300 into transcription initiation complexes on TGF-beta-responsive elements through its binding to CBP/p300. The novel function of Tax as a repressor of TGF-beta signaling may contribute to HTLV-I leukemogenesis. (Blood. 2001;97:2137-2144)

Activin Receptors, Type I↗
PubMed2002

RRR-alpha-tocopheryl succinate induction of DNA synthesis arrest of human MDA-MB-435 cells involves TGF-beta-independent activation of p21Waf1/Cip1.

RRR-alpha-tocopheryl succinate (vitamin E succinate, VES), a derivative of vitamin E, is a potent antitumor agent. Cellular events involved in VES-induced DNA synthesis arrest of human MDA-MB-435 breast cancer cells were studied. VES induces a dose- and time-dependent inhibition of DNA synthesis and a G0/G1 cell cycle arrest. VES induces expression of p21Waf1/Cip1 mRNA and protein, and antisense oligomers to p21 block VES-induced growth arrest. Evidence suggesting that VES modulates p21 expression in a transforming growth factor-beta (TGF-beta)-independent fashion includes failure of TGF-beta-neutralizing antibodies to block VES-induced DNA synthesis arrest or VES activation of a p21 promoter-regulated reporter gene; VES is not capable of inducing the translocation of green fluorescent protein-Smad2 into the nucleus and is not capable of stimulating a TGF-beta-dependent reporter gene, and VES induces growth inhibition and upregulates p21 mRNA levels in TGF-beta receptor-defective cells.

Antineoplastic Agents↗
PubMed1997

Mothers against decapentaplegic-related protein 2 expression in avian granulosa cells is up-regulated by transforming growth factor beta during ovarian follicular development.

Although mothers against dpp (MAD) and its related proteins (MADR) are believed to be important components of the cell signaling pathway for the transforming growth factor beta (TGFbeta) superfamily, the presence and regulation of these signaling molecules in ovarian cells by TGFbeta is not known. In the present studies, we have examined the presence of MADR2 and MADR1, two members of the MADR family, in hen granulosa cells at different stages of follicular development. The influence of TGFbeta in vitro on their expression was assessed, particularly in the context of TGFbeta-induced down-regulation of cytosolic phospholipase A2 (cPLA2), a key enzyme in the biosynthesis of eicosanoids. We have demonstrated for the first time the presence of MADR2 and MADR1 in hen granulosa cells at different stages of follicular development. The expression of MADR2, but not of MADR1, was up-regulated by TGFbeta in vitro in a concentration- and time-dependent manner. Granulosa cell MADR2 expression was maximal during early stages of follicular development, when the granulosa cell cPLA2 system is most responsive to the growth factor. The changes in MADR2 expression were accompanied by reciprocal alterations in the expression of cPLA2. These findings are consistent with the hypothesis that homologous up-regulation of MADR2 in granulosa cells may be an important determinant in its follicular stage-specific responsiveness to TGFbeta and possibly in the suppression of cPLA2 gene transcription by the growth factor.

Animals↗