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    Jeffrey Alan Nickerson PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentCell and Developmental Biology
    AddressUniversity of Massachusetts Medical School
    55 Lake Avenue North
    Worcester MA 01655
    Phone508-856-2312
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCell Biology

        Overview 
        Narrative

        Cell and Developmental Biology

        Academic Background

        Ph.D., 1985, Michigan State University

        Nuclear Architecture and Gene Expression

        Nucleic acid metabolism is architecturally organized in the eukaryotic nucleus. Nucleic acids themselves- as well as their metabolism in transcription, RNA processing, and RNA export- are structurally constrained to dynamic nuclear domains. Our larger goal is to understand the mechanisms that accomplish the self-assembly of these domains and achieve the spatial organization of gene expression. Our approach is an interdisciplinary one, combining biochemistry and molecular biology with confocal and electron microscopy.

        One ongoing project studies the regulation of mRNA export by the PI3 kinase/AKT signal transduction pathway.  Two complexes forming on an mRNA may play a role in its export to the cytoplasm.   The export proteins UAP56, ALY/REF, and NXF1-p15 sequentially bind to a TRanscription/EXport (TREX) complex, located at the 5’ end NXF1 recruited to the complex may subsequently bind at nuclear pores for export of the mRNA to the cytoplasm.   A second complex, the Exon Junction Complex (EJC), with a core of eIF4A3, MLN51, MAGOH, and Y14, forms on the mRNA at sites 24 nucleotides upstream from exon-exon junctions.  We used fluorescence recovery after photobleaching (FRAP) as a live cell screen to find signal transduction pathways that alter the binding of these proteins in mRNA complexes.  Our results show that PI3 kinase/ AKT regulate the binding affinity of UAP56, NXF1, eIF4A3, MAGOH, and Y14 in mRNA-associated complexes in live cells.   In addition, MAGOH binding is strongly reduced by the inhibition of mTORC1.   The active PI3 Kinase/AKT pathway causes increased nuclear retention of a subset of mRNAs in the nucleus, consistent with this signal transduction pathway regulating the export of mRNA.

        A second ongoing project, conducted as a long-term collaboration with the laboratory of Tony Imbalzano, also in this department, studies the role of chromatin remodeling in breast cancer.  This project has shown that the SWI/SNF chromatin remodeling enzymes BRG1 and BRM are required for the proliferation of human mammary epithelial cells in conventional tissue culture and in three dimensional reconstituted basement membrane cultures where these cells develop into tissue-like acini.  In addition, reduction in BRG1 levels causes nuclear shape changes that are independent of nuclear-cytoskeletal connections and are mediated by internal nuclear forces.

        We have presented evidence that nuclear RNA and the ongoing synthesis of RNA are required for maintaining the normal architecture of the nucleus and have proposed that long non-coding RNAs play this structural role.  A goal for future work is to test this hypothesis and identify specific architectural RNAs in the nucleus.

        Director for Cell Biology Confocal Core - Three Dimensional Microscopy - www.umassmed.edu/3dml


        Figure

        Figure

        Figure: Resinless section of a CaSki cell nuclear matrix. Solubleproteins and chromatin have been removed from this nucleus, uncovering thenuclear matrix which consists of two parts. The nuclear lamina isthe outer shell of the matrix which lies just under the nuclear envelopeand is primarily composed to the lamin proteins A, B, and C. Connected tothe lamina and extending throughout the nuclear volume is the internalnuclear matrix, an intricate structure built on a scaffolding of 10nm filaments whose molecular composition remains unknown. The largest massesremaining in the interior are remnants of nucleoli.



        Rotation Projects

        Potential Rotation Projects

             Identify the AKT phosphorylation sites on mRNA export proteins.  Determine the effect that point mutation of those sites has on mRNA export complex assembly and on the export of specific mRNAs.

             Investigate the role of chromatin remodeling in driving the important metabolic changes occurring during breast tumorigenesis.



        Post Docs

        POSTDOCTORAL POSITION

        A Postdoctoral Position is available immediately in the Department of Cell and Developmental Biology to study the regulation of RNA processing and export by signal transduction pathways. So far in this project we have found that the assembly of mRNA export complexes in live cells is regulated by the PI3 kinase/AKT signal transduction pathway and that, for a subset of mRNAs, nuclear export is AKT regulated. The experimental approach for this project integrates molecular techniques and microscopy, especially live cell microscopy. The postdoc in this position could also be involved in studies of the role of nuclear architecture in regulating gene expression and in studying the role of chromatin remodeling enzymes in breast cancer.  Candidates with a strong background in cell biology, biochemistry, or molecular biology are especially desirable.

        Quaresma, A.J., Sievert, R. & Nickerson, J.A. Regulation of mRNA export by the PI3 kinase/AKT signal transduction pathway. Mol Biol Cell 24, 1208-1221 (2013).

        The University of Massachusetts Medical School is located in Worcester, at the western edge of the Boston Metropolitan Area. The Department of Cell and Developmental Biology has especially strong research programs in nuclear and chromatin structure, cytoskeletal function, and mitotic architecture.


        Interested candidates should contact:

        Jeffrey A. Nickerson, Ph.D.
        Department of Cell and Developmental Biology S7-214
        University of Massachusetts Medical School
        55 Lake Avenue North
        Worcester, MA 01655
        (508) 856-2312
        jeffrey.nickerson@umassmed.edu



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Baron DM, Kaushansky LJ, Ward CL, Sama RR, Chian RJ, Boggio KJ, Quaresma AJ, Nickerson JA, Bosco DA. Amyotrophic lateral sclerosis-linked FUS/TLS alters stress granule assembly and dynamics. Mol Neurodegener. 2013; 8(1):30.
          View in: PubMed
        2. Damiano L, Stewart KM, Cohet N, Mouw JK, Lakins JN, Debnath J, Reisman D, Nickerson JA, Imbalzano AN, Weaver VM. Oncogenic targeting of BRM drives malignancy through C/EBPß-dependent induction of a5 integrin. Oncogene. 2014 May 8; 33(19):2441-53.
          View in: PubMed
        3. Imbalzano AN, Imbalzano KM, Nickerson JA. BRG1, a SWI/SNF chromatin remodeling enzyme ATPase, is required for maintenance of nuclear shape and integrity. Commun Integr Biol. 2013 Sep 1; 6(5):e25153.
          View in: PubMed
        4. Lovett DB, Shekhar N, Nickerson JA, Roux KJ, Lele TP. Modulation of Nuclear Shape by Substrate Rigidity. Cell Mol Bioeng. 2013 Jun 1; 6(2):230-238.
          View in: PubMed
        5. Quaresma AJ, Sievert R, Nickerson JA. Regulation of mRNA export by the PI3 kinase/AKT signal transduction pathway. Mol Biol Cell. 2013 Apr; 24(8):1208-21.
          View in: PubMed
        6. Imbalzano KM, Cohet N, Wu Q, Underwood JM, Imbalzano AN, Nickerson JA. Nuclear shape changes are induced by knockdown of the SWI/SNF ATPase BRG1 and are independent of cytoskeletal connections. PLoS One. 2013; 8(2):e55628.
          View in: PubMed
        7. Tortelote GG, Hernández-Hernández JM, Quaresma AJ, Nickerson JA, Imbalzano AN, Rivera-Pérez JA. Wnt3 function in the epiblast is required for the maintenance but not the initiation of gastrulation in mice. Dev Biol. 2013 Feb 1; 374(1):164-73.
          View in: PubMed
        8. Morello LG, Coltri PP, Quaresma AJ, Simabuco FM, Silva TC, Singh G, Nickerson JA, Oliveira CC, Moore MJ, Zanchin NI. The human nucleolar protein FTSJ3 associates with NIP7 and functions in pre-rRNA processing. PLoS One. 2011; 6(12):e29174.
          View in: PubMed
        9. Pockwinse SM, Kota KP, Quaresma AJ, Imbalzano AN, Lian JB, van Wijnen AJ, Stein JL, Stein GS, Nickerson JA. Live cell imaging of the cancer-related transcription factor RUNX2 during mitotic progression. J Cell Physiol. 2011 May; 226(5):1383-9.
          View in: PubMed
        10. Stein GS, Stein JL, van Wijnen AJ, Lian JB, Zaidi SK, Nickerson JA, Montecino MA, Young DW. An architectural genetic and epigenetic perspective. Integr Biol (Camb). 2011 Apr; 3(4):297-303.
          View in: PubMed
        11. Goel HL, Underwood JM, Nickerson JA, Hsieh CC, Languino LR. Beta1 integrins mediate cell proliferation in three-dimensional cultures by regulating expression of the sonic hedgehog effector protein, GLI1. J Cell Physiol. 2010 Jul; 224(1):210-7.
          View in: PubMed
        12. Cohet N, Stewart KM, Mudhasani R, Asirvatham AJ, Mallappa C, Imbalzano KM, Weaver VM, Imbalzano AN, Nickerson JA. SWI/SNF chromatin remodeling enzyme ATPases promote cell proliferation in normal mammary epithelial cells. J Cell Physiol. 2010 Jun; 223(3):667-78.
          View in: PubMed
        13. Zaidi SK, Medina RF, Pockwinse SM, Bakshi R, Kota KP, Ali SA, Young DW, Nickerson JA, Javed A, Montecino M, van Wijnen AJ, Lian JB, Stein JL, Stein GS. Subnuclear localization and intranuclear trafficking of transcription factors. Methods Mol Biol. 2010; 647:77-93.
          View in: PubMed
        14. Stein GS, van Wijnen AJ, Imbalzano AN, Montecino M, Zaidi SK, Lian JB, Nickerson JA, Stein JL. Architectural genetic and epigenetic control of regulatory networks: compartmentalizing machinery for transcription and chromatin remodeling in nuclear microenvironments. Crit Rev Eukaryot Gene Expr. 2010; 20(2):149-55.
          View in: PubMed
        15. Pratap J, Imbalzano KM, Underwood JM, Cohet N, Gokul K, Akech J, van Wijnen AJ, Stein JL, Imbalzano AN, Nickerson JA, Lian JB, Stein GS. Ectopic runx2 expression in mammary epithelial cells disrupts formation of normal acini structure: implications for breast cancer progression. Cancer Res. 2009 Sep 1; 69(17):6807-14.
          View in: PubMed
        16. Imbalzano KM, Tatarkova I, Imbalzano AN, Nickerson JA. Increasingly transformed MCF-10A cells have a progressively tumor-like phenotype in three-dimensional basement membrane culture. Cancer Cell Int. 2009; 9:7.
          View in: PubMed
        17. Nickerson JA. The biochemistry of RNA metabolism studied in situ. RNA Biol. 2009 Jan-Mar; 6(1):25-30.
          View in: PubMed
        18. Kota KP, Wagner SR, Huerta E, Underwood JM, Nickerson JA. Binding of ATP to UAP56 is necessary for mRNA export. J Cell Sci. 2008 May 1; 121(Pt 9):1526-37.
          View in: PubMed
        19. Young DW, Hassan MQ, Pratap J, Galindo M, Zaidi SK, Lee SH, Yang X, Xie R, Javed A, Underwood JM, Furcinitti P, Imbalzano AN, Penman S, Nickerson JA, Montecino MA, Lian JB, Stein JL, van Wijnen AJ, Stein GS. Mitotic occupancy and lineage-specific transcriptional control of rRNA genes by Runx2. Nature. 2007 Jan 25; 445(7126):442-6.
          View in: PubMed
        20. Lele T, Wagner SR, Nickerson JA, Ingber DE. Methods for measuring rates of protein binding to insoluble scaffolds in living cells: histone H1-chromatin interactions. J Cell Biochem. 2006 Dec 1; 99(5):1334-42.
          View in: PubMed
        21. Underwood JM, Imbalzano KM, Weaver VM, Fischer AH, Imbalzano AN, Nickerson JA. The ultrastructure of MCF-10A acini. J Cell Physiol. 2006 Jul; 208(1):141-8.
          View in: PubMed
        22. Pockwinse SM, Rajgopal A, Young DW, Mujeeb KA, Nickerson J, Javed A, Redick S, Lian JB, van Wijnen AJ, Stein JL, Stein GS, Doxsey SJ. Microtubule-dependent nuclear-cytoplasmic shuttling of Runx2. J Cell Physiol. 2006 Feb; 206(2):354-62.
          View in: PubMed
        23. Vradii D, Wagner S, Doan DN, Nickerson JA, Montecino M, Lian JB, Stein JL, van Wijnen AJ, Imbalzano AN, Stein GS. Brg1, the ATPase subunit of the SWI/SNF chromatin remodeling complex, is required for myeloid differentiation to granulocytes. J Cell Physiol. 2006 Jan; 206(1):112-8.
          View in: PubMed
        24. Liu F, Wagner S, Campbell RB, Nickerson JA, Schiffer CA, Ross AH. PTEN enters the nucleus by diffusion. J Cell Biochem. 2005 Oct 1; 96(2):221-34.
          View in: PubMed
        25. McCracken S, Longman D, Marcon E, Moens P, Downey M, Nickerson JA, Jessberger R, Wilde A, Caceres JF, Emili A, Blencowe BJ. Proteomic analysis of SRm160-containing complexes reveals a conserved association with cohesin. J Biol Chem. 2005 Dec 23; 280(51):42227-36.
          View in: PubMed
        26. Hill DA, Chiosea S, Jamaluddin S, Roy K, Fischer AH, Boyd DD, Nickerson JA, Imbalzano AN. Inducible changes in cell size and attachment area due to expression of a mutant SWI/SNF chromatin remodeling enzyme. J Cell Sci. 2004 Nov 15; 117(Pt 24):5847-54.
          View in: PubMed
        27. Zink D, Fischer AH, Nickerson JA. Nuclear structure in cancer cells. Nat Rev Cancer. 2004 Sep; 4(9):677-87.
          View in: PubMed
        28. Lele T, Oh P, Nickerson JA, Ingber DE. An improved mathematical approach for determination of molecular kinetics in living cells with FRAP. Mech Chem Biosyst. 2004 Sep; 1(3):181-90.
          View in: PubMed
        29. Wagner S, Chiosea S, Ivshina M, Nickerson JA. In vitro FRAP reveals the ATP-dependent nuclear mobilization of the exon junction complex protein SRm160. J Cell Biol. 2004 Mar 15; 164(6):843-50.
          View in: PubMed
        30. Wagner S, Chiosea S, Nickerson JA. The spatial targeting and nuclear matrix binding domains of SRm160. Proc Natl Acad Sci U S A. 2003 Mar 18; 100(6):3269-74.
          View in: PubMed
        31. Barseguian K, Lutterbach B, Hiebert SW, Nickerson J, Lian JB, Stein JL, van Wijnen AJ, Stein GS. Multiple subnuclear targeting signals of the leukemia-related AML1/ETO and ETO repressor proteins. Proc Natl Acad Sci U S A. 2002 Nov 26; 99(24):15434-9.
          View in: PubMed
        32. Herbert A, Wagner S, Nickerson JA. Induction of protein translation by ADAR1 within living cell nuclei is not dependent on RNA editing. Mol Cell. 2002 Nov; 10(5):1235-46.
          View in: PubMed
        33. Nickerson J. Experimental observations of a nuclear matrix. J Cell Sci. 2001 Feb; 114(Pt 3):463-74.
          View in: PubMed
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