Publications by authors named "Berta N Vazquez"

15 Publications

  • Page 1 of 1

Sirtuins in female meiosis and in reproductive longevity.

Mol Reprod Dev 2020 12 13;87(12):1175-1187. Epub 2020 Nov 13.

Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, New Jersey, USA.

Transmission of genetic material through high-quality gametes to progeny requires accurate homologous chromosome recombination and segregation during meiosis. A failure to accomplish these processes can have major consequences in reproductive health, including infertility, and development disorders in offspring. Sirtuins, a family of NAD -dependent protein deacetylases and ADP-ribosyltransferases, play key roles in genome maintenance, metabolism, and aging. In recent years, Sirtuins have emerged as regulators of several reproductive processes and interventions aiming to target Sirtuin activity are of great interest in the reproductive biology field. Sirtuins are pivotal to protect germ cells against oxidative stress, a major determinant influencing ovarian aging and the quality of gametes. Sirtuins also safeguard the integrity of the genome through epigenetic programs required for regulating gene repression, DNA repair, and chromosome segregation, among others. Although these functions are relatively well characterized in many somatic tissues, how they contribute to reproductive functions is not well understood. This review summarizes our current knowledge on the role of Sirtuins in female reproductive systems and discusses the underlying molecular pathways. In addition, we highlight the importance of Sirtuins as antiaging factors in the ovary and summarize current preclinical efforts to identify treatments to extend female reproductive longevity.
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http://dx.doi.org/10.1002/mrd.23437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775317PMC
December 2020

SirT7 auto-ADP-ribosylation regulates glucose starvation response through mH2A1.

Sci Adv 2020 Jul 24;6(30):eaaz2590. Epub 2020 Jul 24.

Chromatin Biology Laboratory, Josep Carreras Leukaemia Research Institute (IJC), Ctra de Can Ruti, Camí de les Escoles s/n, 08916 Badalona, Barcelona, Catalonia, Spain.

Sirtuins are key players of metabolic stress response. Originally described as deacetylases, some sirtuins also exhibit poorly understood mono-adenosine 5'-diphosphate (ADP)-ribosyltransferase (mADPRT) activity. We report that the deacetylase SirT7 is a dual sirtuin, as it also features auto-mADPRT activity. SirT7 mADPRT occurs at a previously undefined active site, and its abrogation alters SirT7 chromatin distribution. We identify an epigenetic pathway by which ADP-ribosyl-SirT7 is recognized by the ADP-ribose reader mH2A1.1 under glucose starvation, inducing SirT7 relocalization to intergenic regions. SirT7 promotes mH2A1 enrichment in a subset of nearby genes, many of them involved in second messenger signaling, resulting in their specific up- or down-regulation. The expression profile of these genes under calorie restriction is consistently abrogated in SirT7-deficient mice, resulting in impaired activation of autophagy. Our work provides a novel perspective on sirtuin duality and suggests a role for SirT7/mH2A1.1 axis in glucose homeostasis and aging.
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http://dx.doi.org/10.1126/sciadv.aaz2590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439345PMC
July 2020

SIRT7 promotes chromosome synapsis during prophase I of female meiosis.

Chromosoma 2019 09 29;128(3):369-383. Epub 2019 Jun 29.

Department of Genetics, Rutgers University, 145 Bevier Rd., Piscataway, NJ, 08854, USA.

Sirtuins are NAD-dependent protein deacylases and ADP-ribosyltransferases that are involved in a wide range of cellular processes including genome homeostasis and metabolism. Sirtuins are expressed in human and mouse oocytes yet their role during female gamete development are not fully understood. Here, we investigated the role of a mammalian sirtuin member, SIRT7, in oocytes using a mouse knockout (KO) model. Sirt7 KO females have compromised fecundity characterized by a rapid fertility decline with age, suggesting the existence of a diminished oocyte pool. Accordingly, Sirt7 KO females produced fewer oocytes and ovulated fewer eggs. Because of the documented role of SIRT7 in DNA repair, we investigated whether SIRT7 regulates prophase I when meiotic recombination occurs. Sirt7 KO pachynema-like staged oocytes had approximately twofold increased γH2AX signals associated with regions with unsynapsed chromosomes. Consistent with the presence of asynaptic chromosome regions, Sirt7 KO oocytes had fewer MLH1 foci (~one less), a mark of crossover-mediated repair, than WT oocytes. Moreover, this reduced level of crossing over is consistent with an observed twofold increased incidence of aneuploidy in Metaphase II eggs. In addition, we found that acetylated lysine 18 of histone H3 (H3K18ac), an established SIRT7 substrate, was increased at asynaptic chromosome regions suggesting a functional relationship between this epigenetic mark and chromosome synapsis. Taken together, our findings demonstrate a pivotal role for SIRT7 in oocyte meiosis by promoting chromosome synapsis and have unveiled the importance of SIRT7 as novel regulator of the reproductive lifespan.
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http://dx.doi.org/10.1007/s00412-019-00713-9DOI Listing
September 2019

SIRT7 mediates L1 elements transcriptional repression and their association with the nuclear lamina.

Nucleic Acids Res 2019 09;47(15):7870-7885

Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854, USA.

Long interspersed elements-1 (LINE-1, L1) are retrotransposons that hold the capacity of self-propagation in the genome with potential mutagenic outcomes. How somatic cells restrict L1 activity and how this process becomes dysfunctional during aging and in cancer cells is poorly understood. L1s are enriched at lamin-associated domains, heterochromatic regions of the nuclear periphery. Whether this association is necessary for their repression has been elusive. Here we show that the sirtuin family member SIRT7 participates in the epigenetic transcriptional repression of L1 genome-wide in both mouse and human cells. SIRT7 depletion leads to increased L1 expression and retrotransposition. Mechanistically, we identify a novel interplay between SIRT7 and Lamin A/C in L1 repression. Our results demonstrate that SIRT7-mediated H3K18 deacetylation regulates L1 expression and promotes L1 association with elements of the nuclear lamina. The failure of such activity might contribute to the observed genome instability and compromised viability in SIRT7 knockout mice. Overall, our results reveal a novel function of SIRT7 on chromatin organization by mediating the anchoring of L1 to the nuclear envelope, and a new functional link of the nuclear lamina with transcriptional repression.
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http://dx.doi.org/10.1093/nar/gkz519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735864PMC
September 2019

Genetic Interactions between the Aurora Kinases Reveal New Requirements for AURKB and AURKC during Oocyte Meiosis.

Curr Biol 2018 11 25;28(21):3458-3468.e5. Epub 2018 Oct 25.

Department of Genetics, Rutgers University, 145 Bevier Road, Piscataway, NJ 08854, USA. Electronic address:

Errors in chromosome segregation during female meiosis I occur frequently, and aneuploid embryos account for 1/3 of all miscarriages in humans [1]. Unlike mitotic cells that require two Aurora kinase (AURK) homologs to help prevent aneuploidy (AURKA and AURKB), mammalian germ cells also require a third (AURKC) [2, 3]. AURKA is the spindle-pole-associated homolog, and AURKB/C are the chromosome-localized homologs. In mitosis, AURKB has essential roles as the catalytic subunit of the chromosomal passenger complex (CPC), regulating chromosome alignment, kinetochore-microtubule attachments, cohesion, the spindle assembly checkpoint, and cytokinesis [4, 5]. In mouse oocyte meiosis, AURKC takes over as the predominant CPC kinase [6], although the requirement for AURKB remains elusive [7]. In the absence of AURKC, AURKB compensates, making defining potential non-overlapping functions difficult [6, 8]. To investigate the role(s) of AURKB and AURKC in oocytes, we analyzed oocyte-specific Aurkb and Aurkc single- and double-knockout (KO) mice. Surprisingly, we find that double KO female mice are fertile. We demonstrate that, in the absence of AURKC, AURKA localizes to chromosomes in a CPC-dependent manner. These data suggest that AURKC prevents AURKA from localizing to chromosomes by competing for CPC binding. This competition is important for adequate spindle length to support meiosis I. We also describe a unique requirement for AURKB to negatively regulate AURKC to prevent aneuploidy. Together, our work reveals oocyte-specific roles for the AURKs in regulating each other's localization and activity. This inter-kinase regulation is critical to support wild-type levels of fecundity in female mice.
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http://dx.doi.org/10.1016/j.cub.2018.08.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234855PMC
November 2018

SIRT6-dependent cysteine monoubiquitination in the PRE-SET domain of Suv39h1 regulates the NF-κB pathway.

Nat Commun 2018 01 9;9(1):101. Epub 2018 Jan 9.

Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Av. Gran Via de l'Hospitalet 199-203, 08908, L'Hospitalet de Llobregat (Barcelona), Spain.

Sirtuins are NAD-dependent deacetylases that facilitate cellular stress response. They include SirT6, which protects genome stability and regulates metabolic homeostasis through gene silencing, and whose loss induces an accelerated aging phenotype directly linked to hyperactivation of the NF-κB pathway. Here we show that SirT6 binds to the H3K9me3-specific histone methyltransferase Suv39h1 and induces monoubiquitination of conserved cysteines in the PRE-SET domain of Suv39h1. Following activation of NF-κB signaling Suv39h1 is released from the IκBα locus, subsequently repressing the NF-κB pathway. We propose that SirT6 attenuates the NF-κB pathway through IκBα upregulation via cysteine monoubiquitination and chromatin eviction of Suv39h1. We suggest a mechanism based on SirT6-mediated enhancement of a negative feedback loop that restricts the NF-κB pathway.
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http://dx.doi.org/10.1038/s41467-017-02586-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760577PMC
January 2018

Sirtuins and DNA damage repair: SIRT7 comes to play.

Nucleus 2017 Mar 17;8(2):107-115. Epub 2017 Feb 17.

a Rutgers University, Department of Genetics , Human Genetics Institute of New Jersey , Piscataway , NJ , USA.

Aging is characterized by a cumulative loss of genome integrity, which involves chromatin reorganization, transcriptional dysregulation and the accumulation of DNA damage. Sirtuins participate in the protection against these aging processes by promoting genome homeostasis in response to cellular stress. We recently reported that SirT7 mice suffer from partial embryonic lethality and a progeroid like phenotype. At the cellular level, SIRT7 depletion results in the impaired repair of DNA double-strand breaks (DSBs), one the most dangerous DNA lesions, leading to genome instability. SIRT7 is recruited to DSBs, where it specifically deacetylates histone H3 at lysine 18 and affects the focal accumulation of the DNA damage response factor 53BP1, thus influencing the efficiency of repair. Here, we integrate our findings with the current knowledge on the mode of action of other sirtuin family members in DNA repair. We emphasize their capacity to regulate chromatin structure as a response to DNA damage within the constraints imposed by cellular status.
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http://dx.doi.org/10.1080/19491034.2016.1264552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403131PMC
March 2017

SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair.

EMBO J 2016 07 24;35(14):1488-503. Epub 2016 May 24.

Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ, USA

Sirtuins, a family of protein deacetylases, promote cellular homeostasis by mediating communication between cells and environment. The enzymatic activity of the mammalian sirtuin SIRT7 targets acetylated lysine in the N-terminal tail of histone H3 (H3K18Ac), thus modulating chromatin structure and transcriptional competency. SIRT7 deletion is associated with reduced lifespan in mice through unknown mechanisms. Here, we show that SirT7-knockout mice suffer from partial embryonic lethality and a progeroid-like phenotype. Consistently, SIRT7-deficient cells display increased replication stress and impaired DNA repair. SIRT7 is recruited in a PARP1-dependent manner to sites of DNA damage, where it modulates H3K18Ac levels. H3K18Ac in turn affects recruitment of the damage response factor 53BP1 to DNA double-strand breaks (DSBs), thereby influencing the efficiency of non-homologous end joining (NHEJ). These results reveal a direct role for SIRT7 in DSB repair and establish a functional link between SIRT7-mediated H3K18 deacetylation and the maintenance of genome integrity.
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http://dx.doi.org/10.15252/embj.201593499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884211PMC
July 2016

MiR-93 Controls Adiposity via Inhibition of Sirt7 and Tbx3.

Cell Rep 2015 Sep 28;12(10):1594-605. Epub 2015 Aug 28.

Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28028, Spain; Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK. Electronic address:

Conquering obesity has become a major socioeconomic challenge. Here, we show that reduced expression of the miR-25-93-106b cluster, or miR-93 alone, increases fat mass and, subsequently, insulin resistance. Mechanistically, we discovered an intricate interplay between enhanced adipocyte precursor turnover and increased adipogenesis. First, miR-93 controls Tbx3, thereby limiting self-renewal in early adipocyte precursors. Second, miR-93 inhibits the metabolic target Sirt7, which we identified as a major driver of in vivo adipogenesis via induction of differentiation and maturation of early adipocyte precursors. Using mouse parabiosis, obesity in mir-25-93-106b(-/-) mice could be rescued by restoring levels of circulating miRNA and subsequent inhibition of Tbx3 and Sirt7. Downregulation of miR-93 also occurred in obese ob/ob mice, and this phenocopy of mir-25-93-106b(-/-) was partially reversible with injection of miR-93 mimics. Our data establish miR-93 as a negative regulator of adipogenesis and a potential therapeutic option for obesity and the metabolic syndrome.
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http://dx.doi.org/10.1016/j.celrep.2015.08.006DOI Listing
September 2015

New insights on the transcriptional regulation of CD69 gene through a potent enhancer located in the conserved non-coding sequence 2.

Mol Immunol 2015 Aug 22;66(2):171-9. Epub 2015 Mar 22.

Activación Immunológica Group, Carlos III National Health Institute (ISCIII), Majadahonda, Spain. Electronic address:

The CD69 type II C-type lectin is one of the earliest indicators of leukocyte activation acting in lymphocyte migration and cytokine secretion. CD69 expression in hematopoietic lineage undergoes rapid changes depending on the cell-lineage, the activation state or the localization of the cell where it is expressed, suggesting a complex and tightly controlled regulation. Here we provide new insights on the transcriptional regulation of CD69 gene in mammal species. Through in silico studies, we analyzed several regulatory features of the 4 upstream conserved non-coding sequences (CNS 1-4) previously described, confirming a major function of CNS2 in the transcriptional regulation of CD69. In addition, multiple transcription binding sites are identified in the CNS2 region by DNA cross-species conservation analysis. By functional approaches we defined a core region of 226bp located within CNS2 as the main enhancer element of CD69 transcription in the hematopoietic cells analyzed. By chromatin immunoprecipitation, binding of RUNX1 to the core-CNS2 was shown in a T cell line. In addition, we found an activating but not essential role of RUNX1 in CD69 gene transcription by site-directed mutagenesis and RNA silencing, probably through the interaction with this potent enhancer specifically in the hematopoietic lineage. In summary, in this study we contribute with new evidences to the landscape of the transcriptional regulation of the CD69 gene.
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http://dx.doi.org/10.1016/j.molimm.2015.02.031DOI Listing
August 2015

Chromatin profiling reveals regulatory network shifts and a protective role for hepatocyte nuclear factor 4α during colitis.

Mol Cell Biol 2014 Sep 30;34(17):3291-304. Epub 2014 Jun 30.

Human Genetics Institute of New Jersey and Department of Genetics, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA

Transcriptional regulatory mechanisms likely contribute to the etiology of inflammatory bowel disease (IBD), as genetic variants associated with the disease are disproportionately found at regulatory elements. However, the transcription factors regulating colonic inflammation are unclear. To identify these transcription factors, we mapped epigenomic changes in the colonic epithelium upon inflammation. Epigenetic marks at transcriptional regulatory elements responded dynamically to inflammation and indicated a shift in epithelial transcriptional factor networks. Active enhancer chromatin structure at regulatory regions bound by the transcription factor hepatocyte nuclear factor 4α (HNF4A) was reduced during colitis. In agreement, upon an inflammatory stimulus, HNF4A was downregulated and showed a reduced ability to bind chromatin. Genetic variants that confer a predisposition to IBD map to HNF4A binding sites in the human colon cell line CaCo2, suggesting impaired HNF4A binding could underlie genetic susceptibility to IBD. Despite reduced HNF4A binding during inflammation, a temporal knockout model revealed HNF4A still actively protects against inflammatory phenotypes and promotes immune regulatory gene expression in the inflamed colonic epithelium. These findings highlight the potential for HNF4A agonists as IBD therapeutics.
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http://dx.doi.org/10.1128/MCB.00349-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135557PMC
September 2014

Chromatin structure, pluripotency and differentiation.

Exp Biol Med (Maywood) 2013 Mar;238(3):259-70

Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, 145 Bevier Road, Piscataway, NJ 08854, USA.

The state of cell differentiation in adult tissues was once thought to be permanent and irreversible. Since Dolly's cloning and, more recently, the generation of induced pluripotent stem cells (iPSCs) from differentiated cells, the traditional paradigm of cell identity has been reexamined. Much effort has been directed toward understanding how cellular identity is achieved and maintained, and studies are ongoing to investigate how cellular identity can be changed. Cell-specific transcription patterns can be altered by modulating the expression of a few transcription factors, which are known as master regulators of cell fate. Epigenetics also plays a major role in cell type specification because the differentiation process is accompanied by major chromatin remodeling. Moreover, whole-genome analyses reveal that nuclear architecture, as defined by the establishment of chromatin domains, regulates gene interactions in a cell-type-specific manner. In this paper, we review the current knowledge of chromatin states that are relevant to both pluripotency and gene expression during differentiation. Information about the epigenetic regulation of gene expression in iPSCs or naïve embryonic stem cells, compared with their differentiated derivatives, will be important as a practical consideration in the long-term maintenance of pluripotent cell cultures for therapeutic purposes.
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http://dx.doi.org/10.1177/1535370213480718DOI Listing
March 2013

The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation.

Genes Dev 2013 Mar 6;27(6):639-53. Epub 2013 Mar 6.

Department of Genetics, the Human Genetics Institute of New Jersey, Rutgers University, Piscataway, New Jersey 08854, USA.

The establishment of the epigenetic mark H4K20me1 (monomethylation of H4K20) by PR-Set7 during G2/M directly impacts S-phase progression and genome stability. However, the mechanisms involved in the regulation of this event are not well understood. Here we show that SirT2 regulates H4K20me1 deposition through the deacetylation of H4K16Ac (acetylation of H4K16) and determines the levels of H4K20me2/3 throughout the cell cycle. SirT2 binds and deacetylates PR-Set7 at K90, modulating its chromatin localization. Consistently, SirT2 depletion significantly reduces PR-Set7 chromatin levels, alters the size and number of PR-Set7 foci, and decreases the overall mitotic deposition of H4K20me1. Upon stress, the interaction between SirT2 and PR-Set7 increases along with the H4K20me1 levels, suggesting a novel mitotic checkpoint mechanism. SirT2 loss in mice induces significant defects associated with defective H4K20me1-3 levels. Accordingly, SirT2-deficient animals exhibit genomic instability and chromosomal aberrations and are prone to tumorigenesis. Our studies suggest that the dynamic cross-talk between the environment and the genome during mitosis determines the fate of the subsequent cell cycle.
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http://dx.doi.org/10.1101/gad.211342.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613611PMC
March 2013

CD69 gene is differentially regulated in T and B cells by evolutionarily conserved promoter-distal elements.

J Immunol 2009 Nov 19;183(10):6513-21. Epub 2009 Oct 19.

Departament de Fisiologia, Universitat de Barcelona, Barcelona, Spain.

CD69 is a type II C-type lectin involved in lymphocyte migration and cytokine secretion. CD69 expression represents one of the earliest available indicators of leukocyte activation and its rapid induction occurs through transcriptional activation. In this study we examined the molecular mechanism underlying mouse CD69 gene transcription in vivo in T and B cells. Analysis of the 45-kb region upstream of the CD69 gene revealed evolutionary conservation at the promoter and at four noncoding sequences (CNS) that were called CNS1, CNS2, CNS3, and CNS4. These regions were found to be hypersensitive sites in DNase I digestion experiments, and chromatin immunoprecipitation assays showed specific epigenetic modifications. CNS2 and CNS4 displayed constitutive and inducible enhancer activity in transient transfection assays in T cells. Using a transgenic approach to test CNS function, we found that the CD69 promoter conferred developmentally regulated expression during positive selection of thymocytes but could not support regulated expression in mature lymphocytes. Inclusion of CNS1 and CNS2 caused suppression of CD69 expression, whereas further addition of CNS3 and CNS4 supported developmental-stage and lineage-specific regulation in T cells but not in B cells. We concluded CNS1-4 are important cis-regulatory elements that interact both positively and negatively with the CD69 promoter and that differentially contribute to CD69 expression in T and B cells.
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http://dx.doi.org/10.4049/jimmunol.0900839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2787097PMC
November 2009

Induction of tumor NK-cell immunity by anti-CD69 antibody therapy.

Blood 2005 Jun 3;105(11):4399-406. Epub 2005 Feb 3.

Departamento de Fisiología, Universidad de Barcelona, Av Diagonal, 645 Barcelona 08028, Spain.

The leukocyte activation marker CD69 is a novel regulator of the immune response, modulating the production of cytokines including transforming growth factor-beta (TGF-beta). We have generated an antimurine CD69 monoclonal antibody (mAb), CD69.2.2, which down-regulates CD69 expression in vivo but does not deplete CD69-expressing cells. Therapeutic administration of CD69.2.2 to wild-type mice induces significant natural killer (NK) cell-dependent antitumor responses to major histocompatibility complex (MHC) class I low RMA-S lymphomas and to RM-1 prostatic carcinoma lung metastases. These in vivo antitumor responses are comparable to those seen in CD69(-/-) mice. Enhanced host NK cytotoxic activity correlates with a reduction in NK-cell TGF-beta production and is independent of tumor priming. In vitro studies demonstrate the novel ability of anti-CD69 mAbs to activate resting NK cells in an Fc receptor-independent manner, resulting in a substantial increase in both NK-cell cytolytic activity and interferon gamma (IFNgamma) production. Modulation of the innate immune system with monoclonal antibodies to host CD69 thus provides a novel means to antagonize tumor growth and metastasis.
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http://dx.doi.org/10.1182/blood-2004-10-3854DOI Listing
June 2005
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