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    Michael R Green MD, PhD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentProgram in Molecular Medicine
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB-628
    Worcester MA 01605
    Phone508-856-5331
      Other Positions
      InstitutionUMMS - School of Medicine
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - School of Medicine
      DepartmentSurgery

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBioinformatics and Computational Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCancer Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentBioinformatics and Integrative Biology

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentCenter for AIDS Research

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentProgram in Gene Function and Expression

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentRNA Therapeutics Institute

        Overview 
        Narrative

        Academic Background

        Michael R. Green received his MD and PhD degrees from Washington University School of Medicine in 1981. He was awarded a Helen Hay Whitney Postdoctoral Fellowship to perform postdoctoral work at Harvard University in the Department of Biochemistry and Molecular Biology. He became a faculty member in that department at Harvard in 1984, where he remained until he joined the Program in Molecular Medicine at the University of Massachusetts Medical School in 1990. He has been the recipient of the Searle Scholar Award, the Presidential Young Investigators Award, the McKnight Neuroscience Award, and in 1993 was invited to deliver a Harvey Lecture. In 1994 Dr. Green was made an Investigator of the Howard Hughes Medical Institute.

        Eukaryotic Gene Regulation and Cancer Molecular Biology

        Michael P. Green, M.D., Ph.D.We are interested in the mechanisms that regulate gene expression in eukaryotes, and the role of gene expression in various human disease states. To pursue these interests we use transcription-based approaches and functional screens to identify new genes and regulatory pathways involved in cancer. These studies are intended to enhance our understanding of how normal cells become cancerous and reveal potential new targets for therapeutic intervention.

        Transcriptional Regulation

        Much of eukaryotic gene expression is regulated at the transcriptional level through interactions between promoter-specific activator proteins (activators) and the general transcription machinery. The general transcription factor TFIID comprises the TATA-box binding protein (TBP) and a set of highly conserved associated factors (TAFs). We have identified a new, vertebrate-specific TBP-related factor (TRF) that we have named TRF3. To elucidate TRF3 function we have used zebrafish embryos as an experimental system (in collaboration with Nathan Lawson, University of Massachusetts Medical School). Zebrafish embryos depleted of Trf3 exhibit multiple developmental defects and fail to undergo hematopoiesis. Expression profiling for Trf3-dependent genes identified mespa, which encodes a transcription factor whose murine ortholog is required for mesoderm specification; chromatin immunoprecipitation verified that Trf3 binds to the mespa promoter. Depletion of Mespa results in a developmental defect strikingly similar to that induced by Trf3 depletion. Injection of mespa mRNA restores normal development to a Trf3-depleted embryo, indicating mespa is the single Trf3 target gene required for zebrafish embryogenesis. Zebrafish embryos depleted of Trf3 or Mespa also fail to express cdx4, a caudal-related gene required for hematopoiesis. MespA binds to the cdx4 promoter, and epistasis analysis revealed an ordered trf3-mespa-cdx4 pathway. Thus, in vertebrates, commitment of mesoderm to the hematopoietic lineage occurs through a transcription factor pathway initiated by a TBP-related factor.

        Transcriptional regulation also plays a key role in modulating expression of genes involved in tumorigenesis. For example, in many instances, inactivation of genes critical for cancer development (tumor suppressor genes) occurs by epigenetic silencing that often involves hypermethylation of CpG-rich promoter regions. Whether silencing occurs by random acquisition of epigenetic marks that confer a selective growth advantage, or through a specific pathway initiated by an oncogene, remains to be determined. To address this question, we performed a genome-wide RNA interference (RNAi) screen to identify genes required for Ras-mediated epigenetic silencing of the proapoptotic Fas gene. Using K-ras-transformed NIH 3T3 cells, we identified 28 genes required for Ras-mediated silencing of Fas that encode cell signaling molecules, chromatin modifiers, transcription factors, components of transcriptional repression complexes, and the DNA methyltransferase DNMT1. At least nine of these Ras epigenetic silencing effectors (RESEs), including DNMT1, are directly associated with specific regions of the Fas promoter in K-ras-transformed NIH 3T3 cells but not in untransformed NIH 3T3 cells. RNAi-mediated knockdown of any of the 28 RESEs results in failure to recruit DNMT1 to the Fas promoter, loss of Fas promoter hypermethylation, and derepression of Fas expression. Analysis of five other epigenetically repressed genes indicates that Ras directs silencing of multiple, unrelated genes through a largely common pathway. Finally, we have shown that nine RESEs are required for anchorage-independent growth and tumorigenicity of K-ras-transformed NIH 3T3 cells; these nine genes have not been previously implicated in transformation by Ras. Our results demonstrate that Ras-mediated epigenetic silencing occurs through a specific, unexpectedly complex pathway involving components that are required for maintenance of a fully transformed phenotype.

        RNA Splicing

        In higher eukaryotes gene expression is also regulated at the post-transcriptional level. We have a long-standing interest in the mechanisms involved in splicing of messenger RNA precursors (pre-mRNAs). Splicing occurs in a large multi-subunit complex, the spliceosome, the formation of which is dependent upon multiple proteins and small nuclear ribonucleoprotein proteins (snRNPs). We are particularly interested in splicing factors that act early during spliceosome assembly; these factors play a critical role in defining splice sites and are targets for splicing regulators. One such factor that we originally identified and continue to study is U2 snRNP Auxiliary Factor (U2AF), a heterodimer, comprised of large (U2AF65) and small (U2AF35) subunits, which binds to the pre-mRNA and initiates the process of spliceosome assembly.

        Using a yeast two-hybrid screen, we identified a human 56 kDa DExD/H-box protein that interacts with U2AF65 [U2AF65-Associated Protein (hUAP56)]. Recently, we have used a series of hUAP56 mutants that are defective for ATP-binding, ATP hydrolysis or double-stranded RNA (dsRNA) unwindase/helicase activity, to assess the relative contributions of these biochemical functions to pre-mRNA splicing. We found that pre-spliceosome assembly requires hUAP56's ATP-binding and ATPase activities, which, unexpectedly, are required for hUAP56 to interact with U2AF65 and be recruited into splicing complexes. Surprisingly, hUAP56 is also required for mature spliceosome assembly, which requires, in addition to the ATP-binding and ATPase activities, hUAP56's dsRNA unwindase/helicase activity. We demonstrated that hUAP56 directly contacts U4 and U6 snRNAs and can promote unwinding of the U4/U6 duplex, and that both these activities are dependent upon U2AF65. Our results indicate that hUAP56 first interacts with U2AF65 in an ATP-dependent manner, and subsequently with U4/U6 snRNAs to facilitate stepwise assembly of the spliceosome.

        Another group of proteins that are required for spliceosome assembly are serine-arginine (SR) proteins, a family of general metazoan splicing factors that contain an essential arginine-serine-rich (RS) domain. We have previously found that on typical U2-type introns, mammalian spliceosome assembly involves a series of sequential interactions between RS domains and two splicing signals, the branchpoint and 5' splice site, which promote base-pairing with U small nuclear RNAs (snRNAs). More recently, we analyzed the role of SR proteins in splicing of U12-type introns and in the second step of U2-type intron splicing. We found that RS domains also contact the branchpoint and 5' splice site of a U12-type intron. On a U2-type intron, the RS domain contacts the pre-mRNA at the site of the U6 snRNA-5' splice site interaction during the first step of splicing and, unexpectedly, then shifts to contact the pre-mRNA at the site of the U5 snRNA-exon 1 interaction during the second step. Our results reveal alternative interactions between the RS domain and the 5' splice site region that facilitate remodeling of the spliceosome between the two steps of splicing.

        Cancer Molecular Biology

        Programmed cell death (apoptosis) is a critical aspect of both the genesis and treatment of cancer. There is substantial evidence that certain types of apoptosis may be transcriptionally regulated and that there are transcriptionally activated genes whose products induce cell death. We are using a variety of experimental systems to identify transcriptionally regulated death-inducing genes and new apoptotic pathways.

        Using DNA microarrays to analyze interleukin-3 (IL-3)-dependent murine FL5.12 pro-B cells, we found that the gene undergoing maximal transcriptional induction following cytokine withdrawal is 24p3, which encodes a secreted lipocalin. Addition of 24p3 induces apoptosis in a variety of lymphoid cells. 24p3 has also been implicated in other physiological responses, including iron uptake and differentiation. We used expression cloning to isolate a complementary DNA encoding a 24p3 cell surface receptor (24p3R). Ectopic 24p3R expression confers on cells the ability to undergo 24p3-dependent iron uptake or apoptosis. The differential response is controlled by the iron status of 24p3: iron-loaded 24p3 increases intracellular iron concentration without promoting apoptosis; iron-lacking 24p3 decreases intracellular iron levels, which induces Bim, a proapoptotic BCL-2 protein, resulting in apoptosis. Unexpectedly, we found that the BCR-ABL oncoprotein activates expression of 24p3 and represses expression of 24p3R. The down-regulation of 24p3R renders BCR-ABL+ cells refractory to the secreted 24p3. Intracellular iron delivery blocks apoptosis resulting from 24p3 addition, IL-3 deprivation, or imatinib treatment of BCR-ABL-transformed cells. Our results reveal an unanticipated role of intracellular iron regulation in an apoptotic pathway relevant to BCR-ABL-induced myeloproliferative disease and its treatment.

        The acquisition of apoptotic resistance is one of the hallmarks of cancer. Paradoxically, however, expression of an oncogene in a primary cell can induce apoptosis or senescence, and thus block cellular proliferation through pathways that remain to be elucidated. We have performed genome-wide RNAi screening to identify 17 genes required for an activated BRAF oncogene (BRAFV600E) to block proliferation of human primary fibroblasts and melanocytes. Surprisingly, we found that a secreted protein, IGFBP7, has a central role in BRAFV600E-mediated senescence and apoptosis. Expression of BRAFV600E in primary cells leads to synthesis and secretion of IGFBP7, which acts through autocrine/paracrine pathways to inhibit BRAF-MEK-ERK signaling and induce senescence and apoptosis. Apoptosis results from IGFBP7-mediated up-regulation of BNIP3L, a pro-apoptotic BCL2 family protein. Recombinant IGFBP7 (rIGFBP7) induces apoptosis in BRAFV600E-positive human melanoma cell lines, and systemically administered rIGFBP7 markedly suppresses growth of BRAFV600E-positive tumors in xenografted mice. Immunohistochemical analysis of human skin, nevi and melanoma samples implicates loss of IGFBP7 expression as a critical step in melanoma genesis.

        We have also used genome-wide RNAi screens to identify new metastasis suppressors genes that inhibit one or more steps required for metastasis without affecting primary tumor formation. Following expression in weakly metastatic B16-F0 mouse melanoma cells, small hairpin RNAs (shRNAs) were selected based upon enhanced satellite colony formation in a three-dimensional cell culture system and confirmed in a mouse experimental metastasis assay. Using this approach we discovered 22 genes whose knockdown increases metastasis without affecting primary tumor growth. We focused on one of these genes, Gas1, because we found that it is substantially down-regulated in highly metastatic B16-F10 melanoma cells, which contributes to the high metastatic potential of this mouse cell line. We further demonstrated that Gas1 has all the expected properties of a melanoma tumor suppressor including: suppression of metastasis in a spontaneous metastasis assay, promotion of apoptosis following dissemination of cells to secondary sites, and frequent down-regulation in human melanoma metastasis-derived cell lines and metastatic tumor samples. Thus, we have developed a genome-wide shRNA screening strategy that enables the discovery of new metastasis suppressor genes. to identify factors involved in oncogene-induced senescence and apoptosis, factors required for cancer cell survival, factors that mediate the induction of apoptosis by chemotherapeutic agents, new tumor suppressor genes and genes that regulate metastasis.

        Figure

        The lipocalin mouse 24p3 has been implicated in diverse physiological processes, including apoptosis due to interleukin-3 (IL-3) deprivation and iron transport. We have isolated by expression cloning a complementary DNA encoding a 24p3 cell surface receptor (24p3R). Ectopic 24p3R expression confers on cells the ability to undergo either iron uptake or apoptosis, dependent upon the iron content of the ligand: iron-loaded 24p3 (holo-24p3) increases intracellular iron concentration withough promoting apoptosis; iron-lacking 24p3 (apo-24p3) decreases intracellular iron levels, which induces expression of the proapoptotic protein Bim, resulting in apoptosis.



        Rotation Projects

        Rotation Projects

        Numerous rotation projects are available to work on a variety of ongoing problems in eukaryotic gene regulation at the transcriptional and post-transcriptional levels, and the relevance of gene regulation to certain human disease states. Techniques associated with specific projects include (but are not limited to) DNA manipulations and cloning, protein biochemistry and purification, yeast genetics, mammalian tissue-culture and virology. Specific rotation projects will be individually developed by the student and Dr. Green based upon the students background, interests, and goals for the rotation. Students can choose to rotate either for a half- or full-semester.



        Post Docs
        A postdoctoral position is available to study in this laboratory. Please contact Dr. Green for additional details.



        Bibliographic 
        selected publications
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        1. Pistis G, Okonkwo SU, Traglia M, Sala C, Shin SY, Masciullo C, Buetti I, Massacane R, Mangino M, Thein SL, Spector TD, Ganesh S, Pirastu N, Gasparini P, Soranzo N, Camaschella C, Hart D, Green MR, Toniolo D. Genome Wide Association Analysis of a Founder Population Identified TAF3 as a Gene for MCHC in Humans. PLoS One. 2013; 8(7):e69206.
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        2. Oh HK, Lee E, Jang HN, Lee J, Moon H, Sheng Z, Jun Y, Loh TJ, Cho S, Zhou J, Green MR, Zheng X, Shen H. hnRNP A1 contacts exon 5 to promote exon 6 inclusion of apoptotic Fas gene. Apoptosis. 2013 Jul; 18(7):825-35.
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        3. Fang M, Xia F, Mahalingam M, Virbasius CM, Wajapeyee N, Green MR. MEN1 Is a Melanoma Tumor Suppressor That Preserves Genomic Integrity by Stimulating Transcription of Genes That Promote Homologous Recombination-Directed DNA Repair. Mol Cell Biol. 2013 Jul; 33(13):2635-47.
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        4. Jenkins JL, Agrawal AA, Gupta A, Green MR, Kielkopf CL. U2AF65 adapts to diverse pre-mRNA splice sites through conformational selection of specific and promiscuous RNA recognition motifs. Nucleic Acids Res. 2013 Apr 1; 41(6):3859-73.
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        5. Yang ZF, Zhang H, Ma L, Peng C, Chen Y, Wang J, Green MR, Li S, Rosmarin AG. GABP transcription factor is required for development of chronic myelogenous leukemia via its control of PRKD2. Proc Natl Acad Sci U S A. 2013 Feb 5; 110(6):2312-7.
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        6. Green MR, Gentles AJ, Nair RV, Irish JM, Kihira S, Liu CL, Kela I, Hopmans ES, Myklebust JH, Ji H, Plevritis SK, Levy R, Alizadeh AA. Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma. Blood. 2013 Feb 28; 121(9):1604-11.
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        7. Myklebust JH, Irish JM, Brody J, Czerwinski DK, Houot R, Kohrt HE, Timmerman J, Said J, Green MR, Delabie J, Kolstad A, Alizadeh AA, Levy R. High PD-1 expression and suppressed cytokine signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells. Blood. 2013 Feb 21; 121(8):1367-76.
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        8. Wajapeyee N, Deibler SK, Green MR. Genome-Wide RNAi Screening to Identify Regulators of Oncogene-Induced Cellular Senescence. Methods Mol Biol. 2013; 965:373-82.
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        9. Wang W, Maucuer A, Gupta A, Manceau V, Thickman KR, Bauer WJ, Kennedy SD, Wedekind JE, Green MR, Kielkopf CL. Structure of Phosphorylated SF1 Bound to U2AF(65) in an Essential Splicing Factor Complex. Structure. 2013 Feb 5; 21(2):197-208.
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        10. Xie L, Gazin C, Park SM, Zhu LJ, Debily MA, Kittler EL, Zapp ML, Lapointe D, Gobeil S, Virbasius CM, Green MR. A Synthetic Interaction Screen Identifies Factors Selectively Required for Proliferation and TERT Transcription in p53-Deficient Human Cancer Cells. PLoS Genet. 2012 Dec; 8(12):e1003151.
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        11. Maston GA, Zhu LJ, Chamberlain L, Lin L, Fang M, Green MR. Non-canonical TAF complexes regulate active promoters in human embryonic stem cells. elife. 2012; 1:e00068.
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        12. Wang SZ, Ou J, Zhu LJ, Green MR. Transcription factor ATF5 is required for terminal differentiation and survival of olfactory sensory neurons. Proc Natl Acad Sci U S A. 2012 Nov 6; 109(45):18589-94.
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        13. Zhang H, Peng C, Hu Y, Li H, Sheng Z, Chen Y, Sullivan C, Cerny J, Hutchinson L, Higgins A, Miron P, Zhang X, Brehm MA, Li D, Green MR, Li S. The Blk pathway functions as a tumor suppressor in chronic myeloid leukemia stem cells. Nat Genet. 2012 Jul 15.
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        14. Maston GA, Landt SG, Snyder M, Green MR. Characterization of Enhancer Function from Genome-Wide Analyses. Annu Rev Genomics Hum Genet. 2012 Jun 11.
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        15. Den RB, Kamrava M, Sheng Z, Werner-Wasik M, Dougherty E, Marinucchi M, Lawrence YR, Hegarty S, Hyslop T, Andrews DW, Glass J, Friedman DP, Green MR, Camphausen K, Dicker AP. A phase I study of the combination of sorafenib with temozolomide and radiation therapy for the treatment of primary and recurrent high-grade gliomas. Int J Radiat Oncol Biol Phys. 2013 Feb 1; 85(2):321-8.
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        16. Lin L, Chamberlain L, Zhu LJ, Green MR. Analysis of Gal4-directed transcription activation using Tra1 mutants selectively defective for interaction with Gal4. Proc Natl Acad Sci U S A. 2012 Feb 7; 109(6):1997-2002.
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        17. Wajapeyee N, Green MR. Induction of senescence in melanoma: thinking outside the cell. Pigment Cell Melanoma Res. 2011 Oct; 24(5):874-5.
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        18. Sheng Z, Ma L, Sun JE, Zhu LJ, Green MR. BCR-ABL suppresses autophagy through ATF5-mediated regulation of mTOR transcription. Blood. 2011 Sep 8; 118(10):2840-8.
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        19. Liu Z, Yang A, Wang Z, Bunting KD, Davuluri G, Green MR, Devireddy LR. Multiple apoptotic defects in hematopoietic cells from mice lacking lipocalin 24p3. J Biol Chem. 2011 Jun 10; 286(23):20606-14.
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        20. Shen H, Zheng X, Luecke S, Green MR. 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. Genes Dev. 2010 Nov 1; 24(21):2389-94.
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        21. Shin J, Bossenz M, Chung Y, Ma H, Byron M, Taniguchi-Ishigaki N, Zhu X, Jiao B, Hall LL, Green MR, Jones SN, Hermans-Borgmeyer I, Lawrence JB, Bach I. Maternal Rnf12/RLIM is required for imprinted X-chromosome inactivation in mice. Nature. 2010 Oct 21; 467(7318):977-81.
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        22. Sheng Z, Evans SK, Green MR. An activating transcription factor 5-mediated survival pathway as a target for cancer therapy? Oncotarget. 2010 Oct; 1(6):457-60.
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        23. Devireddy LR, Hart DO, Goetz DH, Green MR. A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production. Cell. 2010 Jun 11; 141(6):1006-17.
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        24. Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR. Role for IGFBP7 in senescence induction by BRAF. Cell. 2010 May 28; 141(5):746-7.
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        25. Sheng Z, Li L, Zhu LJ, Smith TW, Demers A, Ross AH, Moser RP, Green MR. A genome-wide RNA interference screen reveals an essential CREB3L2-ATF5-MCL1 survival pathway in malignant glioma with therapeutic implications. Nat Med. 2010 Jun; 16(6):671-7.
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        26. Zhu LJ, Gazin C, Lawson ND, Pagès H, Lin SM, Lapointe DS, Green MR. ChIPpeakAnno: a Bioconductor package to annotate ChIP-seq and ChIP-chip data. BMC Bioinformatics. 2010; 11:237.
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        27. Wajapeyee N, Wang SZ, Serra RW, Solomon PD, Nagarajan A, Zhu X, Green MR. Senescence induction in human fibroblasts and hematopoietic progenitors by leukemogenic fusion proteins. Blood. 2010 Jun 17; 115(24):5057-60.
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        28. Wajapeyee N, Kapoor V, Mahalingam M, Green MR. Efficacy of IGFBP7 for treatment of metastatic melanoma and other cancers in mouse models and human cell lines. Mol Cancer Ther. 2009 Nov; 8(11):3009-14.
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        29. Palakurthy RK, Wajapeyee N, Santra MK, Gazin C, Lin L, Gobeil S, Green MR. Epigenetic silencing of the RASSF1A tumor suppressor gene through HOXB3-mediated induction of DNMT3B expression. Mol Cell. 2009 Oct 23; 36(2):219-30.
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        30. Hart DO, Santra MK, Raha T, Green MR. Selective interaction between Trf3 and Taf3 required for early development and hematopoiesis. Dev Dyn. 2009 Oct; 238(10):2540-9.
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        31. Emley A, Yang S, Wajapeyee N, Green MR, Mahalingam M. Oncogenic BRAF and the tumor suppressor IGFBP7 in the genesis of atypical spitzoid nevomelanocytic proliferations. J Cutan Pathol. 2010 Mar; 37(3):344-9.
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        32. Welch C, Santra MK, El-Assaad W, Zhu X, Huber WE, Keys RA, Teodoro JG, Green MR. Identification of a protein, G0S2, that lacks Bcl-2 homology domains and interacts with and antagonizes Bcl-2. Cancer Res. 2009 Sep 1; 69(17):6782-9.
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        33. Santra MK, Wajapeyee N, Green MR. F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage. Nature. 2009 Jun 4; 459(7247):722-5.
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        34. Sheng Z, Wang SZ, Green MR. Transcription and signalling pathways involved in BCR-ABL-mediated misregulation of 24p3 and 24p3R. EMBO J. 2009 Apr 8; 28(7):866-76.
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        35. Gobeil S, Zhu X, Doillon CJ, Green MR. A genome-wide shRNA screen identifies GAS1 as a novel melanoma metastasis suppressor gene. Genes Dev. 2008 Nov 1; 22(21):2932-40.
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        36. Hart DO, Green MR. Targeting a TAF to make muscle. Mol Cell. 2008 Oct 24; 32(2):164-6.
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        37. Jenkins JL, Shen H, Green MR, Kielkopf CL. Solution conformation and thermodynamic characteristics of RNA binding by the splicing factor U2AF65. J Biol Chem. 2008 Nov 28; 283(48):33641-9.
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        38. Green MR. Senescence: not just for tumor suppression. Cell. 2008 Aug 22; 134(4):562-4.
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        39. Shen H, Zheng X, Shen J, Zhang L, Zhao R, Green MR. Distinct activities of the DExD/H-box splicing factor hUAP56 facilitate stepwise assembly of the spliceosome. Genes Dev. 2008 Jul 1; 22(13):1796-803.
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        40. Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell. 2008 Feb 8; 132(3):363-74.
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        41. Hart DO, Raha T, Lawson ND, Green MR. Initiation of zebrafish haematopoiesis by the TATA-box-binding protein-related factor Trf3. Nature. 2007 Dec 13; 450(7172):1082-5.
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        42. Gazin C, Wajapeyee N, Gobeil S, Virbasius CM, Green MR. An elaborate pathway required for Ras-mediated epigenetic silencing. Nature. 2007 Oct 25; 449(7165):1073-7.
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        43. Tran K, Mahr JA, Choi J, Teodoro JG, Green MR, Spector DH. Accumulation of substrates of the anaphase-promoting complex (APC) during human cytomegalovirus infection is associated with the phosphorylation of Cdh1 and the dissociation and relocalization of APC subunits. J Virol. 2008 Jan; 82(1):529-37.
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        44. Garifulin O, Qi Z, Shen H, Patnala S, Green MR, Boyartchuk V. Irf3 polymorphism alters induction of interferon beta in response to Listeria monocytogenes infection. PLoS Genet. 2007 Sep; 3(9):1587-97.
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        45. Shen H, Green MR. RS domain-splicing signal interactions in splicing of U12-type and U2-type introns. Nat Struct Mol Biol. 2007 Jul; 14(7):597-603.
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        46. Teodoro JG, Evans SK, Green MR. Inhibition of tumor angiogenesis by p53: a new role for the guardian of the genome. J Mol Med. 2007 Nov; 85(11):1175-86.
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        47. Teodoro JG, Parker AE, Zhu X, Green MR. p53-mediated inhibition of angiogenesis through up-regulation of a collagen prolyl hydroxylase. Science. 2006 Aug 18; 313(5789):968-71.
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        48. Heilman DW, Teodoro JG, Green MR. Apoptin nucleocytoplasmic shuttling is required for cell type-specific localization, apoptosis, and recruitment of the anaphase-promoting complex/cyclosome to PML bodies. J Virol. 2006 Aug; 80(15):7535-45.
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        49. Sickmier EA, Frato KE, Shen H, Paranawithana SR, Green MR, Kielkopf CL. Structural basis for polypyrimidine tract recognition by the essential pre-mRNA splicing factor U2AF65. Mol Cell. 2006 Jul 7; 23(1):49-59.
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        50. Shen H, Green MR. RS domains contact splicing signals and promote splicing by a common mechanism in yeast through humans. Genes Dev. 2006 Jul 1; 20(13):1755-65.
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        51. Maston GA, Evans SK, Green MR. Transcriptional regulatory elements in the human genome. Annu Rev Genomics Hum Genet. 2006; 7:29-59.
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        52. Evans SK, Aiello DP, Green MR. Fluorescence resonance energy transfer as a method for dissecting in vivo mechanisms of transcriptional activation. Biochem Soc Symp. 2006; (73):217-24.
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        53. Devireddy LR, Gazin C, Zhu X, Green MR. A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell. 2005 Dec 29; 123(7):1293-305.
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        54. Oh SW, Mukhopadhyay A, Dixit BL, Raha T, Green MR, Tissenbaum HA. Identification of direct DAF-16 targets controlling longevity, metabolism and diapause by chromatin immunoprecipitation. Nat Genet. 2006 Feb; 38(2):251-7.
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        55. Ghigna C, Giordano S, Shen H, Benvenuto F, Castiglioni F, Comoglio PM, Green MR, Riva S, Biamonti G. Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene. Mol Cell. 2005 Dec 22; 20(6):881-90.
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        56. Gabellini D, D'Antona G, Moggio M, Prelle A, Zecca C, Adami R, Angeletti B, Ciscato P, Pellegrino MA, Bottinelli R, Green MR, Tupler R. Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1. Nature. 2006 Feb 23; 439(7079):973-7.
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        57. Green MR. Eukaryotic transcription activation: right on target. Mol Cell. 2005 May 13; 18(4):399-402.
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        58. Heilman DW, Green MR, Teodoro JG. The anaphase promoting complex: a critical target for viral proteins and anti-cancer drugs. Cell Cycle. 2005 Apr; 4(4):560-3.
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        59. Raha T, Cheng SW, Green MR. HIV-1 Tat stimulates transcription complex assembly through recruitment of TBP in the absence of TAFs. PLoS Biol. 2005 Feb; 3(2):e44.
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        60. Shen H, Green MR. A pathway of sequential arginine-serine-rich domain-splicing signal interactions during mammalian spliceosome assembly. Mol Cell. 2004 Nov 5; 16(3):363-73.
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        61. Teodoro JG, Heilman DW, Parker AE, Green MR. The viral protein Apoptin associates with the anaphase-promoting complex to induce G2/M arrest and apoptosis in the absence of p53. Genes Dev. 2004 Aug 15; 18(16):1952-7.
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        62. Zhao R, Shen J, Green MR, MacMorris M, Blumenthal T. Crystal structure of UAP56, a DExD/H-box protein involved in pre-mRNA splicing and mRNA export. Structure. 2004 Aug; 12(8):1373-81.
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        63. Kielkopf CL, Lücke S, Green MR. U2AF homology motifs: protein recognition in the RRM world. Genes Dev. 2004 Jul 1; 18(13):1513-26.
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        64. Gabellini D, Green MR, Tupler R. When enough is enough: genetic diseases associated with transcriptional derepression. Curr Opin Genet Dev. 2004 Jun; 14(3):301-7.
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        65. Shen H, Kan JL, Ghigna C, Biamonti G, Green MR. A single polypyrimidine tract binding protein (PTB) binding site mediates splicing inhibition at mouse IgM exons M1 and M2. RNA. 2004 May; 10(5):787-94.
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        66. Shen H, Kan JL, Green MR. Arginine-serine-rich domains bound at splicing enhancers contact the branchpoint to promote prespliceosome assembly. Mol Cell. 2004 Feb 13; 13(3):367-76.
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        67. Bhaumik SR, Raha T, Aiello DP, Green MR. In vivo target of a transcriptional activator revealed by fluorescence resonance energy transfer. Genes Dev. 2004 Feb 1; 18(3):333-43.
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        70. Devireddy LR, Green MR. Transcriptional program of apoptosis induction following interleukin 2 deprivation: identification of RC3, a calcium/calmodulin binding protein, as a novel proapoptotic factor. Mol Cell Biol. 2003 Jul; 23(13):4532-41.
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        71. Shen WC, Bhaumik SR, Causton HC, Simon I, Zhu X, Jennings EG, Wang TH, Young RA, Green MR. Systematic analysis of essential yeast TAFs in genome-wide transcription and preinitiation complex assembly. EMBO J. 2003 Jul 1; 22(13):3395-402.
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        72. Gabellini D, Tupler R, Green MR. Transcriptional derepression as a cause of genetic diseases. Curr Opin Genet Dev. 2003 Jun; 13(3):239-45.
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        73. Persengiev SP, Green MR. The role of ATF/CREB family members in cell growth, survival and apoptosis. Apoptosis. 2003 Jun; 8(3):225-8.
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        74. Reese JC, Green MR. Functional analysis of TFIID components using conditional mutants. Methods Enzymol. 2003; 370:415-30.
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        75. Bhaumik SR, Green MR. Interaction of Gal4p with components of transcription machinery in vivo. Methods Enzymol. 2003; 370:445-54.
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        76. Bhaumik SR, Green MR. Differential requirement of SAGA components for recruitment of TATA-box-binding protein to promoters in vivo. Mol Cell Biol. 2002 Nov; 22(21):7365-71.
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        77. Gabellini D, Green MR, Tupler R. Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle. Cell. 2002 Aug 9; 110(3):339-48.
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        78. Li XY, Bhaumik SR, Zhu X, Li L, Shen WC, Dixit BL, Green MR. Selective recruitment of TAFs by yeast upstream activating sequences. Implications for eukaryotic promoter structure. Curr Biol. 2002 Jul 23; 12(14):1240-4.
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        79. Persengiev SP, Devireddy LR, Green MR. Inhibition of apoptosis by ATFx: a novel role for a member of the ATF/CREB family of mammalian bZIP transcription factors. Genes Dev. 2002 Jul 15; 16(14):1806-14.
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        80. Gollan TJ, Green MR. Selective targeting and inducible destruction of human cancer cells by retroviruses with envelope proteins bearing short peptide ligands. J Virol. 2002 Apr; 76(7):3564-9.
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        81. Gollan TJ, Green MR. Redirecting retroviral tropism by insertion of short, nondisruptive peptide ligands into envelope. J Virol. 2002 Apr; 76(7):3558-63.
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        82. Virbasius CM, Holstege FC, Young RA, Green MR. Promoter-specific activation defects by a novel yeast TBP mutant compromised for TFIIB interaction. Curr Biol. 2001 Nov 13; 11(22):1794-8.
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        83. Devireddy LR, Teodoro JG, Richard FA, Green MR. Induction of apoptosis by a secreted lipocalin that is transcriptionally regulated by IL-3 deprivation. Science. 2001 Aug 3; 293(5531):829-34.
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        84. Bhaumik SR, Green MR. SAGA is an essential in vivo target of the yeast acidic activator Gal4p. Genes Dev. 2001 Aug 1; 15(15):1935-45.
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        85. Purohit P, Dupont S, Stevenson M, Green MR. Sequence-specific interaction between HIV-1 matrix protein and viral genomic RNA revealed by in vitro genetic selection. RNA. 2001 Apr; 7(4):576-84.
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        86. Tupler R, Perini G, Green MR. Expressing the human genome. Nature. 2001 Feb 15; 409(6822):832-3.
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        87. Zhang M, Green MR. Identification and characterization of yUAP/Sub2p, a yeast homolog of the essential human pre-mRNA splicing factor hUAP56. Genes Dev. 2001 Jan 1; 15(1):30-5.
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        88. Li XY, Bhaumik SR, Green MR. Distinct classes of yeast promoters revealed by differential TAF recruitment. Science. 2000 May 19; 288(5469):1242-4.
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        89. Green MR. TBP-associated factors (TAFIIs): multiple, selective transcriptional mediators in common complexes. Trends Biochem Sci. 2000 Feb; 25(2):59-63.
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        90. Wu S, Romfo CM, Nilsen TW, Green MR. Functional recognition of the 3' splice site AG by the splicing factor U2AF35. Nature. 1999 Dec 16; 402(6763):832-5.
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        91. Dupont S, Sharova N, DéHoratius C, Virbasius CM, Zhu X, Bukrinskaya AG, Stevenson M, Green MR. A novel nuclear export activity in HIV-1 matrix protein required for viral replication. Nature. 1999 Dec 9; 402(6762):681-5.
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        92. Tupler R, Perini G, Pellegrino MA, Green MR. Profound misregulation of muscle-specific gene expression in facioscapulohumeral muscular dystrophy. Proc Natl Acad Sci U S A. 1999 Oct 26; 96(22):12650-4.
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        93. Virbasius CM, Wagner S, Green MR. A human nuclear-localized chaperone that regulates dimerization, DNA binding, and transcriptional activity of bZIP proteins. Mol Cell. 1999 Aug; 4(2):219-28.
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        94. Li XY, Virbasius A, Zhu X, Green MR. Enhancement of TBP binding by activators and general transcription factors. Nature. 1999 Jun 10; 399(6736):605-9.
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        95. Perini G, Oetjen E, Green MR. The hepatitis B pX protein promotes dimerization and DNA binding of cellular basic region/leucine zipper proteins by targeting the conserved basic region. J Biol Chem. 1999 May 14; 274(20):13970-7.
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        96. Kan JL, Green MR. Pre-mRNA splicing of IgM exons M1 and M2 is directed by a juxtaposed splicing enhancer and inhibitor. Genes Dev. 1999 Feb 15; 13(4):462-71.
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        97. Shen WC, Green MR. Analysis of selective gene activation in yeast by differential display. Methods. 1998 Dec; 16(4):415-22.
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        98. Apone LM, Virbasius CA, Holstege FC, Wang J, Young RA, Green MR. Broad, but not universal, transcriptional requirement for yTAFII17, a histone H3-like TAFII present in TFIID and SAGA. Mol Cell. 1998 Nov; 2(5):653-61.
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        99. Werstuck G, Green MR. Controlling gene expression in living cells through small molecule-RNA interactions. Science. 1998 Oct 9; 282(5387):296-8.
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        100. Li XY, Green MR. The HIV-1 Tat cellular coactivator Tat-SF1 is a general transcription elongation factor. Genes Dev. 1998 Oct 1; 12(19):2992-6.
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        101. Shen WC, Apone LM, Virbasius CM, Li XY, Monsalve M, Green MR. Functional analysis of TFIID components. Cold Spring Harb Symp Quant Biol. 1998; 63:219-27.
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        102. Walker SS, Shen WC, Reese JC, Apone LM, Green MR. Yeast TAF(II)145 required for transcription of G1/S cyclin genes and regulated by the cellular growth state. Cell. 1997 Aug 22; 90(4):607-14.
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        103. Shen WC, Green MR. Yeast TAF(II)145 functions as a core promoter selectivity factor, not a general coactivator. Cell. 1997 Aug 22; 90(4):615-24.
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        104. Gaur RK, McLaughlin LW, Green MR. Functional group substitutions of the branchpoint adenosine in a nuclear pre-mRNA and a group II intron. RNA. 1997 Aug; 3(8):861-9.
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        105. Wu S, Green MR. Identification of a human protein that recognizes the 3' splice site during the second step of pre-mRNA splicing. EMBO J. 1997 Jul 16; 16(14):4421-32.
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        106. Fleckner J, Zhang M, Valcárcel J, Green MR. U2AF65 recruits a novel human DEAD box protein required for the U2 snRNP-branchpoint interaction. Genes Dev. 1997 Jul 15; 11(14):1864-72.
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        107. Zhang G, Zapp ML, Yan G, Green MR. Localization of HIV-1 RNA in mammalian nuclei. J Cell Biol. 1996 Oct; 135(1):9-18.
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        108. Valcárcel J, Gaur RK, Singh R, Green MR. Interaction of U2AF65 RS region with pre-mRNA branch point and promotion of base pairing with U2 snRNA [corrected]. Science. 1996 Sep 20; 273(5282):1706-9.
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        109. Apone LM, Virbasius CM, Reese JC, Green MR. Yeast TAF(II)90 is required for cell-cycle progression through G2/M but not for general transcription activation. Genes Dev. 1996 Sep 15; 10(18):2368-80.
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        110. Walker SS, Reese JC, Apone LM, Green MR. Transcription activation in cells lacking TAFIIS. Nature. 1996 Sep 12; 383(6596):185-8.
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        111. Li XY, Green MR. Transcriptional elongation and cancer. Tumorigenesis. Curr Biol. 1996 Aug 1; 6(8):943-4.
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        112. Fritz CC, Green MR. HIV Rev uses a conserved cellular protein export pathway for the nucleocytoplasmic transport of viral RNAs. Curr Biol. 1996 Jul 1; 6(7):848-54.
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        113. Green MR, Stillman B. Chromosomes and expression mechanisms. Curr Opin Genet Dev. 1996 Apr 1; 6(2):139-40.
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        114. Li XY, Green MR. Intramolecular inhibition of activating transcription factor-2 function by its DNA-binding domain. Genes Dev. 1996 Mar 1; 10(5):517-27.
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        115. Denis GV, Green MR. A novel, mitogen-activated nuclear kinase is related to a Drosophila developmental regulator. Genes Dev. 1996 Feb 1; 10(3):261-71.
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        116. Werstuck G, Zapp ML, Green MR. A non-canonical base pair within the human immunodeficiency virus rev-responsive element is involved in both rev and small molecule recognition. Chem Biol. 1996 Feb; 3(2):129-37.
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        117. Perini G, Wagner S, Green MR. Recognition of bZIP proteins by the human T-cell leukaemia virus transactivator Tax. Nature. 1995 Aug 17; 376(6541):602-5.
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        118. Fritz CC, Zapp ML, Green MR. A human nucleoporin-like protein that specifically interacts with HIV Rev. Nature. 1995 Aug 10; 376(6540):530-3.
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        119. Gaur RK, Valcárcel J, Green MR. Sequential recognition of the pre-mRNA branch point by U2AF65 and a novel spliceosome-associated 28-kDa protein. RNA. 1995 Jun; 1(4):407-17.
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        120. Singh R, Valcárcel J, Green MR. Distinct binding specificities and functions of higher eukaryotic polypyrimidine tract-binding proteins. Science. 1995 May 26; 268(5214):1173-6.
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        121. Roberts SG, Choy B, Walker SS, Lin YS, Green MR. A role for activator-mediated TFIIB recruitment in diverse aspects of transcriptional regulation. Curr Biol. 1995 May 1; 5(5):508-16.
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        122. Southgate CD, Green MR. Delineating minimal protein domains and promoter elements for transcriptional activation by lentivirus Tat proteins. J Virol. 1995 Apr; 69(4):2605-10.
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        123. Kwon H, Green MR. The RNA polymerase I transcription factor, upstream binding factor, interacts directly with the TATA box-binding protein. J Biol Chem. 1994 Dec 2; 269(48):30140-6.
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        124. Zhang G, Taneja KL, Singer RH, Green MR. Localization of pre-mRNA splicing in mammalian nuclei. Nature. 1994 Dec 22-29; 372(6508):809-12.
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        125. Roberts SG, Green MR. Activator-induced conformational change in general transcription factor TFIIB. Nature. 1994 Oct 20; 371(6499):717-20.
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        126. Reese JC, Apone L, Walker SS, Griffin LA, Green MR. Yeast TAFIIS in a multisubunit complex required for activated transcription. Nature. 1994 Oct 6; 371(6497):523-7.
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        127. Kwon H, Imbalzano AN, Khavari PA, Kingston RE, Green MR. Nucleosome disruption and enhancement of activator binding by a human SW1/SNF complex. Nature. 1994 Aug 11; 370(6489):477-81.
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