Person: Lieberman, Judy
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Lieberman
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Judy
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Lieberman, Judy
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Publication Gasdermin E suppresses tumour growth by activating anti-tumour immunity(Springer Science and Business Media LLC, 2020-03-11) Zhang, Zhibin; Zhang, Ying-Yi; Xia, Shiyu; Junqueira, Caroline; Sengupta, Satyaki; Wu, Hao; Lieberman, JudyCleavage of the gasdermins to produce a pore-forming N-terminal fragment causes inflammatory death (pyroptosis)1. Caspase-3 cleaves gasdermin E (GSDME, also known as DFNA5), mutated in familial aging-related hearing loss2, which converts noninflammatory apoptosis to pyroptosis in GSDME-expressing cells3-5. GSDME expression is suppressed in many cancers and reduced GSDME is associated with decreased breast cancer survival2,6, suggesting GSDME might be a tumor suppressor. Here we show reduced GSDME function of 20 of 22 tested cancer-associated mutations. Gsdme knockout in GSDME-expressing tumors enhances, while ectopic expression in Gsdme-repressed tumors inhibits, tumor growth. Tumor suppression is mediated by cytotoxic lymphocyte killing since it is abrogated in perforin-deficient or killer lymphocyte-depleted mice. GSDME expression enhances tumor-associated macrophage phagocytosis and the number and functions of tumor-infiltrating NK and CD8+ T lymphocytes. Killer cell granzyme B also activates caspase-independent pyroptosis in target cells by directly cleaving GSDME at the same site as caspase-3. Non-cleavable or pore-defective GSDME are not tumor suppressive. Thus, tumor GSDME is a tumor suppressor by activating pyroptosis, which enhances anti-tumor immunity.Publication The Rab2A GTPase Promotes Breast Cancer Stem Cells and Tumorigenesis via Erk Signaling Activation(2015) Luo, Man-Li; Gong, Chang; Chen, Chun-Hau; Hu, Hai; Huang, Pengyu; Zheng, Min; Yao, Yandan; Wei, Shuo; Wulf, Gerburg; Lieberman, Judy; Zhou, Xiao; Song, Erwei; Lu, Kun PingSUMMARY Proline-directed phosphorylation is regulated by the prolyl isomerase Pin1, which plays a fundamental role in driving breast cancer stem-like cells (BCSCs). Rab2A is a small GTPase critical for vesicle trafficking. Here, we show that Pin1 increases Rab2A transcription to promote BCSC expansion and tumorigenesis in vitro and in vivo. Mechanistically, Rab2A directly interacts with and prevents dephosphorylation/inactivation of Erk1/2 by the MKP3 phosphatase, resulting in Zeb1 upregulation and β-catenin nuclear translocation. In cancer cells, Rab2A is activated via gene amplification, mutation or Pin1 overexpression. Rab2A overexpression or mutation endows BCSC traits to primary normal human breast epithelial cells, whereas silencing Rab2A potently inhibits the expansion and tumorigenesis of freshly isolated BCSCs. Finally, Rab2A overexpression correlates with poor clinical outcome in breast cancer patients. Thus, Pin1/Rab2A/Erk drives BCSC expansion and tumorigenicity, suggesting potential drug targets.Publication Efficient and specific gene knockdown by small interfering RNAs produced in bacteria(2013) Huang, Linfeng; Jin, Jingmin; Deighan, Padraig; Kiner, Evgeny; McReynolds, Larry; Lieberman, JudySynthetic small interfering RNAs (siRNAs) are an indispensable tool to investigate gene function in eukaryotic cells1,2 and may be used for therapeutic purposes to knockdown genes implicated in disease3. Thus far, most synthetic siRNAs have been produced by chemical synthesis. Here we present a method to produce highly potent siRNAs in E. coli. This method relies on ectopic expression of p19, a siRNA-binding protein found in a plant RNA virus4, 5. When expressed in E. coli, p19 stabilizes ~21 nt siRNA-like species produced by bacterial RNase III. Transfection of mammalian cells with siRNAs, generated in bacteria expressing p19 and a hairpin RNA encoding 200 or more nucleotides of a target gene, at low nanomolar concentrations reproducibly knocks down gene expression by ~90% without immunogenicity or off-target effects. Because bacterially produced siRNAs contain multiple sequences against a target gene, they may be especially useful for suppressing polymorphic cellular or viral genes.Publication miR-34 and p53: New Insights into a Complex Functional Relationship(Public Library of Science, 2015) Navarro, Francisco; Lieberman, JudymiR-34, a tumor suppressor miRNA family transcriptionally activated by p53, is considered a critical mediator of p53 function. However, knockout of the mouse miR-34 family has little or no effect on the p53 response. The relative contribution of different miR-34 family members to p53 function or how much p53 relies on miR-34 in human cells is unclear. Here we show that miR-34a has a complex effect on the p53 response in human cells. In HCT116 cells miR-34a overexpression enhances p53 transcriptional activity, but the closely related family members, miR-34b and miR-34c, even when over-expressed, have little effect. Both TP53 itself and MDM4, a strong p53 transactivation inhibitor, are direct targets of miR-34a. The genes regulated by miR-34a also include four other post-translational inhibitors of p53. miR-34a overexpression leads to variable effects on p53 levels in p53-sufficient human cancer cell lines. In HCT116, miR-34a overexpression increases p53 protein levels and stability. About a quarter of all mRNAs that participate in the human p53 network bind to biotinylated miR-34a, suggesting that many are direct miR-34a targets. However, only about a fifth of the mRNAs that bind to miR-34a also bind to miR-34b or miR-34c. Two human cell lines knocked out for miR-34a have unimpaired p53-mediated responses to genotoxic stress, like mouse cells. The complex positive and negative effects of miR-34 on the p53 network suggest that rather than simply promoting the p53 response, miR-34a might act at a systems level to stabilize the robustness of the p53 response to genotoxic stress.Publication Blocking the recruitment of naive CD4+ T cells reverses immunosuppression in breast cancer(Nature Publishing Group, 2017) Su, Shicheng; Liao, Jianyou; Liu, Jiang; Huang, Di; He, Chonghua; Chen, Fei; Yang, LinBing; Wu, Wei; Chen, Jianing; Lin, Ling; Zeng, Yunjie; Ouyang, Nengtai; Cui, Xiuying; Yao, Herui; Su, Fengxi; Huang, Jian-dong; Lieberman, Judy; Liu, Qiang; Song, ErweiThe origin of tumor-infiltrating Tregs, critical mediators of tumor immunosuppression, is unclear. Here, we show that tumor-infiltrating naive CD4+ T cells and Tregs in human breast cancer have overlapping TCR repertoires, while hardly overlap with circulating Tregs, suggesting that intratumoral Tregs mainly develop from naive T cells in situ rather than from recruited Tregs. Furthermore, the abundance of naive CD4+ T cells and Tregs is closely correlated, both indicating poor prognosis for breast cancer patients. Naive CD4+ T cells adhere to tumor slices in proportion to the abundance of CCL18-producing macrophages. Moreover, adoptively transferred human naive CD4+ T cells infiltrate human breast cancer orthotopic xenografts in a CCL18-dependent manner. In human breast cancer xenografts in humanized mice, blocking the recruitment of naive CD4+ T cells into tumor by knocking down the expression of PITPNM3, a CCL18 receptor, significantly reduces intratumoral Tregs and inhibits tumor progression. These findings suggest that breast tumor-infiltrating Tregs arise from chemotaxis of circulating naive CD4+ T cells that differentiate into Tregs in situ. Inhibiting naive CD4+ T cell recruitment into tumors by interfering with PITPNM3 recognition of CCL18 may be an attractive strategy for anticancer immunotherapy.Publication Sequencing of Captive Target Transcripts Identifies the Network of Regulated Genes and Functions of Primate-Specific miR-522(Elsevier BV, 2014) Tan, Shen Mynn; Kirchner, Rory; Jin, Jingmin; Hofmann, Oliver; McReynolds, Larry; Hide, Winston; Lieberman, JudyIdentifying microRNA (miRNA)-regulated genes is key to understanding miRNA function. However, many miRNA recognition elements (MREs) do not follow canonical “seed” base-pairing rules, making identification of bona fide targets challenging. Here, we apply an unbiased sequencing-based systems approach to characterize miR-522, a member of the oncogenic primate-specific chromosome 19 miRNA cluster, highly expressed in poorly differentiated cancers. To identify miRNA targets, we sequenced full-length transcripts captured by a biotinylated miRNA mimic. Within these targets, mostly noncanonical MREs were identified by sequencing RNase-resistant fragments. miR-522 overexpression reduced mRNA, protein levels, and luciferase activity of >70% of a random list of candidate target genes and MREs. Bioinformatic analysis suggested that miR-522 regulates cell proliferation, detachment, migration, and epithelial-mesenchymal transition. miR-522 induces G1 cell-cycle arrest and causes cells to detach without anoikis, become invasive, and express mesenchymal genes. Thus, our method provides a simple but effective technique for identifying miRNA-regulated genes and biological function.Publication Ex Vivo Cytosolic Delivery of Functional Macromolecules to Immune Cells(Public Library of Science, 2015) Sharei, Armon; Trifonova, Radiana; Jhunjhunwala, Siddharth; Hartoularos, George C.; Eyerman, Alexandra T.; Lytton-Jean, Abigail; Angin, Mathieu; Sharma, Siddhartha; Poceviciute, Roberta; Mao, Shirley; Heimann, Megan; Liu, Sophia; Talkar, Tanya; Khan, Omar F.; Addo, Marylyn; von Andrian-Werburg, Ulrich; Anderson, Daniel G.; Langer, Robert; Lieberman, Judy; Jensen, Klavs F.Intracellular delivery of biomolecules, such as proteins and siRNAs, into primary immune cells, especially resting lymphocytes, is a challenge. Here we describe the design and testing of microfluidic intracellular delivery systems that cause temporary membrane disruption by rapid mechanical deformation of human and mouse immune cells. Dextran, antibody and siRNA delivery performance is measured in multiple immune cell types and the approach’s potential to engineer cell function is demonstrated in HIV infection studies.Publication Harnessing RNA interference to prevent or treat HSV-2 and HIV(BioMed Central, 2006) Lieberman, JudyPublication Streptococcal Pyrogenic Exotoxin B Cleaves GSDMA and Triggers Pyroptosis(Springer Science and Business Media LLC, 2022-02-02) Deng, Wanyan; Bai, Yang; Deng, Fan; Pan, Youdong; Mei, Shenglin; Zheng, Zengzhang; Min, Rui; Wu, Zeyu; Li, Wu; Miao, Rui; Zhang, Zhibin; Kupper, Thomas; Lieberman, Judy; Liu, Xing