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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 Intramolecular inhibition of activating transcription factor-2 function by its DNA-binding domain.
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 Enhancement of TBP binding by activators and general transcription factors.
Academic Article Identification and characterization of yUAP/Sub2p, a yeast homolog of the essential human pre-mRNA splicing factor hUAP56.
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 The HIV-1 Tat cellular coactivator Tat-SF1 is a general transcription elongation factor.
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 U2AF homology motifs: protein recognition in the RRM world.
Academic Article Crystal structure of UAP56, a DExD/H-box protein involved in pre-mRNA splicing and mRNA export.
Academic Article Functional analysis of TFIID components.
Academic Article A pathway of sequential arginine-serine-rich domain-splicing signal interactions during mammalian spliceosome assembly.
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 Structural basis for polypyrimidine tract recognition by the essential pre-mRNA splicing factor U2AF65.
Academic Article Irf3 polymorphism alters induction of interferon beta in response to Listeria monocytogenes infection.
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 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 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 Role for IGFBP7 in senescence induction by BRAF.
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 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 Transcription factor ATF5 is required for terminal differentiation and survival of olfactory sensory neurons.
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 Functional analysis of TFIID components using conditional mutants.
Academic Article Sequential recognition of the pre-mRNA branch point by U2AF65 and a novel spliceosome-associated 28-kDa protein.
Academic Article A role for activator-mediated TFIIB recruitment in diverse aspects of transcriptional regulation.
Academic Article Distinct binding specificities and functions of higher eukaryotic polypyrimidine tract-binding 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 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 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 An activating transcription factor 5-mediated survival pathway as a target for cancer therapy?
Academic Article GABP transcription factor is required for development of chronic myelogenous leukemia via its control of PRKD2.
Academic Article U2AF65 adapts to diverse pre-mRNA splice sites through conformational selection of specific and promiscuous RNA recognition motifs.
Academic Article Genome wide association analysis of a founder population identified TAF3 as a gene for MCHC in humans.
Concept Vascular Endothelial Growth Factor A
Concept Transcription Factor TFIIA
Concept Receptor, Fibroblast Growth Factor, Type 1
Concept PAX5 Transcription Factor
Concept Cleavage Stimulation Factor
Concept Activating Transcription Factor 2
Concept STAT5 Transcription Factor
Concept Insulin-Like Growth Factor I
Concept GA-Binding Protein Transcription Factor
Concept Tumor Necrosis Factor-alpha
Concept Transcription Factor TFIIB
Concept Cleavage And Polyadenylation Specificity Factor
Concept Transcription Factor TFIID
Concept Hepatocyte Growth Factor
Concept Interferon Regulatory Factor-3
Concept MafG Transcription Factor
Concept Core Binding Factor Alpha 2 Subunit
Concept Insulin-Like Growth Factor Binding Proteins
Concept STAT1 Transcription Factor
Concept Activating Transcription Factor 4
Concept Receptors, Tumor Necrosis Factor
Concept Eukaryotic Initiation Factor-4A
Academic Article A 2-nt RNA enhancer on exon 11 promotes exon 11 inclusion of the Ron proto-oncogene.
Academic Article PSF contacts exon 7 of SMN2 pre-mRNA to promote exon 7 inclusion.
Academic Article A diphtheria toxin negative selection in RNA interference screening.
Academic Article A large-scale RNAi-based mouse tumorigenesis screen identifies new lung cancer tumor suppressors that repress FGFR signaling.
Academic Article Cancer-relevant splicing factor CAPER? engages the essential splicing factor SF3b155 in a specific ternary complex.
Academic Article The BRAF oncoprotein functions through the transcriptional repressor MAFG to mediate the CpG Island Methylator phenotype.
Academic Article Resistance to therapy in BRCA2 mutant cells due to loss of the nucleosome remodeling factor CHD4.
Academic Article Global Promotion of Alternative Internal Exon Usage by mRNA 3' End Formation Factors.
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 U2AF35(S34F) Promotes Transformation by Directing Aberrant ATG7 Pre-mRNA 3' End Formation.
Academic Article ATF5 regulates ?-cell survival during stress.
Academic Article Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling.
Academic Article Loss of KLHL6 promotes diffuse large B-cell lymphoma growth and survival by stabilizing the mRNA decay factor roquin2.
Academic Article RUNX1-targeted therapy for AML expressing somatic or germline mutation in RUNX1.
Academic Article A KLF4-DYRK2-mediated pathway regulating self-renewal in CML stem cells.
Academic Article Mechanistic basis and efficacy of targeting the ?-catenin-TCF7L2-JMJD6-c-Myc axis to overcome resistance to BET inhibitors.
Academic Article Effective therapy for AML with RUNX1 mutation by cotreatment with inhibitors of protein translation and BCL2.
Concept Tumor Necrosis Factor alpha-Induced Protein 3
Concept Splicing Factor U2AF
Concept PTB-Associated Splicing Factor
Concept Transcription Factor 7-Like 2 Protein
Concept Heparin-binding EGF-like Growth Factor
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