Alexander M Ishov

Alexander M Ishov, PhD

Associate Professor

Department: MD-ANATOMY
Business Phone: (352) 273-8202
Business Email: ishov@ufl.edu

Teaching Profile

Courses Taught
2018-2025
GMS6690 Molecular Cell Biology Journal Club
2007,2009-2011,2011-2015,2013-2019,2015-2022,2017-2023,2019-2023,2022-2023
GMS6061 Nuclear Structure and Dynamics
2013-2014,2016-2023
GMS6001 Fundamentals of Biomedical Sciences I
2016-2018,2020-2024
GMS6064 Tumor Biology
2014,2016-2020,2020-2025
GMS6421 Cell Biology
2014,2016-2018
GMS6062 Protein Trafficking
2015-2017
GMS6895 CTS Journal Club
2014
GMS6692 Research Conference in Anatomy and Cell Biology
2021
GMS6063 Cell Biology of Aging
2022-2023
GMS6647 Transcriptional and Translational Control of Cell Growth and Proliferation

Research Profile

RESEARCH INTEREST

Functions of histone variants in castration-resistant prostate cancer

Chemoresistance in breast cancer

Nuclear Structure and Function

Epigenetic Regulation of Gene Expression

Tumor Suppression

RESEARCH PROJECTS

Functions of histone variants in castration-resistant prostate cancer – Prostate cancer (PCa) is the second leading cause of cancer-related mortality in American men. Androgen ablation therapies are initially effective in ~90% of PCa patients. Unfortunately, these therapies offer only a temporary relief and the disease eventually recurs with a lethal outcome. PCa that relapsed after hormonal therapies is the major cause of disease lethality and is referred to as castration-resistant PC (CRPC). To make progress in CRPC treatment, we must develop evidence-based strategies for choosing therapy interventions. A better understanding of mechanisms that control androgen receptor (AR) activation and allow CRPC to circumvent hormonal ablation therapies is critically important for improving disease outcome. Advantages in the PCa field have clearly demonstrated that transcriptional control of AR-induced genes is regulated by epigenetic modifications of chromatin. The main chromatin unit, nucleosome, can be modulated by post-translational histones modifications, and also by the incorporation of histone variants, that, in combination, determines epigenetics properties and transcription activity of chromatin. The “histone variants barcode” hypothesis is based on differences between histone variants, and postulates that incorporation of transcription-associated H3.3 and H2A.Z variants creates active territories of chromatin. Specifically, we aim to answer two questions: First, do histone variants contribute to CRPC etiology, and second, is interaction between histone chaperones and AR play a role in this process. Altogether, this work supposes to rationally identify novel targeted and combinatorial therapeutic regimens for treatment of CRPC.

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.

Open Researcher and Contributor ID (ORCID)

0000-0002-8823-8640

Publications

2024
Overcoming ABCB1 mediated multidrug resistance in castration resistant prostate cancer.
Research square. [DOI] 10.21203/rs.3.rs-4238716/v1. [PMID] 38746435.
2023
HIRA-mediated loading of histone variant H3.3 controls androgen-induced transcription by regulation of AR/BRD4 complex assembly at enhancers
Nucleic Acids Research. 51(19):10194-10217 [DOI] 10.1093/nar/gkad700. [PMID] 37638746.
2023
HIRA-mediated loading of histone variant H3.3 controls androgen-induced transcription by regulation of AR/BRD4 complex assembly at enhancers.
bioRxiv : the preprint server for biology. [DOI] 10.1101/2023.05.08.536256. [PMID] 37214820.
2022
Inhibition of Mps1 kinase enhances taxanes efficacy in castration resistant prostate cancer
Cell Death & Disease. 13(10) [DOI] 10.1038/s41419-022-05312-8. [PMID] 36229449.
2021
Super-enhancer mediated regulation of adult β-globin gene expression: the role of eRNA and Integrator.
Nucleic acids research. 49(3):1383-1396 [DOI] 10.1093/nar/gkab002. [PMID] 33476375.
2020
Coordination of transcription, processing, and export of highly expressed RNAs by distinct biomolecular condensates.
Emerging topics in life sciences. 4(3):281-291 [DOI] 10.1042/ETLS20190160. [PMID] 32338276.
2018
Magnetic nanoparticle hyperthermia potentiates paclitaxel activity in sensitive and resistant breast cancer cells
International Journal of Nanomedicine. Volume 13:4771-4779 [DOI] 10.2147/ijn.s171130.
2017
CENP-B protects centromere chromatin integrity by facilitating histone deposition via the H3.3-specific chaperone Daxx
Epigenetics & Chromatin. 10(1) [DOI] 10.1186/s13072-017-0164-y. [PMID] 29273057.
2017
Inhibitor of H3K27 demethylase JMJD3/UTX GSK-J4 is a potential therapeutic option for castration resistant prostate cancer.
Oncotarget. 8(37):62131-62142 [DOI] 10.18632/oncotarget.19100. [PMID] 28977932.
2015
The histone chaperone DAXX maintains the structural organization of heterochromatin domains.
Epigenetics & chromatin. 8 [DOI] 10.1186/s13072-015-0036-2. [PMID] 26500702.
2014
Usp7 protects genomic stability by regulating Bub3.
Oncotarget. 5(11):3728-42 [PMID] 25003721.
2013
Function of Daxx/Atrx Complex At Centromeric and Pericentromeric Heterochromatin
Febs Journal. 280
2013
Targeting mitotic exit with hyperthermia or APC/C inhibition to increase paclitaxel efficacy.
Cell cycle (Georgetown, Tex.). 12(16):2598-607 [DOI] 10.4161/cc.25591. [PMID] 23907120.
2013
USP7 and Daxx regulate mitosis progression and taxane sensitivity by affecting stability of Aurora-A kinase.
Cell death and differentiation. 20(5):721-31 [DOI] 10.1038/cdd.2012.169. [PMID] 23348568.
2012
Dualistic function of Daxx at centromeric and pericentromeric heterochromatin in normal and stress conditions.
Nucleus (Austin, Tex.). 3(3):276-85 [DOI] 10.4161/nucl.20180. [PMID] 22572957.
2012
Regulation of mitosis and taxane response by Daxx and Rassf1.
Oncogene. 31(1):13-26 [DOI] 10.1038/onc.2011.211. [PMID] 21643015.
2011
Tandemly repeated DNA families in the mouse genome.
BMC genomics. 12 [DOI] 10.1186/1471-2164-12-531. [PMID] 22035034.
2011
The herpes simplex virus immediate-early ubiquitin ligase ICP0 induces degradation of the ICP0 repressor protein E2FBP1.
Journal of virology. 85(7):3356-66 [DOI] 10.1128/JVI.02105-10. [PMID] 21248039.
2010
Structural characterization of the DAXX N-terminal helical bundle domain and its complex with Rassf1C.
Structure (London, England : 1993). 18(12):1642-53 [DOI] 10.1016/j.str.2010.09.016. [PMID] 21134643.
2009
Daxx is a predominately nuclear protein that does not translocate to the cytoplasm in response to cell stress.
Cell cycle (Georgetown, Tex.). 8(10):1544-51 [PMID] 19372739.
2008
PML NBs (ND10) and Daxx: from nuclear structure to protein function.
Frontiers in bioscience : a journal and virtual library. 13:7132-42 [PMID] 18508722.
2008
Regulation of c-met expression by transcription repressor Daxx.
Oncogene. 27(15):2177-86 [PMID] 17952115.
2007
Daxx shortens mitotic arrest caused by paclitaxel.
Cell cycle (Georgetown, Tex.). 6(10):1200-4 [PMID] 17471023.
2005
The cellular protein daxx interacts with avian sarcoma virus integrase and viral DNA to repress viral transcription.
Journal of virology. 79(8):4610-8 [PMID] 15795247.
2004
Heterochromatin and ND10 are cell-cycle regulated and phosphorylation-dependent alternate nuclear sites of the transcription repressor Daxx and SWI/SNF protein ATRX.
Journal of cell science. 117(Pt 17):3807-20 [PMID] 15252119.
2003
Determination of minimum herpes simplex virus type 1 components necessary to localize transcriptionally active DNA to ND10.
Journal of virology. 77(10):5821-8 [PMID] 12719575.
2003
Heat shock and Cd2+ exposure regulate PML and Daxx release from ND10 by independent mechanisms that modify the induction of heat-shock proteins 70 and 25 differently.
Journal of cell science. 116(Pt 3):513-24 [PMID] 12508112.
2002
Activity and intracellular localization of the human cytomegalovirus protein pp71.
The Journal of general virology. 83(Pt 7):1601-1612 [DOI] 10.1099/0022-1317-83-7-1601. [PMID] 12075078.
2002
Daxx-mediated accumulation of human cytomegalovirus tegument protein pp71 at ND10 facilitates initiation of viral infection at these nuclear domains.
Journal of virology. 76(15):7705-12 [PMID] 12097584.
2001
[Monoclonal antibodies against protein Daxx and its localization in nuclear domains 10].
Tsitologiia. 43(12):1123-9 [PMID] 11881150.
2001
Evidence for separate ND10-binding and homo-oligomerization domains of Sp100.
Journal of cell science. 114(Pt 1):59-68 [PMID] 11112690.
2000
Non-apoptotic chromosome condensation induced by stress: delineation of interchromosomal spaces.
Chromosoma. 109(4):266-79 [PMID] 10968255.
2000
Review: properties and assembly mechanisms of ND10, PML bodies, or PODs.
Journal of structural biology. 129(2-3):278-87 [PMID] 10806078.
1999
PML is critical for ND10 formation and recruits the PML-interacting protein daxx to this nuclear structure when modified by SUMO-1.
The Journal of cell biology. 147(2):221-34 [PMID] 10525530.
1998
BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression.
Oncogene. 16(9):1097-112 [PMID] 9528852.
1998
Nuclear redistribution of BRCA1 during viral infection.
Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research. 9(9):743-55 [PMID] 9751118.
1997
Human cytomegalovirus immediate early interaction with host nuclear structures: definition of an immediate transcript environment.
The Journal of cell biology. 138(1):5-16 [PMID] 9214377.
1996
Adenovirus replication is coupled with the dynamic properties of the PML nuclear structure.
Genes & development. 10(2):196-207 [PMID] 8566753.
1996
Nuclear domain 10 as preexisting potential replication start sites of herpes simplex virus type-1.
Virology. 217(1):67-75 [PMID] 8599237.
1996
The periphery of nuclear domain 10 (ND10) as site of DNA virus deposition.
The Journal of cell biology. 134(4):815-26 [PMID] 8769408.
1995
Nuclear domain 10 (ND10) associated proteins are also present in nuclear bodies and redistribute to hundreds of nuclear sites after stress.
Journal of cellular biochemistry. 59(4):498-513 [PMID] 8749719.
1994
[Cloning universal probes for detecting mycoplasma contamination of cell cultures].
Molekuliarnaia biologiia. 28(2):444-52 [PMID] 8183277.
1976
Comparative studies on the structure and aggregative properties of the myosin molecule. III. The in vitro aggregative properties of the lobster myosin molecule.
Biochimica et biophysica acta. 420(2):406-16 [PMID] 3216.

Grants

Sep 2018 – Jun 2024
The Role of H3.3 histone variant in the pathogenesis of oral Kaposi's Sarcoma
Role: Faculty
Funding: NATL INST OF HLTH NIDCR
Sep 2016 – Aug 2019
Functions of histone variants in castration-resistent prostate cancer
Role: Principal Investigator
Funding: NATL INST OF HLTH NCI
Mar 2016 – Aug 2016
functions of histone variants in castration-resistance prostate cancer
Role: Principal Investigator
Funding: FL DEPT OF HLTH BANKHEAD-COLEY CANCER RE
Jul 2015 – Jun 2018
Function of histone chaperones in HSV-1 chromatin sturcture during latency, establishing maintenance and reactivation
Role: Principal Investigator
Funding: NATL INST OF HLTH NIAID
Feb 2015 – Oct 2023
UF Health Cancer Center Pilot Project Grants funded through the Florida Consortium of National Cancer Institute Centers Program
Role: Project Manager
Funding: UF HEALTH SHANDS HOSPITAL
Jan 2015 – May 2024
UF Health Cancer Center Bridge Seed Grant funded through the Florida Consortium of National Cancer Institute Centers Program
Role: Project Manager
Funding: UF HEALTH SHANDS HOSPITAL
Jul 2014 – Jun 2017
Histone variant H3.3 and KSHV LANA in the pathogenesis of oral Kaposis sarcoma
Role: Project Manager
Funding: NATL INST OF HLTH NIDCR

Education

Post Doctoral Training
1994-1997 · The Wistar Institute, Philadelphia, PA
PhD, Cellular and Molecular Biology
1994 · Institute of Cytology, Russian Academy of Science, St. Petersburg, Russia
MS, Genetics
1989 · State Pedagogical University, St. Petersburg, Russia
BS, Biology
1987 · State Pedagogical University, St. Petersburg, Russia

Contact Details

Phones:
Business:
(352) 273-8202
Emails:
Business:
ishov@ufl.edu
Addresses:
Business Mailing:
PO Box 103633
GAINESVILLE FL 32610
Business Street:
CGRC 358
2033 MOWRY RD
GAINESVILLE FL 32610