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Brief Biography

Michael Green received his MD and PhD degrees from Washington University School of Medicine in 1981. He carried out postdoctoral work at Harvard University, where he joined as a faculty member in 1984. In 1990, he joined the Program in Molecular Medicine at the University of Massachusetts Medical School (UMMS), and in 1999 became the Director of the Program of Gene Function and Expression (PGFE). In 2014, PGFE merged with the Department of Cancer Biology, and Dr. Green was appointed as Chair of the new Department of Molecular, Cell and Cancer Biology (MCCB). In addition to his role as Chair of MCCB, he is also Vice Provost of Strategic Research Initiatives, Director of the Cancer Center, and Co-Director of The Li Weibo Institute for Rare Diseases Research.

Dr. Green has made pioneering contributions to our understanding of the mechanisms that regulate gene expression in eukaryotes and how alterations in gene expression contribute to cancer and other human diseases. He is an elected member of the National Academy of Sciences, the National Academy of Medicine, the American Academy of Arts and Sciences, and the European Molecular Biology Organization.

Discovery of Therapeutically Targetable Pathways in Cancer and Other Diseases

Identification of New Factors and Regulatory Pathways that Promote or Prevent Cancer

My laboratory has used transcription-based approaches, functional screens (such as genome-wide loss-of-function RNAi- and CRISPR-based screens) and genomic methods to identify new genes and regulatory pathways that contribute to cancer. These studies are intended to enhance our understanding of the molecular basis of cancer and reveal potential new targets for therapeutic intervention. These approaches have enabled us to discover new oncogenes, such as the H2A ubiquitin ligase TRIM37 (Bhatnagar et al. 2014), tumor suppressor genes, such as the CREB coactivator CRTC2 (Fang et al. 2015) and repressors of FGFR signaling (Lin et al. 2014), and metastasis suppressor genes, such as GAS1 (Gobeil et al. 2008) and the histone H3K9 demethylase KDM3A (Pedanou et al. 2016). We have also identified two therapeutically targetable mechanisms that render chronic myeloid leukemia (CML) stem cells resistant to the drug imatinib mesylate (also known as Gleevec), the first-line treatment for CML (Ma et al. 2014; Ma et al. 2019). We are currently conducting functional screens to identify new factors involved in various aspects of cancer biology including transformation, cancer stem cell formation and maintenance, regulation of the epithelial-to-mesenchymal transition, and cancer drug resistance.

Alterations in pre-mRNA splicing lead to numerous diseases, including cancer. We have a long-standing interest in regulation of gene expression at the level of RNA processing, in particular pre-mRNA splicing. The essential splicing factor U2AF, which initiates spliceosome assembly by binding to the intronic polypyrimidine tract/3’ splice site, was originally discovered in our laboratory. Subsequent cancer genome sequencing studies revealed driver mutations in the U2AF 35 kDa subunit (U2AF35). We have shown that oncogenic U2AF35 mutants promote transformation through mis-regulation of both spicing and mRNA 3’ end formation (Park et al. 2016). We are continuing to investigate the role of aberrant RNA processing in cancer as well as other diseases.

Modulating Gene Expression as a Therapeutic Approach

Factors that drive cancer progression are often not druggable and thus their therapeutic inhibition is challenging. We are taking a novel approach to identify inhibitors of these “undruggable” cancer-promoting factors. First, we have developed and carried out reporter-based CRISPR screening strategies to identify factors and pathways required for expression of a cancer-promoting gene. Based upon this information, we then identify biological or small molecule inhibitors of these factors and pathways, which abrogate expression of the cancer-promoting gene and suppress tumor growth. We have used this approach to identify inhibitors of expression of oncogenes and other genes that affect tumor development such as suppressors of anti-tumor immunity. This approach can also be used to identify antagonists of proteins that cause diseases other than cancer, such as neurodegenerative diseases.

Cancer and other diseases can also arise due to the inappropriate transcriptional inactivation of specific genes. My lab has developed and successfully used functional genomic and proteomic approaches to identify factors and pathways involved in epigenetic silencing of tumor suppressor genes. Biological or small molecule inhibitors of these factors and pathways can reactivate expression of the tumor suppressor gene, which is a therapeutic approach that can be used to treat cancer. For example, we have delineated two independent oncoprotein-directed pathways that lead to widespread DNA hypermethylation and epigenetic silencing (known as the CpG island methylator phenotype; CIMP) in colorectal cancers, and shown that genetic or pharmacological inhibition of the pathways can reactivate expression of the silenced genes (Serra et al. 2014; Fang et al. 2014). The epigenetic silencing pathways we have identified are directly linked to cellular transformation, have enhanced our understanding of how normal cells become cancerous, and have revealed new therapeutic targets.

We are taking a similar approach to identify small molecule inhibitors that will reactivate genes whose aberrant epigenetic silencing causes rare monogenic disorders such as Fragile X Syndrome and Friedreich ataxia. We also work on X-linked dominant disorders, such as Rett Syndrome and CDKL5 Deficiency, which are caused by heterozygous mutations in the X-linked genes MECP2 and CDKL5, respectively, and for which reactivation of the wild-type gene on the inactive X chromosome (Xi) is a potential therapeutic approach. For example, we have identified a number of cellular factors that are required for silencing of the Xi (Bhatnagar et al. 2014). Small molecule inhibitors of these factors can reactivate expression of the wild-type Xi-linked MECP2 gene in cultured cells and cerebral cortical neurons of adult living mice (Bhatnagar et al. 2014; Przanowski et al., 2018).

Development of New Gene Therapy Approaches

We have previously identified IGFBP7 (insulin-like growth factor binding protein 7) as a secreted tumor suppressor protein and shown in mouse models that systemic administration of recombinant IGFBP7 can suppress tumor growth of human melanoma and colorectal cancer xenografts expressing oncogenic BRAF or RAS (Wajapeyee et al. 2008, 2009). More recently, in collaboration with Dr. Guangping Gao (Director, UMMS Gene Therapy Center) we have shown that IGFBP7 can also be effectively delivered into mice using an adeno-associated virus (AAV) vector. Intramuscular injection of an AAV9-IGFBP7 vector results in the expression and secretion of IGFBP7 and markedly reduces growth of human melanoma and colorectal cancer xenografts. We have confirmed the generality of this approach using another secreted tumor suppressor protein. Our results indicate that AAV9 delivery of secreted tumor suppressors is a new and promising anti-cancer treatment.

In collaboration with Guangping Gao and Miguel Sena-Esteves (UMMS Gene Therapy Center), we are developing a novel AAV-based gene therapy approach for Rett Syndrome. Several lines of evidence indicate that MECP2 expression levels must be tightly regulated to maintain normal neuronal function and development. We are therefore developing self-regulating AAV vectors that can express MECP2 within a narrow range of levels compatible with normal development and neuronal function.

One or more keywords matched the following items that are connected to Green, Michael
Item TypeName
Academic Article A novel, mitogen-activated nuclear kinase is related to a Drosophila developmental regulator.
Academic Article Intramolecular inhibition of activating transcription factor-2 function by its DNA-binding domain.
Academic Article HIV Rev uses a conserved cellular protein export pathway for the nucleocytoplasmic transport of viral RNAs.
Academic Article Yeast TAF(II)90 is required for cell-cycle progression through G2/M but not for general transcription activation.
Academic Article Yeast TAF(II)145 required for transcription of G1/S cyclin genes and regulated by the cellular growth state.
Academic Article Yeast TAF(II)145 functions as a core promoter selectivity factor, not a general coactivator.
Academic Article Transcription activation in cells lacking TAFIIS.
Academic Article Interaction of U2AF65 RS region with pre-mRNA branch point and promotion of base pairing with U2 snRNA [corrected].
Academic Article Broad, but not universal, transcriptional requirement for yTAFII17, a histone H3-like TAFII present in TFIID and SAGA.
Academic Article Pre-mRNA splicing of IgM exons M1 and M2 is directed by a juxtaposed splicing enhancer and inhibitor.
Academic Article Analysis of selective gene activation in yeast by differential display.
Academic Article The hepatitis B pX protein promotes dimerization and DNA binding of cellular basic region/leucine zipper proteins by targeting the conserved basic region.
Academic Article Enhancement of TBP binding by activators and general transcription factors.
Academic Article Distinct classes of yeast promoters revealed by differential TAF recruitment.
Academic Article Identification and characterization of yUAP/Sub2p, a yeast homolog of the essential human pre-mRNA splicing factor hUAP56.
Academic Article Sequence-specific interaction between HIV-1 matrix protein and viral genomic RNA revealed by in vitro genetic selection.
Academic Article Promoter-specific activation defects by a novel yeast TBP mutant compromised for TFIIB interaction.
Academic Article U2AF65 recruits a novel human DEAD box protein required for the U2 snRNP-branchpoint interaction.
Academic Article Identification of a human protein that recognizes the 3' splice site during the second step of pre-mRNA splicing.
Academic Article Inhibition of apoptosis by ATFx: a novel role for a member of the ATF/CREB family of mammalian bZIP transcription factors.
Academic Article Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle.
Academic Article The role of ATF/CREB family members in cell growth, survival and apoptosis.
Academic Article Transcriptional program of apoptosis induction following interleukin 2 deprivation: identification of RC3, a calcium/calmodulin binding protein, as a novel proapoptotic factor.
Academic Article Interaction of Gal4p with components of transcription machinery in vivo.
Academic Article In vivo target of a transcriptional activator revealed by fluorescence resonance energy transfer.
Academic Article Arginine-serine-rich domains bound at splicing enhancers contact the branchpoint to promote prespliceosome assembly.
Academic Article When enough is enough: genetic diseases associated with transcriptional derepression.
Academic Article U2AF homology motifs: protein recognition in the RRM world.
Academic Article A pathway of sequential arginine-serine-rich domain-splicing signal interactions during mammalian spliceosome assembly.
Academic Article A human nuclear-localized chaperone that regulates dimerization, DNA binding, and transcriptional activity of bZIP proteins.
Academic Article Profound misregulation of muscle-specific gene expression in facioscapulohumeral muscular dystrophy.
Academic Article HIV-1 Tat stimulates transcription complex assembly through recruitment of TBP in the absence of TAFs.
Academic Article A novel nuclear export activity in HIV-1 matrix protein required for viral replication.
Academic Article Functional recognition of the 3' splice site AG by the splicing factor U2AF35.
Academic Article TBP-associated factors (TAFIIs): multiple, selective transcriptional mediators in common complexes.
Academic Article Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1.
Academic Article Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene.
Academic Article Fluorescence resonance energy transfer as a method for dissecting in vivo mechanisms of transcriptional activation.
Academic Article Structural basis for polypyrimidine tract recognition by the essential pre-mRNA splicing factor U2AF65.
Academic Article Initiation of zebrafish haematopoiesis by the TATA-box-binding protein-related factor Trf3.
Academic Article Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7.
Academic Article SAGA is an essential in vivo target of the yeast acidic activator Gal4p.
Academic Article Induction of apoptosis by a secreted lipocalin that is transcriptionally regulated by IL-3 deprivation.
Academic Article Solution conformation and thermodynamic characteristics of RNA binding by the splicing factor U2AF65.
Academic Article Targeting a TAF to make muscle.
Academic Article A genome-wide shRNA screen identifies GAS1 as a novel melanoma metastasis suppressor gene.
Academic Article F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage.
Academic Article Identification of a protein, G0S2, that lacks Bcl-2 homology domains and interacts with and antagonizes Bcl-2.
Academic Article Oncogenic BRAF and the tumor suppressor IGFBP7 in the genesis of atypical spitzoid nevomelanocytic proliferations.
Academic Article Epigenetic silencing of the RASSF1A tumor suppressor gene through HOXB3-mediated induction of DNMT3B expression.
Academic Article A genome-wide RNA interference screen reveals an essential CREB3L2-ATF5-MCL1 survival pathway in malignant glioma with therapeutic implications.
Academic Article Role for IGFBP7 in senescence induction by BRAF.
Academic Article Redirecting retroviral tropism by insertion of short, nondisruptive peptide ligands into envelope.
Academic Article Selective targeting and inducible destruction of human cancer cells by retroviruses with envelope proteins bearing short peptide ligands.
Academic Article The U2AF35-related protein Urp contacts the 3' splice site to promote U12-type intron splicing and the second step of U2-type intron splicing.
Academic Article Multiple apoptotic defects in hematopoietic cells from mice lacking lipocalin 24p3.
Academic Article Analysis of Gal4-directed transcription activation using Tra1 mutants selectively defective for interaction with Gal4.
Academic Article A phase I study of the combination of sorafenib with temozolomide and radiation therapy for the treatment of primary and recurrent high-grade gliomas.
Academic Article The Blk pathway functions as a tumor suppressor in chronic myeloid leukemia stem cells.
Academic Article Differential requirement of SAGA components for recruitment of TATA-box-binding protein to promoters in vivo.
Academic Article Structure of phosphorylated SF1 bound to U2AF?? in an essential splicing factor complex.
Academic Article TRF3, a TATA-box-binding protein-related factor, is vertebrate-specific and widely expressed.
Academic Article Sequential recognition of the pre-mRNA branch point by U2AF65 and a novel spliceosome-associated 28-kDa protein.
Academic Article Distinct binding specificities and functions of higher eukaryotic polypyrimidine tract-binding proteins.
Academic Article Delineating minimal protein domains and promoter elements for transcriptional activation by lentivirus Tat proteins.
Academic Article Yeast TAFIIS in a multisubunit complex required for activated transcription.
Academic Article Activator-induced conformational change in general transcription factor TFIIB.
Academic Article The RNA polymerase I transcription factor, upstream binding factor, interacts directly with the TATA box-binding protein.
Academic Article Nucleosome disruption and enhancement of activator binding by a human SW1/SNF complex.
Academic Article The viral protein Apoptin associates with the anaphase-promoting complex to induce G2/M arrest and apoptosis in the absence of p53.
Academic Article The anaphase promoting complex: a critical target for viral proteins and anti-cancer drugs.
Academic Article Eukaryotic transcription activation: right on target.
Academic Article A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake.
Academic Article Identification of direct DAF-16 targets controlling longevity, metabolism and diapause by chromatin immunoprecipitation.
Academic Article RS domains contact splicing signals and promote splicing by a common mechanism in yeast through humans.
Academic Article Apoptin nucleocytoplasmic shuttling is required for cell type-specific localization, apoptosis, and recruitment of the anaphase-promoting complex/cyclosome to PML bodies.
Academic Article RS domain-splicing signal interactions in splicing of U12-type and U2-type introns.
Academic Article Distinct activities of the DExD/H-box splicing factor hUAP56 facilitate stepwise assembly of the spliceosome.
Academic Article Transcription and signalling pathways involved in BCR-ABL-mediated misregulation of 24p3 and 24p3R.
Academic Article Selective interaction between Trf3 and Taf3 required for early development and hematopoiesis.
Academic Article Efficacy of IGFBP7 for treatment of metastatic melanoma and other cancers in mouse models and human cell lines.
Academic Article Senescence induction in human fibroblasts and hematopoietic progenitors by leukemogenic fusion proteins.
Academic Article A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production.
Academic Article Maternal Rnf12/RLIM is required for imprinted X-chromosome inactivation in mice.
Academic Article BCR-ABL suppresses autophagy through ATF5-mediated regulation of mTOR transcription.
Academic Article A synthetic interaction screen identifies factors selectively required for proliferation and TERT transcription in p53-deficient human cancer cells.
Academic Article U2AF65 adapts to diverse pre-mRNA splice sites through conformational selection of specific and promiscuous RNA recognition motifs.
Academic Article MEN1 is a melanoma tumor suppressor that preserves genomic integrity by stimulating transcription of genes that promote homologous recombination-directed DNA repair.
Academic Article A human nucleoporin-like protein that specifically interacts with HIV Rev.
Academic Article Recognition of bZIP proteins by the human T-cell leukaemia virus transactivator Tax.
Concept Membrane Proteins
Concept Viral Regulatory and Accessory Proteins
Concept DNA-Binding Proteins
Concept Oncogene Proteins, Fusion
Concept Muscle Proteins
Concept Proto-Oncogene Proteins c-pim-1
Concept Nuclear Pore Complex Proteins
Concept Calmodulin-Binding Proteins
Concept Proto-Oncogene Proteins B-raf
Concept Mitochondrial Proteins
Concept Fanconi Anemia Complementation Group Proteins
Concept Oncogene Proteins
Concept Carrier Proteins
Concept Proto-Oncogene Proteins c-bcl-2
Concept Cell Cycle Proteins
Concept Nuclear Proteins
Concept Recombinant Proteins
Concept Fusion Proteins, bcr-abl
Concept Acute-Phase Proteins
Concept Pol1 Transcription Initiation Complex Proteins
Concept Intracellular Signaling Peptides and Proteins
Concept tau Proteins
Concept Proto-Oncogene Proteins c-mdm2
Concept Cyclin-Dependent Kinase Inhibitor Proteins
Concept Viral Proteins
Concept Repressor Proteins
Concept Proto-Oncogene Proteins c-akt
Concept Proteins
Concept Proto-Oncogene Proteins c-bcl-6
Concept Zebrafish Proteins
Concept F-Box Proteins
Concept Homeodomain Proteins
Concept Adaptor Proteins, Signal Transducing
Concept Proto-Oncogene Proteins c-myc
Concept Escherichia coli Proteins
Concept Green Fluorescent Proteins
Concept ras Proteins
Concept Bacterial Proteins
Concept Recombinant Fusion Proteins
Concept Capsid Proteins
Concept Fungal Proteins
Concept Saccharomyces cerevisiae Proteins
Concept Neoplasm Proteins
Concept Caenorhabditis elegans Proteins
Concept Drosophila Proteins
Concept Insulin-Like Growth Factor Binding Proteins
Concept Proto-Oncogene Proteins p21(ras)
Concept I-kappa B Proteins
Concept TATA Box Binding Protein-Like Proteins
Concept Apoptosis Regulatory Proteins
Concept Retroviridae Proteins, Oncogenic
Concept Proto-Oncogene Proteins
Concept Blood Proteins
Concept Viral Envelope Proteins
Concept Nerve Tissue Proteins
Concept Tumor Suppressor Proteins
Concept RNA-Binding Proteins
Academic Article Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors.
Academic Article Resistance to vemurafenib resulting from a novel mutation in the BRAFV600E kinase domain.
Academic Article SC35 promotes splicing of the C5-V6-C6 isoform of CD44 pre-mRNA.
Academic Article A 2-nt RNA enhancer on exon 11 promotes exon 11 inclusion of the Ron proto-oncogene.
Academic Article Exon 9 skipping of apoptotic caspase-2 pre-mRNA is promoted by SRSF3 through interaction with exon 8.
Academic Article miR-146a promotes the initiation and progression of melanoma by activating Notch signaling.
Academic Article A KRAS-directed transcriptional silencing pathway that mediates the CpG island methylator phenotype.
Academic Article PSF contacts exon 7 of SMN2 pre-mRNA to promote exon 7 inclusion.
Academic Article A large-scale RNAi-based mouse tumorigenesis screen identifies new lung cancer tumor suppressors that repress FGFR signaling.
Academic Article PEA15 regulates the DNA damage-induced cell cycle checkpoint and oncogene-directed transformation.
Academic Article Cancer-relevant splicing factor CAPER? engages the essential splicing factor SF3b155 in a specific ternary complex.
Academic Article A therapeutically targetable mechanism of BCR-ABL-independent imatinib resistance in chronic myeloid leukemia.
Academic Article TRIM37 is a new histone H2A ubiquitin ligase and breast cancer oncoprotein.
Academic Article The BRAF oncoprotein functions through the transcriptional repressor MAFG to mediate the CpG Island Methylator phenotype.
Academic Article SRSF2 promotes splicing and transcription of exon 11 included isoform in Ron proto-oncogene.
Academic Article Global Promotion of Alternative Internal Exon Usage by mRNA 3' End Formation Factors.
Academic Article TRIMming down tumor suppressors in breast cancer.
Academic Article F-box protein FBXO31 directs degradation of MDM2 to facilitate p53-mediated growth arrest following genotoxic stress.
Academic Article Common BRAF(V600E)-directed pathway mediates widespread epigenetic silencing in colorectal cancer and melanoma.
Academic Article From polyadenylation to splicing: Dual role for mRNA 3' end formation factors.
Academic Article An extended U2AF(65)-RNA-binding domain recognizes the 3' splice site signal.
Academic Article Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma.
Academic Article Inactivation of 3-hydroxybutyrate dehydrogenase 2 delays zebrafish erythroid maturation by conferring premature mitophagy.
Academic Article The histone H3K9 demethylase KDM3A promotes anoikis by transcriptionally activating pro-apoptotic genes BNIP3 and BNIP3L.
Academic Article High-Throughput Screening of Tyrosine Kinase Inhibitor Resistant Genes in CML.
Academic Article Fluorescence Reporter-Based Genome-Wide RNA Interference Screening to Identify Alternative Splicing Regulators.
Academic Article ATF5 regulates ?-cell survival during stress.
Academic Article Genetic disruption of oncogenic Kras sensitizes lung cancer cells to Fas receptor-mediated apoptosis.
Academic Article An Embryonic Stem Cell-Specific NuRD Complex Functions through Interaction with WDR5.
Academic Article CRISPR-Cas9-mediated saturated mutagenesis screen predicts clinical drug resistance with improved accuracy.
Academic Article Identification of Epigenetic Regulators of DUX4-fl for Targeted Therapy of Facioscapulohumeral Muscular Dystrophy.
Academic Article Degradation of FBXO31 by APC/C is regulated by AKT- and ATM-mediated phosphorylation.
Academic Article A role for Tau protein in maintaining ribosomal DNA stability and cytidine deaminase-deficient cell survival.
Academic Article A large-scale RNA interference screen identifies genes that regulate autophagy at different stages.
Academic Article Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice.
Academic Article Inhibition of Enhancer of zeste homolog 2 (EZH2) induces natural killer cell-mediated eradication of hepatocellular carcinoma cells.
Academic Article Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling.
Academic Article Loss of BOP1 confers resistance to BRAF kinase inhibitors in melanoma by activating MAP kinase pathway.
Academic Article Loss of KLHL6 promotes diffuse large B-cell lymphoma growth and survival by stabilizing the mRNA decay factor roquin2.
Academic Article Prosurvival kinase PIM2 is a therapeutic target for eradication of chronic myeloid leukemia stem cells.
Academic Article Dnmt1 links BCR-ABLp210 to epigenetic tumor stem cell priming in myeloid leukemia.
Academic Article A KLF4-DYRK2-mediated pathway regulating self-renewal in CML stem cells.
Academic Article KLF7 promotes pancreatic cancer growth and metastasis by up-regulating ISG expression and maintaining Golgi complex integrity.
Academic Article TBL1XR1 Mutations Drive Extranodal Lymphoma by Inducing a Pro-tumorigenic Memory Fate.
Academic Article dagLogo: An R/Bioconductor package for identifying and visualizing differential amino acid group usage in proteomics data.
Academic Article Prostaglandin E2 stimulates cAMP signaling and resensitizes human leukemia cells to glucocorticoid-induced cell death.
Academic Article Mechanistic basis and efficacy of targeting the ?-catenin-TCF7L2-JMJD6-c-Myc axis to overcome resistance to BET inhibitors.
Academic Article UBR5 HECT domain mutations identified in mantle cell lymphoma control maturation of B cells.
Academic Article Inhibition of PIM Kinases in DLBCL Targets MYC Transcriptional Program and Augments the Efficacy of Anti-CD20 Antibodies.
Concept GPI-Linked Proteins
Concept Polycomb-Group Proteins
Concept Ataxia Telangiectasia Mutated Proteins
Concept Cdc20 Proteins
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