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Dive into the research topics where Elena Enzo is active.

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Featured researches published by Elena Enzo.


Nature | 2011

Role of YAP/TAZ in mechanotransduction

Sirio Dupont; Leonardo Morsut; Mariaceleste Aragona; Elena Enzo; Stefano Giulitti; Michelangelo Cordenonsi; Francesca Zanconato; Jimmy le Digabel; Mattia Forcato; Silvio Bicciato; Nicola Elvassore; Stefano Piccolo

Cells perceive their microenvironment not only through soluble signals but also through physical and mechanical cues, such as extracellular matrix (ECM) stiffness or confined adhesiveness. By mechanotransduction systems, cells translate these stimuli into biochemical signals controlling multiple aspects of cell behaviour, including growth, differentiation and cancer malignant progression, but how rigidity mechanosensing is ultimately linked to activity of nuclear transcription factors remains poorly understood. Here we report the identification of the Yorkie-homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1) as nuclear relays of mechanical signals exerted by ECM rigidity and cell shape. This regulation requires Rho GTPase activity and tension of the actomyosin cytoskeleton, but is independent of the Hippo/LATS cascade. Crucially, YAP/TAZ are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry; conversely, expression of activated YAP overrules physical constraints in dictating cell behaviour. These findings identify YAP/TAZ as sensors and mediators of mechanical cues instructed by the cellular microenvironment.


Cell | 2010

A MicroRNA Targeting Dicer for Metastasis Control

Graziano Martello; Antonio Rosato; Francesco Ferrari; Andrea Manfrin; Michelangelo Cordenonsi; Sirio Dupont; Elena Enzo; Vincenza Guzzardo; Maria Rondina; Thomas Spruce; Anna Parenti; Maria Grazia Daidone; Silvio Bicciato; Stefano Piccolo

Although specific microRNAs (miRNAs) can be upregulated in cancer, global miRNA downregulation is a common trait of human malignancies. The mechanisms of this phenomenon and the advantages it affords remain poorly understood. Here we identify a microRNA family, miR-103/107, that attenuates miRNA biosynthesis by targeting Dicer, a key component of the miRNA processing machinery. In human breast cancer, high levels of miR-103/107 are associated with metastasis and poor outcome. Functionally, miR-103/107 confer migratory capacities in vitro and empower metastatic dissemination of otherwise nonaggressive cells in vivo. Inhibition of miR-103/107 opposes migration and metastasis of malignant cells. At the cellular level, a key event fostered by miR-103/107 is induction of epithelial-to-mesenchymal transition (EMT), attained by downregulating miR-200 levels. These findings suggest a new pathway by which Dicer inhibition drifts epithelial cancer toward a less-differentiated, mesenchymal fate to foster metastasis.


Cell | 2014

YAP/TAZ Incorporation in the β-Catenin Destruction Complex Orchestrates the Wnt Response

Luca Azzolin; Tito Panciera; Sandra Soligo; Elena Enzo; Silvio Bicciato; Sirio Dupont; Silvia Bresolin; Chiara Frasson; Giuseppe Basso; Vincenza Guzzardo; Ambrogio Fassina; Michelangelo Cordenonsi; Stefano Piccolo

The Hippo transducers YAP/TAZ have been shown to play positive, as well as negative, roles in Wnt signaling, but the underlying mechanisms remain unclear. Here, we provide biochemical, functional, and genetic evidence that YAP and TAZ are integral components of the β-catenin destruction complex that serves as cytoplasmic sink for YAP/TAZ. In Wnt-ON cells, YAP/TAZ are physically dislodged from the destruction complex, allowing their nuclear accumulation and activation of Wnt/YAP/TAZ-dependent biological effects. YAP/TAZ are required for intestinal crypt overgrowth induced by APC deficiency and for crypt regeneration ex vivo. In Wnt-OFF cells, YAP/TAZ are essential for β-TrCP recruitment to the complex and β-catenin inactivation. In Wnt-ON cells, release of YAP/TAZ from the complex is instrumental for Wnt/β-catenin signaling. In line, the β-catenin-dependent maintenance of ES cells in an undifferentiated state is sustained by loss of YAP/TAZ. This work reveals an unprecedented signaling framework relevant for organ size control, regeneration, and tumor suppression.


Nature Genetics | 2013

BMP signaling controls muscle mass.

Roberta Sartori; E. Schirwis; Bert Blaauw; Sergia Bortolanza; Jinghui Zhao; Elena Enzo; Amalia Stantzou; Etienne Mouisel; Luana Toniolo; Arnaud Ferry; Sigmar Stricker; Alfred L. Goldberg; Sirio Dupont; Stefano Piccolo; Helge Amthor; Marco Sandri

Cell size is determined by the balance between protein synthesis and degradation. This equilibrium is affected by hormones, nutrients, energy levels, mechanical stress and cytokines. Mutations that inactivate myostatin lead to excessive muscle growth in animals and humans, but the signals and pathways responsible for this hypertrophy remain largely unknown. Here we show that bone morphogenetic protein (BMP) signaling, acting through Smad1, Smad5 and Smad8 (Smad1/5/8), is the fundamental hypertrophic signal in mice. Inhibition of BMP signaling causes muscle atrophy, abolishes the hypertrophic phenotype of myostatin-deficient mice and strongly exacerbates the effects of denervation and fasting. BMP-Smad1/5/8 signaling negatively regulates a gene (Fbxo30) that encodes a ubiquitin ligase required for muscle loss, which we named muscle ubiquitin ligase of the SCF complex in atrophy-1 (MUSA1). Collectively, these data identify a critical role for the BMP pathway in adult muscle maintenance, growth and atrophy.


Nature | 2012

SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors.

Marco Montagner; Elena Enzo; Mattia Forcato; Francesca Zanconato; Anna Parenti; Elena Rampazzo; Giuseppe Basso; Genesio Leo; Antonio Rosato; Silvio Bicciato; Michelangelo Cordenonsi; Stefano Piccolo

The molecular determinants of malignant cell behaviours in breast cancer remain only partially understood. Here we show that SHARP1 (also known as BHLHE41 or DEC2) is a crucial regulator of the invasive and metastatic phenotype in triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer. SHARP1 is regulated by the p63 metastasis suppressor and inhibits TNBC aggressiveness through inhibition of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α (HIFs). SHARP1 opposes HIF-dependent TNBC cell migration in vitro, and invasive or metastatic behaviours in vivo. SHARP1 is required, and sufficient, to limit expression of HIF-target genes. In primary TNBC, endogenous SHARP1 levels are inversely correlated with those of HIF targets. Mechanistically, SHARP1 binds to HIFs and promotes HIF proteasomal degradation by serving as the HIF-presenting factor to the proteasome. This process is independent of pVHL (von Hippel–Lindau tumour suppressor), hypoxia and the ubiquitination machinery. SHARP1 therefore determines the intrinsic instability of HIF proteins to act in parallel to, and cooperate with, oxygen levels. This work sheds light on the mechanisms and pathways by which TNBC acquires invasiveness and metastatic propensity.


Nature Cell Biology | 2011

USP15 is a deubiquitylating enzyme for receptor-activated SMADs

Masafumi Inui; Andrea Manfrin; Anant Mamidi; Graziano Martello; Leonardo Morsut; Sandra Soligo; Elena Enzo; Stefano Moro; Simona Polo; Sirio Dupont; Michelangelo Cordenonsi; Stefano Piccolo

The TGFβ pathway is critical for embryonic development and adult tissue homeostasis. On ligand stimulation, TGFβ and BMP receptors phosphorylate receptor-activated SMADs (R-SMADs), which then associate with SMAD4 to form a transcriptional complex that regulates gene expression through specific DNA recognition. Several ubiquitin ligases serve as inhibitors of R-SMADs, yet no deubiquitylating enzyme (DUB) for these molecules has so far been identified. This has left unexplored the possibility that ubiquitylation of R-SMADs is reversible and engaged in regulating SMAD function, in addition to degradation. Here we identify USP15 as a DUB for R-SMADs. USP15 is required for TGFβ and BMP responses in mammalian cells and Xenopus embryos. At the biochemical level, USP15 primarily opposes R-SMAD monoubiquitylation, which targets the DNA-binding domains of R-SMADs and prevents promoter recognition. As such, USP15 is critical for the occupancy of endogenous target promoters by the SMAD complex. These data identify an additional layer of control by which the ubiquitin system regulates TGFβ biology.


Nature | 2017

Regeneration of the entire human epidermis using transgenic stem cells

Tobias Hirsch; Tobias Rothoeft; Norbert Teig; Johann W. Bauer; Graziella Pellegrini; Laura De Rosa; Davide Scaglione; Julia Reichelt; Alfred Klausegger; Daniela Kneisz; Oriana Romano; Alessia Secone Seconetti; Roberta Contin; Elena Enzo; Irena Jurman; Sonia Carulli; Frank Jacobsen; Thomas Luecke; Marcus Lehnhardt; Meike Fischer; Maximilian Kueckelhaus; Daniela Quaglino; Michele Morgante; Silvio Bicciato; Sergio Bondanza; Michele De Luca

Junctional epidermolysis bullosa (JEB) is a severe and often lethal genetic disease caused by mutations in genes encoding the basement membrane component laminin-332. Surviving patients with JEB develop chronic wounds to the skin and mucosa, which impair their quality of life and lead to skin cancer. Here we show that autologous transgenic keratinocyte cultures regenerated an entire, fully functional epidermis on a seven-year-old child suffering from a devastating, life-threatening form of JEB. The proviral integration pattern was maintained in vivo and epidermal renewal did not cause any clonal selection. Clonal tracing showed that the human epidermis is sustained not by equipotent progenitors, but by a limited number of long-lived stem cells, detected as holoclones, that can extensively self-renew in vitro and in vivo and produce progenitors that replenish terminally differentiated keratinocytes. This study provides a blueprint that can be applied to other stem cell-mediated combined ex vivo cell and gene therapies.


Development | 2010

Negative control of Smad activity by ectodermin/Tif1γ patterns the mammalian embryo

Leonardo Morsut; Kai-Ping Yan; Elena Enzo; Mariaceleste Aragona; Sandra Soligo; Olivia Wendling; Manuel Mark; Konstantin Khetchoumian; Giorgio M. Bressan; Pierre Chambon; Sirio Dupont; Régine Losson; Stefano Piccolo

The definition of embryonic potency and induction of specific cell fates are intimately linked to the tight control over TGFβ signaling. Although extracellular regulation of ligand availability has received considerable attention in recent years, surprisingly little is known about the intracellular factors that negatively control Smad activity in mammalian tissues. By means of genetic ablation, we show that the Smad4 inhibitor ectodermin (Ecto, also known as Trim33 or Tif1γ) is required to limit Nodal responsiveness in vivo. New phenotypes, which are linked to excessive Nodal activity, emerge from such a modified landscape of Smad responsiveness in both embryonic and extra-embryonic territories. In extra-embryonic endoderm, Ecto is required to confine expression of Nodal antagonists to the anterior visceral endoderm. In trophoblast cells, Ecto precisely doses Nodal activity, balancing stem cell self-renewal and differentiation. Epiblast-specific Ecto deficiency shifts mesoderm fates towards node/organizer fates, revealing the requirement of Smad inhibition for the precise allocation of cells along the primitive streak. This study unveils that intracellular negative control of Smad function by ectodermin/Tif1γ is a crucial element in the cellular response to TGFβ signals in mammalian tissues.


The EMBO Journal | 2015

Aerobic glycolysis tunes YAP/TAZ transcriptional activity

Elena Enzo; Giulia Santinon; Arianna Pocaterra; Mariaceleste Aragona; Silvia Bresolin; Mattia Forcato; Daniela Grifoni; Annalisa Pession; Francesca Zanconato; Giulia Guzzo; Silvio Bicciato; Sirio Dupont

Increased glucose metabolism and reprogramming toward aerobic glycolysis are a hallmark of cancer cells, meeting their metabolic needs for sustained cell proliferation. Metabolic reprogramming is usually considered as a downstream consequence of tumor development and oncogene activation; growing evidence indicates, however, that metabolism on its turn can support oncogenic signaling to foster tumor malignancy. Here, we explored how glucose metabolism regulates gene transcription and found an unexpected link with YAP/TAZ, key transcription factors regulating organ growth, tumor cell proliferation and aggressiveness. When cells actively incorporate glucose and route it through glycolysis, YAP/TAZ are fully active; when glucose metabolism is blocked, or glycolysis is reduced, YAP/TAZ transcriptional activity is decreased. Accordingly, glycolysis is required to sustain YAP/TAZ pro‐tumorigenic functions, and YAP/TAZ are required for the full deployment of glucose growth‐promoting activity. Mechanistically we found that phosphofructokinase (PFK1), the enzyme regulating the first committed step of glycolysis, binds the YAP/TAZ transcriptional cofactors TEADs and promotes their functional and biochemical cooperation with YAP/TAZ. Strikingly, this regulation is conserved in Drosophila, where phosphofructokinase is required for tissue overgrowth promoted by Yki, the fly homologue of YAP. Moreover, gene expression regulated by glucose metabolism in breast cancer cells is strongly associated in a large dataset of primary human mammary tumors with YAP/TAZ activation and with the progression toward more advanced and malignant stages. These findings suggest that aerobic glycolysis endows cancer cells with particular metabolic properties and at the same time sustains transcription factors with potent pro‐tumorigenic activities such as YAP/TAZ.


Stem cell reports | 2014

Long-Term Stability and Safety of Transgenic Cultured Epidermal Stem Cells in Gene Therapy of Junctional Epidermolysis Bullosa

Laura De Rosa; Sonia Carulli; Daniela Quaglino; Elena Enzo; Eleonora Franchini; Alberto Giannetti; Giorgio De Santis; Graziella Pellegrini; Michele De Luca

Summary We report a long-term follow-up (6.5 years) of a phase I/II clinical trial envisaging the use of autologous genetically modified cultured epidermal stem cells for gene therapy of junctional epidermolysis bullosa, a devastating genetic skin disease. The critical goals of the trial were to evaluate the safety and long-term persistence of genetically modified epidermis. A normal epidermal-dermal junction was restored and the regenerated transgenic epidermis was found to be fully functional and virtually indistinguishable from a normal control. The epidermis was sustained by a discrete number of long-lasting, self-renewing transgenic epidermal stem cells that maintained the memory of the donor site, whereas the vast majority of transduced transit-amplifying progenitors were lost within the first few months after grafting. These data pave the way for the safe use of epidermal stem cells in combined cell and gene therapy for genetic skin diseases.

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Silvio Bicciato

University of Modena and Reggio Emilia

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