Papers by Natalia Rubinstein
Suppl. Video 4: Confocal analysis of a Pygo2AE/AE tumor spheroid stained for Axin-2. (Related to ... more Suppl. Video 4: Confocal analysis of a Pygo2AE/AE tumor spheroid stained for Axin-2. (Related to Figure S2D).
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Excel File list of differentially expressed genes (DEGs)
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Suppl. Video 1: Confocal analysis of a Pygo2+/+ tumor spheroid stained for b-catenin. (Related to... more Suppl. Video 1: Confocal analysis of a Pygo2+/+ tumor spheroid stained for b-catenin. (Related to Figure S2C).
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Excel file list of differentially expressed extracellular matrix genes (ECM) in untreated (UT) or... more Excel file list of differentially expressed extracellular matrix genes (ECM) in untreated (UT) or Wnt3a-treated (Wnt3a) AE/AE mutant cells.
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Pygopus 2 (Pygo2) is a coactivator of Wnt/β-catenin signaling that can bind bi- or trimethylated ... more Pygopus 2 (Pygo2) is a coactivator of Wnt/β-catenin signaling that can bind bi- or trimethylated lysine 4 of histone-3 (H3K4me2/3) and participate in chromatin reading and writing. It remains unknown whether the Pygo2–H3K4me2/3 association has a functional relevance in breast cancer progression in vivo. To investigate the functional relevance of histone-binding activity of Pygo2 in malignant progression of breast cancer, we generated a knock-in mouse model where binding of Pygo2 to H3K4me2/3 was rendered ineffective. Loss of Pygo2–histone interaction resulted in smaller, differentiated, and less metastatic tumors, due, in part, to decreased canonical Wnt/β-catenin signaling. RNA- and ATAC-sequencing analyses of tumor-derived cell lines revealed downregulation of TGFβ signaling and upregulation of differentiation pathways such as PDGFR signaling. Increased differentiation correlated with a luminal cell fate that could be reversed by inhibition of PDGFR activity. Mechanistically, the ...
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Suppl. Video 3: Confocal analysis of a Pygo2+/+ tumor spheroid stained for Axin-2. (Related to Fi... more Suppl. Video 3: Confocal analysis of a Pygo2+/+ tumor spheroid stained for Axin-2. (Related to Figure S2D).
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Cells
Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype for which no effectiv... more Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype for which no effective targeted therapies are available. Growing evidence suggests that chemotherapy-resistant cancer cells with stem-like properties (CSC) may repopulate the tumor. The androgen receptor (AR) is expressed in up to 50% of TNBCs, and AR inhibition decreases CSC and tumor initiation. Runt-related transcription factor 1 (RUNX1) correlates with poor prognosis in TNBC and is regulated by the AR in prostate cancer. Our group has shown that RUNX1 promotes TNBC cell migration and regulates tumor gene expression. We hypothesized that RUNX1 is regulated by the AR and that both may work together in TNBC CSC to promote disease recurrence following chemotherapy. Chromatin immunoprecipitation sequencing (ChIP-seq) experiments in MDA-MB-453 revealed AR binding to RUNX1 regulatory regions. RUNX1 expression is upregulated by dihydrotestosterone (DHT) in MDA-MB-453 and in an AR+-TNBC HCI-009 patient-derived xe...
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Scientific Reports
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Since the discovery of SARS-CoV-2, several antigens have been proposed to be part of COVID-19 vac... more Since the discovery of SARS-CoV-2, several antigens have been proposed to be part of COVID-19 vaccines. The receptor binding domain (RBD) of Spike protein is one of the promising candidates to develop effective vaccines since it can induce potent neutralizing antibodies. We previously reported the production of RBD in Pichia pastoris and showed it is structurally identical to the protein produced in mammalian HEK-293T cells. In this work we designed an RBD multimer construct with the purpose of increasing RBD immunogenicity. We produced multimeric particles by a transpeptidation reaction between the RBD expressed in P. pastoris and Lumazine Synthase from Brucella abortus (BLS), which is a highly immunogenic and very stable decameric protein of 170 kDa. We vaccinated mice with two doses 30 days apart, and then we measured humoral immune response. When the number of RBD copies coupled to BLS was high (6-7 RBD molecules per BLS decamer, in average), the immune response was significantl...
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Scientific Reports, 2022
The receptor binding domain (RBD) of the Spike protein from SARS-CoV-2 is a promising candidate t... more The receptor binding domain (RBD) of the Spike protein from SARS-CoV-2 is a promising candidate to develop effective COVID-19 vaccines since it can induce potent neutralizing antibodies. We have previously reported the highly efficient production of RBD in Pichia pastoris, which is structurally similar to the same protein produced in mammalian HEK-293T cells. In this work we designed an RBD multimer with the purpose of increasing its immunogenicity. We produced multimeric particles by a transpeptidation reaction between RBD expressed in P. pastoris and Lumazine Synthase from Brucella abortus (BLS), which is a highly immunogenic and very stable decameric 170 kDa protein. Such particles were used to vaccinate mice with two doses 30 days apart. When the particles ratio of RBD to BLS units was high (6–7 RBD molecules per BLS decamer in average), the humoral immune response was significantly higher than that elicited by RBD alone or by RBD-BLS particles with a lower RBD to BLS ratio (1–2...
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International Journal of Immunopathology and Pharmacology, 2005
Apoptosis of cytotoxic T lymphocytes by herpes simplex virus type-1 (HSV-1) has been reported to ... more Apoptosis of cytotoxic T lymphocytes by herpes simplex virus type-1 (HSV-1) has been reported to be a relevant mechanism of viral immune evasion. Galectin-1 (Gal-1), an endogenous lectin involved in T-cell apoptosis, has recently gained considerable attention as a novel mechanism of tumor-immune evasion. Here we investigated whether infection of cells with HSV-1 can modulate the expression of Gal-1. Results show that pro-apoptotic Gal-1, but not Gal-3, is remarkably up-regulated in cell cultures infected with HSV-1. In addition, this protein is secreted to the extracellular milieu, where it contributes to apoptosis of activated T cells in a carbohydrate-dependent manner. Since many viruses have evolved mechanisms to counteract the antiviral response raised by the infected host, our results suggest that HSV-1 may use galectin-1 as a weapon to kill activated T cells and evade specific immune responses.
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Medicina, 2001
Galectins have emerged as a new family of closely related carbohydrate-binding proteins, which ex... more Galectins have emerged as a new family of closely related carbohydrate-binding proteins, which exert their functions by virtue of their ability to decipher glycocodes on complex glycoconjugates. They have been implicated in different immunological processes, such as lymphocyte adhesion, cytokine production, cell growth regulation, apoptosis and central and peripheral immune tolerance. In the present article we analyze the implications of this protein family in different immune pathologies with up- or down-regulated immune responses, such as autoimmune disorders, acute and chronic inflammation, allergic diseases, infection and metastases. The use of recombinant galectins or their antagonists will have future implications in the diagnosis, prognosis and treatment of these diseases, widening the horizons of molecular immunopathology.
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Journal of Experimental Medicine, 2012
Kaposi’s sarcoma (KS), a multifocal vascular neoplasm linked to human herpesvirus-8 (HHV-8/KS-ass... more Kaposi’s sarcoma (KS), a multifocal vascular neoplasm linked to human herpesvirus-8 (HHV-8/KS-associated herpesvirus [KSHV]) infection, is the most common AIDS-associated malignancy. Clinical management of KS has proven to be challenging because of its prevalence in immunosuppressed patients and its unique vascular and inflammatory nature that is sustained by viral and host-derived paracrine-acting factors primarily released under hypoxic conditions. We show that interactions between the regulatory lectin galectin-1 (Gal-1) and specific target N-glycans link tumor hypoxia to neovascularization as part of the pathogenesis of KS. Expression of Gal-1 is found to be a hallmark of human KS but not other vascular pathologies and is directly induced by both KSHV and hypoxia. Interestingly, hypoxia induced Gal-1 through mechanisms that are independent of hypoxia-inducible factor (HIF) 1α and HIF-2α but involved reactive oxygen species–dependent activation of the transcription factor nuclear...
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ABSTRACTTriple negative breast cancer (TNBC) is an aggressive breast cancer subtype for which no ... more ABSTRACTTriple negative breast cancer (TNBC) is an aggressive breast cancer subtype for which no effective targeted therapies are available. Growing evidence suggests that chemotherapy-resistant cancer cells with stem-like properties (CSC) may repopulate the tumor. Androgen receptor (AR) is expressed in up to 50% of TNBC, and AR inhibition decreases CSC and tumor initiation. Runt-related transcription factor 1 (RUNX1) correlates with poor prognosis in TNBC and is regulated by AR in prostate cancer. Our group has shown that RUNX1 promotes TNBC cell migration and regulates tumor gene expression. We hypothesized that RUNX1 is regulated by AR and that both may work together in TNBC CSC to promote disease recurrence following chemotherapy. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) experiments in MDA-MB-453 revealed AR binding toRUNX1regulatory regions. RUNX1 expression is upregulated by dihydrotestosterone (DHT) in MDA-MB-453 and in HCI-009 patient-derived xenograft (PDX) t...
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Proceedings of the National Academy of Sciences, 2021
Significance Canonical, β-catenin–dependent Wnt signaling is well known to promote a variety of c... more Significance Canonical, β-catenin–dependent Wnt signaling is well known to promote a variety of cancer types. However, the contribution of β-catenin’s cell adhesion function versus its transcriptional output to malignant tumor progression and metastasis has remained unexplored. We dissected β-catenin’s function in cell adhesion from its transcriptional output in Wnt signaling in the mouse mammary tumor virus (MMTV)–PyMT transgenic mouse model of metastatic breast cancer. We found that β-catenin’s dual functions are required for tumor cell survival. In contrast, its transcriptional activity is required for the regulation of epithelial–mesenchymal transition in vitro and metastasis formation in vivo. Altogether, the results delineate at a molecular and mechanistic level β-catenin’s contribution to malignant breast cancer progression. During malignant progression, epithelial cancer cells dissolve their cell–cell adhesion and gain invasive features. By virtue of its dual function, β-cat...
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Oncogene
Canonical Wnt/β-catenin signaling is an established regulator of cellular state and its critical ... more Canonical Wnt/β-catenin signaling is an established regulator of cellular state and its critical contributions to tumor initiation, malignant tumor progression and metastasis formation have been demonstrated in various cancer types. Here, we investigated how the binding of β-catenin to the transcriptional coactivators B-cell CLL/lymphoma 9 (Bcl9) and Bcl9-Like (Bcl9L) affected mammary gland carcinogenesis in the MMTV-PyMT transgenic mouse model of metastatic breast cancer. Conditional knockout of both Bcl9 and Bcl9L resulted into tumor cell death. In contrast, disrupting the interaction of Bcl9/Bcl9L with β-catenin, either by deletion of their HD2 domains or by a point mutation in the N-terminal domain of β-catenin (D164A), diminished primary tumor growth and tumor cell proliferation and reduced tumor cell invasion and lung metastasis. In comparison, the disruption of HD1 domain-mediated binding of Bcl9/Bcl9L to Pygopus had only moderate effects. Interestingly, interfering with the ...
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Cancer Research
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Oncotarget
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Journal of Leukocyte Biology, May 1, 2002
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Medicina (B. …, 2006
Resumen Las interacciones entre proteínas y glicanos juegan un papel fundamental en numerosos eve... more Resumen Las interacciones entre proteínas y glicanos juegan un papel fundamental en numerosos eventos de la regulación de la fisiología del sistema inmune, como maduración tímica, activación, migración y apoptosis de células T. Los carbohidratos son capaces de ...
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Papers by Natalia Rubinstein