Biomedical subjects

Liliana Attisano

Publications and source records attributed to Liliana Attisano.

12 recordsLinked to original sources

PubMed2007

Transcriptional cooperation between the transforming growth factor-beta and Wnt pathways in mammary and intestinal tumorigenesis.

Transforming growth factor-beta (TGF-beta) and Wnt ligands function in numerous developmental processes, and alterations of both signaling pathways are associated with common pathologic conditions, including cancer. To obtain insight into the extent of interdependence of the two signaling cascades in regulating biological responses, we used an oligonucleotide microarray approach to identify Wnt and TGF-beta target genes using normal murine mammary gland epithelial cells as a model. Combination treatment of TGF-beta and Wnt revealed a novel transcriptional program that could not have been predicted from single ligand treatments and included a cohort of genes that were cooperatively induced by both pathways. These included both novel and known components or modulators of TGF-beta and Wnt pathways, suggesting that mutual feedback is a feature of the coordinated activities of the ligands. The majority of the cooperative targets display increased expression in tumors derived from either Min (many intestinal neoplasia) or mouse mammary tumor virus (MMTV)-Wnt1 mice, two models of Wnt-induced tumors, with nine of these genes (Ankrd1, Ccnd1, Ctgf, Gpc1, Hs6st2, IL11, Inhba, Mmp14, and Robo1) showing increases in both. Reduction of TGF-beta signaling by expression of a dominant-negative TGF-beta type II receptor in bigenic MMTV-Wnt1/DNIIR mice increased mammary tumor latency and was correlated with a decrease in expression of Gpc1, Inhba, and Robo1, three of the TGF-beta/Wnt cooperative targets. Our results indicate that the TGF-beta and Wnt/beta-catenin pathways are firmly intertwined and generate a unique gene expression pattern that can contribute to tumor progression.

Adenoma↗

PubMed2007

Endoglin increases eNOS expression by modulating Smad2 protein levels and Smad2-dependent TGF-beta signaling.

The endothelial nitric oxide synthase (eNOS) is a critical regulator of cardiovascular homeostasis, whose dysregulation leads to different vascular pathologies. Endoglin is a component of the transforming growth factor beta (TGF-beta) receptor complex present in endothelial cells that is involved in angiogenesis, cardiovascular development, and vascular homeostasis. Haploinsufficient expression of endoglin has been shown to downregulate endothelium-derived nitric oxide in endoglin(+/-) (Eng(+/-)) mice and cultured endothelial cells. Here, we find that TGF-beta1 leads to an increased vasodilatation in Eng(+/+) mice that is severely impaired in Eng(+/-) mice, suggesting the involvement of endoglin in the TGF-beta regulated vascular homeostasis. The endoglin-dependent induction of eNOS occurs at the transcriptional level and is mediated by the type I TGF-beta receptor ALK5 and its downstream substrate Smad2. In addition, Smad2-specific signaling is upregulated in endoglin-induced endothelial cells, whereas it is downregulated upon endoglin gene suppression with small interference RNA (siRNA). The endoglin-dependent upregulation of Smad2 was confirmed using eNOS and pARE promoters, whose activities are known to be Smad2 dependent, as well as with the interference of Smad2 with siRNA, Smurf2, or a dominant negative form of Smad2. Furthermore, increased expression of endoglin in endoglin-inducible endothelial cells or in transfectants resulted in increased levels of Smad2 protein without affecting the levels of Smad2 mRNA. The increased levels of Smad2 appear to be due to a decreased ubiquitination and proteasome-dependent degradation leading to stabilization of Smad2. These results suggest that endoglin enhances Smad2 protein levels potentiating TGF-beta signaling, and leading to an increased eNOS expression in endothelial cells.

Animals↗

PubMed2006

Embryonic cortical neural stem cells migrate ventrally and persist as postnatal striatal stem cells.

Embryonic cortical neural stem cells apparently have a transient existence, as they do not persist in the adult cortex. We sought to determine the fate of embryonic cortical stem cells by following Emx1(IREScre); LacZ/EGFP double-transgenic murine cells from midgestation into adulthood. Lineage tracing in combination with direct cell labeling and time-lapse video microscopy demonstrated that Emx1-lineage embryonic cortical stem cells migrate ventrally into the striatal germinal zone (GZ) perinatally and intermingle with striatal stem cells. Upon integration into the striatal GZ, cortical stem cells down-regulate Emx1 and up-regulate Dlx2, which is a homeobox gene characteristic of the developing striatum and striatal neural stem cells. This demonstrates the existence of a novel dorsal-to-ventral migration of neural stem cells in the perinatal forebrain.

Animals↗

PubMed2006

Ubiquitin-dependent regulation of TGFbeta signaling in cancer.

The transforming growth factorbeta (TGFbeta) superfamily regulates a broad spectrum of biological responses throughout embryonic development and adult life, including cell proliferation and differentiation, epithelial-to-mesenchymal transition, apoptosis, and angiogenesis. TGFbeta members initiate signaling by bringing together a complex of serine/threonine kinase receptors that transmit signals through intracellular Smad proteins. Genetic alterations in numerous components of the TGFbeta signaling pathway have been associated with several human cancers. In addition, tight regulation of TGFbeta signaling is pivotal to the maintenance of homeostasis and the prevention of carcinogenesis. The ubiquitin/proteosome system is one mechanism by which cells regulate the expression and activity of effectors of the TGFbeta signaling cascade. Mounting evidence also suggests that disruption of the ubiquitin-dependent degradation of components of the TGFbeta pathway leads to the development and progression of cancer. Therefore, understanding how these two pathways intertwine will contribute to the advancement of our knowledge of cancer development.

Apoptosis↗

PubMed2005

The Drosophila type II receptor, Wishful thinking, binds BMP and myoglianin to activate multiple TGFbeta family signaling pathways.

Wishful thinking (Wit) is a Drosophila transforming growth factor-beta (TGFbeta) superfamily type II receptor most related to the mammalian bone morphogenetic protein (BMP) type II receptor, BMPRII. To better understand its function, we undertook a biochemical approach to establish the ligand binding repertoire and downstream signaling pathway. We observed that BMP4 and BMP7, bound to receptor complexes comprised of Wit and the type I receptor thickveins and saxophone to activate a BMP-like signaling pathway. Further we demonstrated that both myoglianin and its most closely related mammalian ligand, myostatin, interacted with a Wit and Baboon (Babo) type II-type I receptor complex to activate TGFbeta/activin-like signaling pathways. These results thereby demonstrate that Wit binds multiple ligands to activate both BMP and TGFbeta-like signaling pathways. Given that myoglianin is expressed in muscle and glial-derived cells, these results also suggest that Wit may mediate myoglianin-dependent signals in the nervous system.

Activin Receptors↗

PubMed2005

DRAGON, a bone morphogenetic protein co-receptor.

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor (TGF)beta superfamily of ligands that regulate many crucial aspects of embryonic development and organogenesis. Unlike other TGFbeta ligands, co-receptors for BMP ligands have not been described. Here we show that DRAGON, a glycosylphosphatidylinositol-anchored member of the repulsive guidance molecule family, which is expressed early in the developing nervous system, enhances BMP but not TGFbeta signaling. DRAGON binds directly to BMP2 and BMP4 but not to BMP7 or other TGFbeta ligands. The enhancing action of DRAGON on BMP signaling is also reduced by administration of Noggin, a soluble BMP antagonist, indicating that the action of DRAGON is ligand-dependent. DRAGON associates directly with BMP type I (ALK2, ALK3, and ALK6) and type II (ActRII and ActRIIB) receptors, and its signaling is reduced by dominant negative Smad1 and ALK3 or -6 receptors. In the Xenopus embryo, DRAGON both reduces the threshold of the ability of Smad1 to induce mesodermal and endodermal markers and alters neuronal and neural crest patterning. The direct interaction of DRAGON with BMP ligands and receptors indicates that it is a BMP co-receptor that potentiates BMP signaling.

Animals↗

PubMed2004

Activation of LIMK1 by binding to the BMP receptor, BMPRII, regulates BMP-dependent dendritogenesis.

The growth and morphological differentiation of dendrites are critical events in the establishment of proper neuronal connectivity and neural function. One extrinsic factor, BMP7, has been shown to specifically affect dendritic morphogenesis; however, the underlying mechanism by which this occurs is unknown. Here we show that LIM kinase 1 (LIMK1), a key downstream effector of Rho GTPases, colocalizes with the BMP receptor, BMPRII, in the tips of neurites and binds to BMPRII. This interaction is required for BMP-dependent induction of the dendritic arbor in cortical neurons. Furthermore, we demonstrate that the physical interaction of LIMK1 with BMPRII synergizes with the Rho GTPase, Cdc42, to activate LIMK1 catalytic activity. These studies thus define a Smad-independent pathway that directly links the BMP receptor to regulation of actin dynamics and provides insights into how extracellular signals modulate LIMK1 activity to permit fine spatial control over cytoskeletal remodelling during dendritogenesis.

Actin Depolymerizing Factors↗

PubMed2004

Regulation of the TGFbeta signalling pathway by ubiquitin-mediated degradation.

The transforming growth factor-beta (TGFbeta) superfamily controls a plethora of biological responses, and alterations in its signalling pathway are associated with a range of human diseases, including cancer. TGFbeta superfamily ligands signal through a heteromeric complex of Ser/Thr kinase receptors that propagate the signal to the Smad family of intracellular proteins. The ubiquitin-mediated proteasomal degradation pathway is an evolutionary conserved cascade that tightly regulates TGFbeta superfamily signalling. Both the size of the Smad pool in unstimulated cells and Smad protein levels subsequent to the activation of the pathway are controlled by ubiquitination. E3 ligases are components of the ubiquitin-degradation complex that specifically recognize targeted proteins and the E3 ligases, Smad ubiquitination-related factor 1 (Smurf1), Smurf2 and SCF/Roc1 have been implicated in Smad degradation. The Smurfs are of particular importance to TGFbeta signalling, as Smads also function as adapters that recruit the Smurfs to various pathway components including the TGFbeta receptor complex and the transcriptional repressor, SnoN, and thereby regulate the degradation of these Smad-associating proteins. Thus, by controlling the level of Smads as well as positive and negative regulators of the pathway, Smurfs provide for complex and fine control of signalling output. Finally, growing evidence demonstrates that ubiquitination and proteasomal degradation is also implicated in the turnover of tumor-derived Smad mutants and may thus contribute to disease progression.

Animals↗

PubMed2004

Foxh1 is essential for development of the anterior heart field.

The anterior heart field (AHF) mediates formation of the outflow tract (OFT) and right ventricle (RV) during looping morphogenesis of the heart. Foxh1 is a forkhead DNA binding transcription factor in the TGFbeta-Smad pathway. Here we demonstrate that Foxh1-/- mutant mouse embryos form a primitive heart tube, but fail to form OFT and RV and display loss of outer curvature markers of the future working myocardium, similar to the phenotype of Mef2c-/- mutant hearts. Further, we show that Mef2c is a direct target of Foxh1, which physically and functionally interacts with Nkx2-5 to mediate strong Smad-dependent activation of a TGFbeta response element in the Mef2c gene. This element directs transgene expression to the presumptive AHF, as well as the RV and OFT, a pattern that closely parallels endogenous Mef2c expression in the heart. Thus, Foxh1 and Nkx2-5 functionally interact and are essential for development of the AHF and its derivatives, the RV and OFT, in response to TGFbeta-like signals.

Animals↗

PubMed2003

TGF-beta1-mediated alterations of renal proximal tubular epithelial cell phenotype.

The aim of this study was to characterize the mechanism of transforming growth factor (TGF)-beta1-mediated alteration of renal proximal tubular cell phenotype. TGF-beta1 altered cell phenotype, with cells appearing elongated and spindle shaped. This was associated with loss of cell-cell contact and rearrangement of the actin cytoskeleton, increased formation of stress fibers, and focal adhesions. Addition of the tyrosine phosphatase inhibitor sodium orthovanadate also led to rapid but transient loss of cell-cell contact, but it did not lead to a change of phenotype comparable to that seen following addition of TGF-beta1. There was, however, no change in the formation of focal adhesions and no associated reorganization of the Factin cytoskeleton. Disruption of the actin cytoskeleton with cytochalasin D prevented phenotypic alterations following addition of TGF-beta1. Transient transfection with Smad2/4 or Smad3/4 expression vectors did not alter cell phenotype. Previously, we demonstrated beta-catenin translocation to proximal tubule cell nuclei and its association with Smad proteins following addition of TGF-beta1, suggesting the possibility that TGF-beta1 may modulate Wnt signaling. The Wnt-responsive Xtwn-reporter construct was, however, silent in response to TGF-beta1. Similarly, a second Wnt/LEF-1-regulated element, Toplflash, which does not contain Smad binding sites, was insensitive to TGF-beta1 signaling. In contrast, phenotypic changes in response to TGF-beta1 were abrogated by inhibitors of the RhoA downstream target ROCK, which also prevented loss of cell-cell contact and adherens junction disassembly.

Adherens Junctions↗

PubMed2002

Signal transduction by the TGF-beta superfamily.

Transforming growth factor-beta (TGF-beta) superfamily members regulate a plethora of developmental processes, and disruption of their activity has been implicated in a variety of human diseases ranging from cancer to chondrodysplasias and pulmonary hypertension. Intense investigations have revealed that SMAD proteins constitute the basic components of the core intracellular signaling cascade and that SMADs function by carrying signals from the cell surface directly to the nucleus. Recent insights have revealed how SMAD proteins themselves are regulated and how appropriate subcellular localization of SMADs and TGF-beta transmembrane receptors is controlled. Current research efforts investigating the contribution of SMAD-independent pathways promise to reveal advances to enhance our understanding of the signaling cascade.

Animals↗

PubMedDate not supplied

TGFbeta and Wnt pathway cross-talk.

Transforming growth factor-betas (TGFbeta) and Wnts represent two distinct families of secreted molecules each of which utilizes different signaling pathways to elicit their biological effects. These factors regulate numerous developmental events and mutations in components of both pathways have been described in human cancers including colorectal carcinomas. Several studies have demonstrated that TGFbeta and Wnt ligands can cooperate to regulate differentiation and cell fate determination by controlling gene expression patterns. In addition, their cooperation in promoting tumorigenesis in mice has been described. Here, we focus on reviewing our current understanding of the molecular mechanisms that may mediate these cooperative effects.

Cell Differentiation↗