Bio

Bio


Dr. Joshua Gruber is an Instructor of Medicine in the division of Medical Oncology at Stanford University Medical Center. He received his Bachelors of Arts, Summa Cum Laude, in biochemistry and physics from the University of Pennsylvania in 2001. He then graduated from the Medical Scientist Training Program at the University of Pennsylvania where he performed doctoral studies in cancer biology and biochemistry. He completed internship and residency in Internal Medicine at Stanford, then was a Clinical Fellowship in Medical Oncology and also a Postdoctoral Fellow in Genetics at Stanford, working in the laboratory of Michael Snyder on integrative genomics of hereditary breast cancer. He is currently has a clinical focus on treating patients with metastatic breast cancer and triple-negative breast cancer and conducts clinical trials on novel therapeutics for these diseases. His laboratory research interests include the molecular biology of breast cancer initiation, the intersection of tumor immunology with cancer growth pathways and the development of molecular tools to interrogate neoplastic tissues.

Clinical Focus


  • Medical Oncology

Academic Appointments


Honors & Awards


  • Post-doctoral Research Fellowship, Susan G. Komen (2017)
  • Young Investigator Award, ASCO & Conquer Cancer Foundation (2017)
  • Jane Coffin Childs Postdoctoral Fellowship, Jane Coffin Childs Memorial Fund (2016-2018)
  • SCI Fellowship Award, Stanford Cancer Institute (2016)
  • Barry M. Goldwater Science Scholarship, Barry Goldwater Scholarship and Excellence in Education Foundation (2000-2001)
  • Dean’s Scholar, University of Pennsylvania (2000)
  • Young International Chemistry Writer of the Year, Pharmacia, Inc. (1999)
  • Roy and Diana Vagelos Science Scholar, University of Pennsylvania (1998-2001)

Professional Education


  • Fellowship:Stanford University Hematology and Oncology Fellowship (2016) CA
  • Residency:Stanford University Internal Medicine Residency (2013) CA
  • Board Certification: Medical Oncology, American Board of Internal Medicine (2017)
  • Medical Education:Perelman School of Medicine University of Pennsylvania (2011) PA
  • Board Certification, Internal Medicine, 2016
  • Fellowship, Stanford University, Medical Oncology (2013)
  • Board Certification: Internal Medicine, American Board of Internal Medicine (2015)
  • Residency, Stanford University, Internal Medicine (2012)

Publications

All Publications


  • Matrix stiffness induces a tumorigenic phenotype in mammary epithelium through changes in chromatin accessibility. Nature biomedical engineering Stowers, R. S., Shcherbina, A., Israeli, J., Gruber, J. J., Chang, J., Nam, S., Rabiee, A., Teruel, M. N., Snyder, M. P., Kundaje, A., Chaudhuri, O. 2019

    Abstract

    In breast cancer, the increased stiffness of the extracellular matrix is a key driver of malignancy. Yet little is known about the epigenomic changes that underlie the tumorigenic impact of extracellular matrix mechanics. Here, we show in a three-dimensional culture model of breast cancer that stiff extracellular matrix induces a tumorigenic phenotype through changes in chromatin state. We found that increased stiffness yielded cells with more wrinkled nuclei and with increased lamina-associated chromatin, that cells cultured in stiff matrices displayed more accessible chromatin sites, which exhibited footprints of Sp1 binding, and that this transcription factor acts along with the histone deacetylases 3 and 8 to regulate the induction of stiffness-mediated tumorigenicity. Just as cell culture on soft environments or in them rather than on tissue-culture plastic better recapitulates the acinar morphology observed in mammary epithelium in vivo, mammary epithelial cells cultured on soft microenvironments or in them also more closely replicate the in vivo chromatin state. Our results emphasize the importance of culture conditions for epigenomic studies, and reveal that chromatin state is a critical mediator of mechanotransduction.

    View details for DOI 10.1038/s41551-019-0420-5

    View details for PubMedID 31285581

  • HAT1 Coordinates Histone Production and Acetylation via H4 Promoter Binding. Molecular cell Gruber, J. J., Geller, B., Lipchik, A. M., Chen, J., Salahudeen, A. A., Ram, A. N., Ford, J. M., Kuo, C. J., Snyder, M. P. 2019

    Abstract

    The energetic costs of duplicating chromatin are large and therefore likely depend on nutrient sensing checkpoints and metabolic inputs. By studying chromatin modifiers regulated by epithelial growth factor, we identified histone acetyltransferase 1 (HAT1) as an induced gene that enhances proliferation through coordinating histone production, acetylation, and glucose metabolism. In addition to its canonical role as a cytoplasmic histone H4 acetyltransferase, we isolated a HAT1-containing complex bound specifically at promoters of H4 genes. HAT1-dependent transcription of H4 genes required an acetate-sensitive promoter element. HAT1 expression was critical for S-phase progression and maintenance of H3 lysine 9 acetylation at proliferation-associated genes, including histone genes. Therefore, these data describe a feedforward circuit whereby HAT1 captures acetyl groups on nascent histones and drives H4 production by chromatin binding to support chromatin replication and acetylation. These findings have important implications for human disease, since high HAT1 levels associate with poor outcomes across multiple cancer types.

    View details for DOI 10.1016/j.molcel.2019.05.034

    View details for PubMedID 31278053

  • Talazoparib beyond BRCA: A phase II trial of talazoparib monotherapy in BRCA1 and BRCA2 wild-type patients with advanced HER2-negative breast cancer or other solid tumors with a mutation in homologous recombination (HR) pathway genes. Gruber, J., Afghahi, A., Hatton, A., Scott, D., McMillan, A., Ford, J. M., Telli, M. L. AMER SOC CLINICAL ONCOLOGY. 2019
  • High-Resolution Bisulfite-Sequencing of Peripheral Blood DNA Methylation in Early-Onset and Familial Risk Breast Cancer Patients. Clinical cancer research : an official journal of the American Association for Cancer Research Chen, J., Haanpää, M. K., Gruber, J. J., Jäger, N., Ford, J. M., Snyder, M. P. 2019

    Abstract

    Understanding and explaining hereditary predisposition to cancer has focused on the genetic etiology of the disease. However, mutations in known genes associated with breast cancer, such as BRCA1 and BRCA2, account for less than 25% of familial cases of breast cancer. Recently, specific epigenetic modifications at BRCA1 have been shown to promote hereditary breast cancer, but the broader potential for epigenetic contribution to hereditary breast cancer is not yet well understood.We examined DNA methylation through deep bisulfite sequencing of CpG islands and known promoter or regulatory regions in peripheral blood DNA from 99 familial or early-onset breast or ovarian cancer patients, 6 unaffected BRCA-mutation carriers, and 49 unaffected controls.In 9% of patients, we observed altered methylation in the promoter regions of genes known to be involved in cancer including hypermethylation at the tumor suppressor PTEN and hypomethylation at the proto-oncogene TEX14 These alterations occur in the form of allelic methylation that span up to hundreds of base-pairs in length.Our observations suggest a broader role for DNA methylation in early-onset, familial risk breast cancer. Further studies are warranted to clarify these mechanisms and the benefits of DNA methylation screening for early risk prediction of familial cancers.

    View details for DOI 10.1158/1078-0432.CCR-18-2423

    View details for PubMedID 31175093

  • Chromatin Remodeling in Response to BRCA2-Crisis. Cell reports Gruber, J. J., Chen, J., Geller, B., Jäger, N., Lipchik, A. M., Wang, G., Kurian, A. W., Ford, J. M., Snyder, M. P. 2019; 28 (8): 2182–93.e6

    Abstract

    Individuals with a single functional copy of the BRCA2 tumor suppressor have elevated risks for breast, ovarian, and other solid tumor malignancies. The exact mechanisms of carcinogenesis due to BRCA2 haploinsufficiency remain unclear, but one possibility is that at-risk cells are subject to acute periods of decreased BRCA2 availability and function ("BRCA2-crisis"), which may contribute to disease. Here, we establish an in vitro model for BRCA2-crisis that demonstrates chromatin remodeling and activation of an NF-κB survival pathway in response to transient BRCA2 depletion. Mechanistically, we identify BRCA2 chromatin binding, histone acetylation, and associated transcriptional activity as critical determinants of the epigenetic response to BRCA2-crisis. These chromatin alterations are reflected in transcriptional profiles of pre-malignant tissues from BRCA2 carriers and, therefore, may reflect natural steps in human disease. By modeling BRCA2-crisis in vitro, we have derived insights into pre-neoplastic molecular alterations that may enhance the development of preventative therapies.

    View details for DOI 10.1016/j.celrep.2019.07.057

    View details for PubMedID 31433991

  • Disruption of mesoderm formation during cardiac differentiation due to developmental exposure to 13-cis-retinoic acid. Scientific reports Liu, Q., Van Bortle, K., Zhang, Y., Zhao, M., Zhang, J. Z., Geller, B. S., Gruber, J. J., Jiang, C., Wu, J. C., Snyder, M. P. 2018; 8 (1): 12960

    Abstract

    13-cis-retinoic acid (isotretinoin, INN) is an oral pharmaceutical drug used for the treatment of skin acne, and is also a known teratogen. In this study, the molecular mechanisms underlying INN-induced developmental toxicity during early cardiac differentiation were investigated using both human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs). Pre-exposure of hiPSCs and hESCs to a sublethal concentration of INN did not influence cell proliferation and pluripotency. However, mesodermal differentiation was disrupted when INN was included in the medium during differentiation. Transcriptomic profiling by RNA-seq revealed that INN exposure leads to aberrant expression of genes involved in several signaling pathways that control early mesoderm differentiation, such as TGF-beta signaling. In addition, genome-wide chromatin accessibility profiling by ATAC-seq suggested that INN-exposure leads to enhanced DNA-binding of specific transcription factors (TFs), including HNF1B, SOX10 and NFIC, often in close spatial proximity to genes that are dysregulated in response to INN treatment. Altogether, these results identify potential molecular mechanisms underlying INN-induced perturbation during mesodermal differentiation in the context of cardiac development. This study further highlights the utility of human stem cells as an alternative system for investigating congenital diseases of newborns that arise as a result of maternal drug exposure during pregnancy.

    View details for PubMedID 30154523

  • VISTA immune checkpoint deregulation in human triple-negative breast cancer Gruber, J. J., Juntilla, M. M., Yang, S., Geller, B., Jager, N., Lin, C., Lipchik, A. M., Chen, J., Ram, A., Vinayak, S., Telli, M. L., West, R. B., Ford, J. M., Snyder, M. P. AMER ASSOC CANCER RESEARCH. 2018
  • Outstanding Questions in the Clinical Management of Triple-Negative Breast Cancer. Journal of oncology practice Gruber, J. J., Telli, M. L. 2017; 13 (5): 305-307

    View details for DOI 10.1200/JOP.2017.023341

    View details for PubMedID 28489983

  • Association of AHSG with alopecia and mental retardation (APMR) syndrome. Human genetics Reza Sailani, M., Jahanbani, F., Nasiri, J., Behnam, M., Salehi, M., Sedghi, M., Hoseinzadeh, M., Takahashi, S., Zia, A., Gruber, J., Lynch, J. L., Lam, D., Winkelmann, J., Amirkiai, S., Pang, B., Rego, S., Mazroui, S., Bernstein, J. A., Snyder, M. P. 2017; 136 (3): 287-296

    Abstract

    Alopecia with mental retardation syndrome (APMR) is a very rare autosomal recessive condition that is associated with total or partial absence of hair from the scalp and other parts of the body as well as variable intellectual disability. Here we present whole-exome sequencing results of a large consanguineous family segregating APMR syndrome with seven affected family members. Our study revealed a novel predicted pathogenic, homozygous missense mutation in the AHSG (OMIM 138680) gene (AHSG: NM_001622:exon7:c.950G>A:p.Arg317His). The variant is predicted to affect a region of the protein required for protein processing and disrupts a phosphorylation motif. In addition, the altered protein migrates with an aberrant size relative to healthy individuals. Consistent with the phenotype, AHSG maps within APMR linkage region 1 (APMR 1) as reported before, and falls within runs of homozygosity (ROH). Previous families with APMR syndrome have been studied through linkage analyses and the linkage resolution did not allow pointing out to a single gene candidate. Our study is the first report to identify a homozygous missense mutation for APMR syndrome through whole-exome sequencing.

    View details for DOI 10.1007/s00439-016-1756-5

    View details for PubMedID 28054173

  • Differentiated Thyroid Cancer: Focus on Emerging Treatments for Radioactive Iodine-Refractory Patients ONCOLOGIST Gruber, J. J., Colevas, A. D. 2015; 20 (2): 113-126

    Abstract

    The treatment of differentiated thyroid cancer refractory to radioactive iodine (RAI) had been hampered by few effective therapies. Recently, tyrosine kinase inhibitors (TKIs) have shown activity in this disease. Clinical guidance on the use of these agents in RAI-refractory thyroid cancer is warranted.Molecular mutations found in RAI-refractory thyroid cancer are summarized. Recent phase II and III clinical trial data for TKIs axitinib, lenvatinib, motesanib, pazopanib, sorafenib, sunitinib, and vandetinib are reviewed including efficacy and side effect profiles. Molecular targets and potencies of these agents are compared. Inhibitors of BRAF, mammalian target of rapamycin, and MEK are considered.Routine testing for molecular alterations prior to therapy is not yet recommended. TKIs produce progression-free survival of approximately 1 year (range: 7.7-19.6 months) and partial response rates of up to 50% by Response Evaluation Criteria in Solid Tumors. Pazopanib and lenvatinib are the most active agents. The majority of patients experienced tumor shrinkage with TKIs. Common adverse toxicities affect dermatologic, gastrointestinal, and cardiovascular systems.Multiple TKIs have activity in RAI-refractory differentiated thyroid cancer. Selection of a targeted agent should depend on disease trajectory, side effect profile, and goals of therapy.

    View details for DOI 10.1634/theoncologist.2014-0313

    View details for Web of Science ID 000351915500007

    View details for PubMedID 25616432

    View details for PubMedCentralID PMC4319630

  • Long-lived microRNA-Argonaute complexes in quiescent cells can be activated to regulate mitogenic responses PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Olejniczak, S. H., La Rocca, G., Gruber, J. J., Thompson, C. B. 2013; 110 (1): 157-162

    Abstract

    Cellular proliferation depends on the integration of mitogenic stimuli with environmental conditions. Increasing evidence suggests that microRNAs play a regulatory role in this integration. Here we show that during periods of cellular quiescence, mature microRNAs are stabilized and stored in Argonaute protein complexes that can be activated by mitogenic stimulation to repress mitogen-stimulated targets, thus influencing subsequent cellular responses. In quiescent cells, the majority of microRNAs exist in low molecular weight, Argonaute protein-containing complexes devoid of essential components of the RNA-induced silencing complex (RISC). For at least 3 wk, this pool of Argonaute-associated microRNAs is stable and can be recruited into RISC complexes subsequent to mitogenic stimulation. Using several model systems, we demonstrate that stable Argonaute protein-associated small RNAs are capable of repressing mitogen-induced transcripts. Therefore, mature microRNAs may represent a previously unappreciated form of cellular memory that allows cells to retain posttranscriptional regulatory information over extended periods of cellular quiescence.

    View details for DOI 10.1073/pnas.1219958110

    View details for Web of Science ID 000313630300043

    View details for PubMedID 23248281

  • Ars2 Promotes Proper Replication-Dependent Histone mRNA 3 ' End Formation MOLECULAR CELL Gruber, J. J., Olejniczak, S. H., Yong, J., La Rocca, G., Dreyfuss, G., Thompson, C. B. 2012; 45 (1): 87-98

    Abstract

    Ars2 is a component of the nuclear cap-binding complex that contributes to microRNA biogenesis and is required for cellular proliferation. Here, we expand on the repertoire of Ars2-dependent microRNAs and determine that Ars2 regulates a number of mRNAs, the largest defined subset of which code for histones. Histone mRNAs are unique among mammalian mRNAs because they are not normally polyadenylated but, rather, are cleaved following a 3' stem loop. A significant reduction in correctly processed histone mRNAs was observed following Ars2 depletion, concurrent with an increase in polyadenylated histone transcripts. Furthermore, Ars2 physically associated with histone mRNAs and the noncoding RNA 7SK. Knockdown of 7SK led to an enhanced ratio of cleaved to polyadenylated histone transcripts, an effect dependent on Ars2. Together, the data demonstrate that Ars2 contributes to histone mRNA 3' end formation and expression and these functional properties of Ars2 are negatively regulated by interaction with 7SK RNA.

    View details for DOI 10.1016/j.molcel.2011.12.020

    View details for Web of Science ID 000299301300012

    View details for PubMedID 22244333

    View details for PubMedCentralID PMC3269315

  • Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Wise, D. R., Ward, P. S., Shay, J. E., Cross, J. R., Gruber, J. J., Sachdeva, U. M., Platt, J. M., DeMatteo, R. G., Simon, M. C., Thompson, C. B. 2011; 108 (49): 19611-19616

    Abstract

    Citrate is a critical metabolite required to support both mitochondrial bioenergetics and cytosolic macromolecular synthesis. When cells proliferate under normoxic conditions, glucose provides the acetyl-CoA that condenses with oxaloacetate to support citrate production. Tricarboxylic acid (TCA) cycle anaplerosis is maintained primarily by glutamine. Here we report that some hypoxic cells are able to maintain cell proliferation despite a profound reduction in glucose-dependent citrate production. In these hypoxic cells, glutamine becomes a major source of citrate. Glutamine-derived α-ketoglutarate is reductively carboxylated by the NADPH-linked mitochondrial isocitrate dehydrogenase (IDH2) to form isocitrate, which can then be isomerized to citrate. The increased IDH2-dependent carboxylation of glutamine-derived α-ketoglutarate in hypoxia is associated with a concomitant increased synthesis of 2-hydroxyglutarate (2HG) in cells with wild-type IDH1 and IDH2. When either starved of glutamine or rendered IDH2-deficient by RNAi, hypoxic cells are unable to proliferate. The reductive carboxylation of glutamine is part of the metabolic reprogramming associated with hypoxia-inducible factor 1 (HIF1), as constitutive activation of HIF1 recapitulates the preferential reductive metabolism of glutamine-derived α-ketoglutarate even in normoxic conditions. These data support a role for glutamine carboxylation in maintaining citrate synthesis and cell growth under hypoxic conditions.

    View details for DOI 10.1073/pnas.1117773108

    View details for Web of Science ID 000297683800041

    View details for PubMedID 22106302

  • Loss of the Birt-Hogg-Dube tumor suppressor results in apoptotic resistance due to aberrant TGF beta-mediated transcription ONCOGENE Cash, T. P., Gruber, J. J., Hartman, T. R., Henske, E. P., Simon, M. C. 2011; 30 (22): 2534-2546

    Abstract

    Birt-Hogg-Dubé (BHD) syndrome is an inherited cancer susceptibility disease characterized by skin and kidney tumors, as well as cystic lung disease, which results from loss-of-function mutations in the BHD gene. BHD is also inactivated in a significant fraction of patients with sporadic renal cancers and idiopathic cystic lung disease, and little is known about its mode of action. To investigate the molecular and cellular basis of BHD tumor suppressor activity, we generated mutant Bhd mice and embryonic stem cell lines. BHD-deficient cells exhibited defects in cell-intrinsic apoptosis that correlated with reduced expression of the BH3-only protein Bim, which was similarly observed in all human and murine BHD-related tumors examined. We further demonstrate that Bim deficiency in Bhd(-/-) cells is not a consequence of elevated mTOR or ERK activity, but results instead from reduced Bim transcription associated with a general loss of TGFβ-mediated transcription and chromatin modifications. In aggregate, this work identifies a specific tumor suppressive mechanism for BHD in regulating TGFβ-dependent transcription and apoptosis, which has implications for the development of targeted therapies.

    View details for DOI 10.1038/onc.2010.628

    View details for Web of Science ID 000291198400005

    View details for PubMedID 21258407

  • Imatinib resistance associated with BCR-ABL upregulation is dependent on HIF-1 alpha-induced metabolic reprograming ONCOGENE Zhao, F., Mancuso, A., Bui, T. V., Tong, X., Gruber, J. J., Swider, C. R., Sanchez, P. V., Lum, J. J., Sayed, N., Melo, J. V., Perl, A. E., Carroll, M., Tuttle, S. W., Thompson, C. B. 2010; 29 (20): 2962-2972

    Abstract

    As chronic myeloid leukemia (CML) progresses from the chronic phase to blast crisis, the levels of BCR-ABL increase. In addition, blast-transformed leukemic cells display enhanced resistance to imatinib in the absence of BCR-ABL-resistance mutations. In this study, we show that when BCR-ABL-transformed cell lines were selected for imatinib resistance in vitro, the cells that grew out displayed a higher BCR-ABL expression comparable to the increase seen in accelerated forms of the disease. This enhanced expression of BCR-ABL was associated with an increased rate of glycolysis but with a decreased rate of proliferation. The higher level of BCR-ABL expression in the selected cells correlated with a nonhypoxic induction of hypoxia-inducible factor-1alpha (HIF-1alpha) that was required for cells to tolerate enhanced BCR-ABL signaling. HIF-1alpha induction resulted in an enhanced rate of glycolysis but with reduced glucose flux through both the tricarboxylic acid cycle and the oxidative arm of the pentose phosphate pathway (PPP). The reduction in oxidative PPP-mediated ribose synthesis was compensated by the HIF-1alpha-dependent activation of the nonoxidative PPP enzyme, transketolase, in imatinib-resistant CML cells. In both primary cultures of cells from patients exhibiting blast transformation and in vivo xenograft tumors, use of oxythiamine, which can inhibit both the pyruvate dehydrogenase complex and transketolase, resulted in enhanced imatinib sensitivity of tumor cells. Together, these results suggest that oxythiamine can enhance imatinib efficacy in patients who present an accelerated form of the disease.

    View details for DOI 10.1038/onc.2010.67

    View details for Web of Science ID 000277890400007

    View details for PubMedID 20228846

  • The glucose-responsive transcription factor ChREBP contributes to glucose-dependent anabolic synthesis and cell proliferation PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Tong, X., Zhao, F., Mancuso, A., Gruber, J. J., Thompson, C. B. 2009; 106 (51): 21660-21665

    Abstract

    Tumor cells are metabolically reprogrammed to fuel cell proliferation. Most transformed cells take up high levels of glucose and produce ATP through aerobic glycolysis. In cells exhibiting aerobic glycolysis, a significant fraction of glucose carbon is also directed into de novo lipogenesis and nucleotide biosynthesis. The glucose-responsive transcription factor carbohydrate responsive element binding protein (ChREBP) was previously shown to be important for redirecting glucose metabolism in support of lipogenesis in nonproliferating hepatocytes. However, whether it plays a more generalized role in reprogramming metabolism during cell proliferation has not been examined. Here, we demonstrated that the expression of ChREBP can be induced in response to mitogenic stimulation and that the induction of ChREBP is required for efficient cell proliferation. Suppression of ChREBP resulted in diminished aerobic glycolysis, de novo lipogenesis, and nucleotide biosynthesis, but stimulated mitochondrial respiration, suggesting a metabolic switch from aerobic glycolysis to oxidative phosphorylation. Cells in which ChREBP was suppressed by RNAi exhibited p53 activation and cell cycle arrest. In vivo, suppression of ChREBP led to a p53-dependent reduction in tumor growth. These results demonstrate that ChREBP plays a key role both in redirecting glucose metabolism to anabolic pathways and suppressing p53 activity.

    View details for DOI 10.1073/pnas.0911316106

    View details for Web of Science ID 000272994200037

    View details for PubMedID 19995986

    View details for PubMedCentralID PMC2799883

  • Ars2 Links the Nuclear Cap-Binding Complex to RNA Interference and Cell Proliferation CELL Gruber, J. J., Zatechka, D. S., Sabin, L. R., Yong, J., Lum, J. J., Kong, M., Zong, W., Zhang, Z., Lau, C., Rawlings, J., Cherry, S., Ihle, J. N., Dreyfuss, G., Thompson, C. B. 2009; 138 (2): 328-339

    Abstract

    Here we identify a component of the nuclear RNA cap-binding complex (CBC), Ars2, that is important for miRNA biogenesis and critical for cell proliferation. Unlike other components of the CBC, Ars2 expression is linked to the proliferative state of the cell. Deletion of Ars2 is developmentally lethal, and deletion in adult mice led to bone marrow failure whereas parenchymal organs composed of nonproliferating cells were unaffected. Depletion of Ars2 or CBP80 from proliferating cells impaired miRNA-mediated repression and led to alterations in primary miRNA processing in the nucleus. Ars2 depletion also reduced the levels of several miRNAs, including miR-21, let-7, and miR-155, that are implicated in cellular transformation. These findings provide evidence for a role for Ars2 in RNA interference regulation during cell proliferation.

    View details for DOI 10.1016/j.cell.2009.04.046

    View details for Web of Science ID 000268277000014

    View details for PubMedID 19632182

    View details for PubMedCentralID PMC2717034

  • Ars2 Regulates Both miRNA- and siRNA-Dependent Silencing and Suppresses RNA Virus Infection in Drosophila CELL Sabin, L. R., Zhou, R., Gruber, J. J., Lukinova, N., Bambina, S., Berman, A., Lau, C., Thompson, C. B., Cherry, S. 2009; 138 (2): 340-351

    Abstract

    Intrinsic immune responses autonomously inhibit viral replication and spread. One pathway that restricts viral infection in plants and insects is RNA interference (RNAi), which targets and degrades viral RNA to limit infection. To identify additional genes involved in intrinsic antiviral immunity, we screened Drosophila cells for modulators of viral infection using an RNAi library. We identified Ars2 as a key component of Drosophila antiviral immunity. Loss of Ars2 in cells, or in flies, increases susceptibility to RNA viruses. Consistent with its antiviral properties, we found that Ars2 physically interacts with Dcr-2, modulates its activity in vitro, and is required for siRNA-mediated silencing. Furthermore, we show that Ars2 plays an essential role in miRNA-mediated silencing, interacting with the Microprocessor and stabilizing pri-miRNAs. The identification of Ars2 as a player in these small RNA pathways provides new insight into the biogenesis of small RNAs that may be extended to other systems.

    View details for DOI 10.1016/j.cell.2009.04.045

    View details for Web of Science ID 000268277000015

    View details for PubMedID 19632183

    View details for PubMedCentralID PMC2717035

  • DR5 knockout mice are compromised in radiation-induced apoptosis MOLECULAR AND CELLULAR BIOLOGY Finnberg, N., Gruber, J. J., Fei, P. W., Rudolph, D., Bric, A., Kim, S. H., Burns, T. F., Ajuha, H., Page, R., Wu, G. S., Chen, Y. H., McKenna, W. G., Bernhard, E., Lowe, S., Mak, T., El-Deiry, W. S. 2005; 25 (5): 2000-2013

    Abstract

    DR5 (also called TRAIL receptor 2 and KILLER) is an apoptosis-inducing membrane receptor for tumor necrosis factor-related apoptosis-inducing ligand (also called TRAIL and Apo2 ligand). DR5 is a transcriptional target of p53, and its overexpression induces cell death in vitro. However, the in vivo biology of DR5 has remained largely unexplored. To better understand the role of DR5 in development and in adult tissues, we have created a knockout mouse lacking DR5. This mouse is viable and develops normally with the exception of having an enlarged thymus. We show that DR5 is not expressed in developing embryos but is present in the decidua and chorion early in development. DR5-null mouse embryo fibroblasts expressing E1A are resistant to treatment with TRAIL, suggesting that DR5 may be the primary proapoptotic receptor for TRAIL in the mouse. When exposed to ionizing radiation, DR5-null tissues exhibit reduced amounts of apoptosis compared to wild-type thymus, spleen, Peyer's patches, and the white matter of the brain. In the ileum, colon, and stomach, DR5 deficiency was associated with a subtle phenotype of radiation-induced cell death. These results indicate that DR5 has a limited role during embryogenesis and early stages of development but plays an organ-specific role in the response to DNA-damaging stimuli.

    View details for DOI 10.1128/MCB.25.5.2000-2003.2005

    View details for Web of Science ID 000227085700036

    View details for PubMedID 15713653

    View details for PubMedCentralID PMC549384