Alexander M. Ishov, Ph.D.

Assistant Professor
Anatomy and Cell Biology
email: ishov@ufl.edu
phone: (352) 273-8202


Major Teaching Responsibilities - Research Interests - Research Projects - References - Biosketch

Major Teaching Responsibilities

    • Course Director:
    • GMS6061 The Nucleus, IDP Graduate Program
    • GMS6001 Fundamentals of Biomedical Science, Section 5 - Cell Biology / Transport, IDP Graduate Program
      • Lecturer:
    • GMS6001 Cell Biology/Transport Section, IDP Graduate Program
    • GMS6064 Tumor Biology Course, IDP Graduate Program
    • GMS6090 Graduate student rotation, IDP Graduate Program
    • GMS7979 Graduate Advanced Research, IDP Graduate Program
    • UFMCB 4905 MCB undergraduate honor research
      • Training grants participation:
    • T32 Training Grant in Surgical Oncology
    • T32 Training Grant in Cancer Biology

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    Research Interests

    • Chemoresistance in breast cancer
    • Nuclear Structure and Function
    • Epigenetic Regulation of Gene Expression
    • Tumor Suppression

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    Research Projects

    • Chemoresistance in breast cancer.
      Taxanes are among the most powerful anticancer agents in breast cancer chemotherapy. A large number of patients are resistant to taxanes. Therefore it is essential to develop prognostic tools and predictive markers for appropriate chemotherapy selection. Deficiency of protein Daxx (see review Lindsay et al., 2008, Frontiers in Bioscience) can determine resistance to taxane-induced mitotic catastrophe by reversibly blocking cells in mitosis (Lindsay et al., Cell Cycle, 2007).
      Current project is to examine Daxx as a paclitaxel sensitivity factor that can be used in selection of breast cancer patients to receive taxane therapy. Specifically, we will: 1. examine the role of Daxx in paclitaxel induced cell death, and 2. elucidate the function of Daxx in mitotic progression as a mechanism of Daxx-dependent resistance to paclitaxel treatment.
    • Tumor supression function of Daxx
      A predominant reason for high mortality rates in breast malignancies is that most patients cannot be effectively diagnosed (and properly treated) for metastasis probabilities. Thus, it is important to develop novel and early markers for metastasis potential of tumors. Over-expression of proto-oncogene c-met results in increased mobility/invasion and correlates with elevated metastatic potential. We described Daxx as a repressor of c-met transcription and cell mobility/invasion (Morozov et al., Oncogene 2008).
      Daxx is down regulated upon hypoxia, which is accompanied by increased accumulation of c-Met. Thus, Daxx is a potential metastasis gatekeeper. The main goal of this project is to evaluate protein Daxx as an early predictive marker for increased probability of metastasis development. We will determine: 1. the mechanism of Daxx mediated repression of human c-met promoter upon hypoxic conditions; 2. the physiological consequences of Daxx reduction upon hypoxic condition; 3. validate Daxx as an early predictive marker for metastasis potential in breast cancer.
    • ND10: a nuclear sensor
      Another scientific interest of our lab is the spatial and temporal regulation of nuclear functions in the context of dynamic changes in protein distribution. The intra-nuclear target of this research, dynamic structure called ND10 or PML body, accumulates several proteins (including Daxx, PML, SP100, SUMO, p53, ATRX) that are involved in a wide range of cellular activities, including regulation of transcription, cell cycle progression, senescence, and apoptosis (Ishov et al., J Cell Biol 1999). ND10 function is a temporary storage site of proteins that can be rapidly released from this domain to perform their activity at alternative locations upon changes in the cell cycle or application of stress conditions, including viral invection (Ishov et al., J Cell Biol 1996, 1997).
      Using a combination of cell biological, genetic, molecular and biochemical strategies, we intend to identify the ND10-associated mechanisms that control nuclear homeostatic balance of specific limiting factors during normal and pathological cellular activities, including carcinogenesis and viral infection.
    • Function of Daxx as an epigenetic marker at heterochromatin
      Heterochromatin generally represents transcriptionaly inactive part of genome that is replicated during the end of S-phase and requires the re-establishment of silent epigenetic markers such as deacetylated histones and methylated DNA to remain repressed after successive cell divisions. Proteins that accumulate at these sites during and after replication are therefore potentially involved in transcription repression. At the end of S-phase Daxx is released from ND10, and is transiently accumulated at heterochromatin where it forms a complex with ATP-dependent chromatin remodeling SWI/SNF protein ATRX (Ishov et al., J Cell Sci 2004).
      To seek for Daxx function at heterochromatin, we performed a search for heterochromatin-associated partners of Daxx using biochemichal purification and genetic screens. We intend to identify specific targets of Daxx mediated repression using the microarray approach, study the mechanisms and investigate the physiological effect of this repression on cellular and organism level.

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    References

    1. Lindsay CR, Giovinazzi S, and Ishov AM. Daxx is a predominately nuclear protein that does not translocate to the cytoplasm in response to cell stress. (2009) Cell Cycle 8(10): 1544-1551.  Pubmed
    2. Lindsay CR, Morozov VM and Ishov AM. PML NBs (ND10) and Daxx: from nuclear structure to protein function. (2008) (invited review, Frontiers in Bioscience 13:7132-7142).  Pubmed
    3. Morozov VM, Massoll NA, Vladimirova OV, Maul GG, and Ishov AM. Regulation of c-met expression by transcription repressor Daxx. (2008) Oncogene 27(15):2177-86.  Pubmed
    4. Lindsay CR, Scholz A, and Ishov AM. Daxx in Cellular Response to Paclitaxel. (2007) Cell Cycle 5;6(10): 1200-4.  Pubmed
    5. Greger JG, Katz RA, Ishov AM, Maul GG, Skalka AM. (2005) The cellular protein daxx interacts with avian sarcoma virus integrase and viral DNA to repress viral transcription. J Virol. 79(8):4610-8.  Pubmed
    6. Ishov AM, Vladimirova OV, and Maul GG. (2004) Heterochromatin and ND10 are cell cycle-regulated and phosphorylation- dependent alternate sites of the transcription repressor Daxx and the SWI/SNF protein ATRX. J Cell Sci. 117(Pt 17):3807-20.  Pubmed
    7. Tang Q, Li L, Ishov AM, Revol V, Epstein AL, Maul GG. (2003) Determination of Minimum Herpes Simplex Virus Type 1 Components Necessary To Localize Transcriptionally Active DNA to ND10. J Virol, 77(10): 5821-8.  Pubmed
    8. Nefkens I, Negorev D, Ishov AM, Muller W, and Maul GG. (2003) Stress by heat shock and Cd++ exposure modifies ND10-associated proteins distribution by different posttranscriptional modification. J Cell Sci, 116(Pt 3): 513-24.  Pubmed
    9. Ishov AM, Vladimirova OV, and Maul GG. (2002) Daxx-mediated accumulation of HCMV tegument protein pp71 at ND10 facilitates initiation of viral infection at these nuclear domains. J Virol, 76(15): 7705-7712.  Pubmed
    10. Marshall KR, Rowley KV, Rinaldi A, Nicholson IP, Ishov AM, Maul GG, and Preston CM. (2002) Activity and intracellular localisation of the human cytomegalovirus protein pp71. J Gen Virol, 83: 1601-1612.  Pubmed
    11. Sotnikov AG, Negorev D, Ishov AM, Maul GG. (2001) Monoclonal antibodies against protein Daxx and its localization in nuclear domains 10. Tsitologiia, 43(12): 1123-9.  Pubmed
    12. Negorev D, Ishov AM, and Maul GG. (2001) Evidence for separate ND10-binding and homo-oligomerization domains of Sp100. J Cell Sci, 114: 59-68.  Pubmed
    13. Plehn-Dujowich D, Bell P, Ishov AM, Baumann C, and Maul GG. (2000) Non-apoptotic Chromosome Condensation Induced by Stress: Delineation of Interchromosomal Spaces. Chromosoma, 109: 266-79.  Pubmed
    14. Maul GG, Negorev D, Bell P, and Ishov AM. (2000) Properties and assembly mechanisms of ND10, PML bodies or PODs. J Struct. Biol, 2/3: 278-287.  Pubmed
    15. Ishov AM, Sotnikov AG, Negorev D, Vladimirova OV, Neff N, Kamitani T, Yeh ETH, Strauss JF III, and Maul GG. (1999) PML is critical for ND10 formation and recruits the PML-interacting protein Daxx to this nuclear structure when modified by SUMO-1. J Cell Biol, 147: 221-233.  Pubmed
    16. Maul GG, Jensen DE, Ishov AM, Herlyn M, and Rauscher FJ. (1998) Nuclear redistribution of BRCA1 during viral infection. Cell Growth Diff, 9: 743-755.  Pubmed
    17. Jensen, DE, Procter M, Marquis ST, Gardner HP, Ha SI, Chodosh LA, Ishov AM, Tommerup N, Vissing H, Sekido Y, Minna J, Brodovsky A, Schulz DC, Wilkinson KD, Maul GG, Barlev N, Berger SL, Prendergast GC, and Rauscher FJ. (1998) BAP1, a novel ubiqitin hydrolase which binds to the BRCA-1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene, 16: 1097-1112.  Pubmed
    18. Ishov AM, Stenberg RM and Maul GG. (1997) Human Cytomegalovirus immediate early interaction with host nuclear structures: definition of an immediate transcript environment. J Cell Biol, 138(1):5-16.  Pubmed
    19. Ishov AM, and Maul GG. (1996) The periphery of Nuclear Domain 10 (ND10) as site of DNA viruses deposition. J Cell Biol, 134: 815-826.  Pubmed
    20. Doucas V, Ishov AM, Romo A, Juguilon J, Weitzman M, Evans RM, and Maul GG. (1996) Adenovirus replication is coupled with the dynamic properties of the PML nuclear structure. Genes Dev, 10: 196-207.  Pubmed
    21. Maul GG, Ishov AM, and Everett RD. (1996) Nuclear Domain 10 as preexisting potential replication start sites of Herpes Simplex Virus type-1. Virology 217: 67-75.  Pubmed
    22. Maul GG, Yu E, Ishov AM, and Epstein AL. (1995) Nuclear Domain 10 (ND10) associated proteins are also present in Nuclear Bodies and redistribute to hundreds of nuclear sites after stress. J of Cell Biochem, 59: 498-513.  Pubmed
    23. Kalachikov SM, Kel AE, Dymshits, GM, Ishov AM, and Borchsenius SN. (1994) Cloning of the universal probes for detection of mycoplasma contamination of cell lines. Molecular Biology, 28: 444-452  Pubmed
    24. Fridlanskaya II, Ishov AM, Letuchaya FM, Komisarchik Y, and Borchsenius SN. (1994) Detection of capsule in mycoplasma Acholeplasma laidlawii. Proc Rus Acad Sci, 334: 375-377

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    Biosketch
      Education
      1987B.S., Biology, State Pedagogical University, St. Petersburg, Russia
      1989M.S., Genetics, State Pedagogical University, St. Petersburg, Russia
      1994Ph.D., Cellular and Molecular Biology, Institute of Cytology, Russian Academy of Science, St. Petersburg, Russia
       
      Postdoctoral Training
      1994-1997The Wistar Institute, Philadelphia, PA
       
      Academic Appointments
      1997-1999Staff Scientist, The Wistar Institute, Philadelphia, PA
      1999-2001Staff Scientist, Director of the Microscopy and Histotechnology Core Facility, The Wistar Institute, Philadelphia, PA
      2001-2002Staff Scientist, The Wistar Institute, Philadelphia, PA
      1/2003-6/2003Senior Scientist, The Wistar Institute, Philadelphia, PA
      7/2003-presentAssistant Professor, Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL
      2003 - presentMember, University of Florida Shands Cancer, Gainesville, FL

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Updated: Monday, January 12, 2009 at 10:58:16 AM, © 2005 University of Florida