Current Positions and Duties

Senior Career Scientist, the Regional Cancer Program of the Hôpital Régional de Sudbury Regional Hospital (HRSRH)

Founding Chair, the Northeastern Ontario Cancer Therapeutics Research Initiative (CTRI)

Professor, the Division of Medical Sciences, the Northern Ontario School of Medicine, Sudbury, Ontario

Professor, the Department of Medicine, the University of Ottawa Medical School, Ottawa, Ontario

Professor, the Department of Biochemistry, Microbiology and Immunology (BMI), the University of Ottawa Medical School, Ottawa, Ontario

Professor, the Biomolecular Sciences Ph.D. program, Laurentian University, Sudbury, Ontario

Cross appointed to the Department of Biology, Laurentian University, Sudbury, Ontario

Education/Training

1992-1994 Postdoctoral Fellow, the University of Virginia Medical School, Virginia USA

1992 Ph.D. University of Guelph, Guelph, Ontario

1988 M.Sc. University of Guelph, Guelph, Ontario

Awards

Premier’s Research Excellence award (2001)

Research Funding

Canadian Institutes of Health research (CIHR) – Replication and Cell Cycle research
National Cancer Institute of Canada (NCIC) / Canadian Cancer Society (CCS) – PCNA research
Natural Sciences and Engineering Council of Canada (NSERC) – Cdc7 domain analysis
Ontario Institute of Cancer Research (OICR) & Cancer Care Ontario (CCO) – Cancer Drug Discovery
Northern Cancer Research Foundation (NCRF) – Cancer Research
Canadian Breast cancer Foundation (CBCF) – Cancer Drug Discovery (for breast cancer)
Ontario Research and Challenge Funds – Chair In Cancer Research Initiative
The Cancer Research Society – Cancer Radioresistance
The Northern Ontario Heritage Fund (NOHF) – Stem cell Research

Research Investigations

ASYMMETRIC BIDIRECTIONAL DNA REPLICATION IN MAMMALIAN CELLS
The objective of this research program is to understand the interactions between cis-acting DNA elements and trans-acting factors that regulate the initiation of DNA replication in mammalian cells. Faithful replication of the entire genome once-per-cell cycle is essential for maintaining genetic stability in all living organisms, and the origin of DNA replication (ori) is a key control point of this regulation. Therefore, understanding the mechanism of ori activation is fundamental to gaining insights into the regulation of genome duplication and genetic stability. A short cis-acting genetic element is all that is required for ori function in prokaryotes and simple eukaryotes. However, the chromatin context and gene organizations are critically important in the regulation of mammalian DNA replication. In particular, transcription and replication often interplay in the regulation of mammalian oris, especially for those located at transcription promoters.

DEVELOPING EFFECTIVE AND SPECIFIC ANTICANCER MODALITIES
Effectively and selectively eliminating tumour cells without causing undesirable side-effects to normal cells is one of the most difficult challenges of cancer therapy. Since certain cellular signals are highly elevated in tumour cells (but not in normal cells), blocking these “cancer-specific” signals can be an effective way of controlling cancer. However, this approach is often not very efficient because selectively blocking a signal can usually be achieved only at low concentrations of the blockers, at which doses the efficacy of cancer-cell killing is low. We postulate that this limitation can be largely overcome by combining with effective and safe sensitizers.

We found that chloroquine, an inexpensive and safe anti-malarial and -rheumatoid drug, can effectively sensitize cancer-cell killing by other agents. Importantly, chloroquine does not, in most cases, sensitize normal-cell killing by cancer drugs. We also take repurposing and repositioning approaches to increase drug efficacy and specificity.

THE ROLE OF CDC7-DBF4 KINASE IN THE REGULATION OF DNA REPLICATION AND CELL-CYCLE CONTROL
The Cdc7-Dbf4 serine/threonine kinase activates the initiation of DNA replication by phosphorylating MCM proteins that are bound to the origins of DNA replication. We reported previously that human Cdc7 nuclear import is mediated directly by importin-β through its binding to the Cdc7 nuclear localization sequence (NLS). We also reported that human Cdc7 nuclear localization is regulated by two additional elements: nuclear retention (NRS) and export sequences (NES). Cdc7 proteins imported into the nucleus are retained in the nucleus by associating with chromatin, for which NRS (306-326) is essential. Importantly, this binding appears to be specific to the origin of DNA replication. Furthermore, an NRS-defective Cdc7 mutant could not be retained in the nucleus, although it was imported into the nucleus normally. Together, our data suggest that NRS plays an important role in the activation of DNA replication by Cdc7. The Cdc7 proteins unassociated with chromatin are bound by CRM1 via two NES elements: NES1 at 458-467 within kinase insert III, and NES2 at 545-554 within the kinase IX domain. The primary function of the Cdc7-CRM1 association may be to translocate nuclear Cdc7 to the cytoplasm. However, the binding of CRM1 with Cdc7 at NES2 raises an interesting possibility that CRM1 may also downregulate Cdc7 by masking its kinase domain.  We currently focus our research on the Cdc7 domain-function relation.

MOLECULAR MECHANISMS OF TUMOR CELL RADIATION- AND CHEMO-RESISTANCE
Despite the fact that radiation and chemotherapy have considerably improved during the last several decades, the failure of these treatments is still unacceptably high. This failure is often due to the selection of more radio- or chemo-resistant subpopulations during cancer therapy. We are trying to understand cellular response to radiation and chemotherapeutics at molecular levels and, eventually, to develop effective combined modalities to control cancers. Our research showed that the PI3K-Akt/PKB signal pathway plays a critical role in tumor cell proliferation, survival and resistant to radiation and chemotherapy. We currently examine the detailed mechanism as to how each Akt/PKB isoform is involved in the regulation of tumor cell growth and survival.

THE STRUCTURE-FUNCTION OF PCNA
Proliferating cell nuclear antigen (PCNA), a DNA replication processivity factor, is an essential component for eukaryotic chromosome replication and is often used as a cancer diagnostic and prognostic marker. PCNA is also involved in a wide range of other cellular activities, including DNA damage repair, cell-cycle control, apoptosis and epigenetic inheritance. The diverse function of PCNA may be regulated largely by post-translational modifications and association with different protein partners at a given time and space. We have previously shown by high-resolutional two-dimensional gel electrophoresis that there are three distinct PCNA isoforms that differ in their acetylation status. The Acidic (A), Main (M) and Basic (B) forms are 34 kDa-pI4.52, -pI4.57 and -pI4.62 proteins, respectively. We also found, in contrast to the currently accepted single homotrimer-ring model, that mammalian PCNA trimers exist in a cell as a back-to-back doublet complex. Since the double-trimer complex exposes two front sides, this structure can provide great flexibility in coordinating DNA replication with diverse cellular functions.

Publications

Recent Publications (2004 – 2010)

James W. Knockleby, Julia Romero, Kathleen A. Kylie, and Hoyun Lee. 2010 The role of Dbf4/Drf1-dependent kinase Cdc7. Current Topics in Biochemistry (In press).

Christina Richard, Carita Lanner, Stanislav N. Naryzhny, Levana Sherman, Hoyun Lee, Paul F. Lambert, Ingeborg Zehbe. 2010. The Asian-American E6 variant of human papillomavirus 16 exhibits higher in vitro immortalization and transforming potential than the E6 prototype. Oncogene (in press).

V. Raja Solomon and Hoyun Lee. 2010. Utilization of NMR-Based techniques, In “Anticancer Drug Development, Structure-Activity Relationship Studies in Drug Development by NMR Spectroscopy” (eds., A.U. Rahman and M.I. Choudhary), Bentham Science Publishers (In press).

Stacey Santi and Hoyun Lee. 2010. The Akt isoforms occupy a distinct subcellular localization within cells. Am J Physiology-Cell physiology (Published on-line, December 16, 2009) (doi:10.1152/ajpcell.00375.2009). (http://www.ncbi.nlm.nih.gov/pubmed/20018949)

V. Raja Solomon, Changkun Hu, and Hoyun Lee. 2010. Design and synthesis of anti-breast cancer agents from 4-piperazinylquinoline: A hybrid pharmacophore approach. Bioorganic & Medicinal Chemistry 18, 1563-1572. (http://www.ncbi.nlm.nih.gov/pubmed/20106668)

Changkun Hu, V. Raja Solomon, Pablo Cano, and Hoyun Lee. 2010. A 4-aminoquinoline derivative that markedly sensitizes tumor cell killing by Akt inhibitors with a minimum cytotoxicity to non-cancer cells. European Journal of Medicinal Chemistry 45, 705-709. (http://www.ncbi.nlm.nih.gov/sites/entrez)

V. Raja Solomon and Hoyun Lee. 2009. Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies (invited review). The European Journal of Pharmacology. 625, 220-233.

(http://www.ncbi.nlm.nih.gov/pubmed/19836374)
V. Raja Solomon, Changkun Hu, and Hoyun Lee. 2009. Hybrid Pharmacophore Design and Synthesis of Isatin-Benzothiazole Analogs for their Anti-Breast Cancer Activity. Bioorganic & Medicinal Chemistry 17, 7585-7592. * Identified as a breaking paper by the LeadDiscovery’s  DailyUpdates. (http://www.ncbi.nlm.nih.gov/pubmed/19804979)

Julia Romero and Hoyun Lee. 2008. One-way PCR-based mapping of a replication initiation point (RIP). Nature Protocols 3, 1720-1735. (http://www.ncbi.nlm.nih.gov/pubmed/18927558)

Changkun Hu, V. Raja Solomon, Gerardo Ulibarri, and Hoyun Lee. 2008. The efficacy and selectivity of tumor cell killing by Akt inhibitors are substantially increased by chloroquine. Bioorganic & Medicinal Chemistry 16, 7888-7893. (http://www.ncbi.nlm.nih.gov/pubmed/18691894)

Byung Ju Kim and Hoyun Lee. 2008. Caspase-mediated cleavage of importin-α increases its affinity for MCM and downregulate DNA synthesis. BBA-Molecular Cell Research 1783, 2287-2293. (http://www.ncbi.nlm.nih.gov/pubmed/18761040)

Byung Ju Kim and Hoyun Lee. 2008. Lys-110 is essential for targeting PCNA to replication and repair foci, and the K110A mutant activates apoptosis. Biology of Cell 100, 675-686. (http://www.ncbi.nlm.nih.gov/pubmed/18498247)

Julia Romero and Hoyun Lee. 2008. Asymmetric bidirectional replication (ABR) at the human Dbf4 locus.  Nature Structural and Molecular Biology 15,722-729. (http://www.ncbi.nlm.nih.gov/pubmed/18536724)

Haiwen Zhang, Raja Solomon, Changkun Hu, Gerardo Ulibarri, and Hoyun Lee. 2008. Synthesis and in vitro cytotoxicity evaluation of 4-aminoquinoline derivatives. Biomedicine and Pharmacotherapy 62, 65-69. (http://www.ncbi.nlm.nih.gov/pubmed/17555912)

Stanislav N. Naryzhny and Hoyun Lee. 2007. Characterization of proliferating cell nuclear antigen (PCNA) isoforms in normal and cancer cells: There is no cancer-associated form of PCNA. FEBS Letter 581, 4917-4920. (http://www.ncbi.nlm.nih.gov/pubmed/17900571)

Byung Ju Kim, So-Young Kim, and Hoyun Lee. 2007. Identification and characterization of Cdc7 nuclear retention and export sequences in the context of chromatin binding. Journal of Biological Chemistry 282, 30029-30038. (http://www.ncbi.nlm.nih.gov/pubmed/17711849)

Stanislav N. Naryzhny, Leroi V. DeSouza, K. W. Michael Siu and Hoyun Lee. 2006. Characterization of human proliferating cell nuclear antigen physico-chemical properties: aspects of double trimer stability. Biochemistry and Cell Biology 84, 669-676.(http://www.ncbi.nlm.nih.gov/pubmed/17167529)

Byung-Ju Kim and Hoyun Lee. 2006. Importin-β mediates the nuclear transportation of human Cdc7 by directly binding to its Kinase Insert II domain, which can be antagonized by importin-α. Journal of Biological Chemistry 281, 12041-12049. * This paper is highlighted by the Faculty of 1000 (Biology) in 2006. (http://www.ncbi.nlm.nih.gov/pubmed/16492669)

Baoqing Guo, Julia Romero, Byung-Ju Kim and Hoyun Lee. 2005. High levels of Cdc7 and Dbf4 proteins can arrest cell cycle progression. European Journal of Cell Biology 84, 927-938. (http://www.ncbi.nlm.nih.gov/pubmed/16325502)

Hoyun Lee, Luc Chouinard, Michel Bonin and Robin N. Michel. 2005. NFATc3 deficiency may contribute to the development of mammary gland adenocarcinoma in aging female mice. Molecular Carcinogenesis 44, 219-222. (http://www.ncbi.nlm.nih.gov/pubmed/16167349)

Stanislav N. Naryzhny, Helen Zhao and Hoyun Lee. 2005. Proliferating cell nuclear antigen (PCNA) may function as a double-homotrimer complex in the mammalian cell. Journal of Biological Chemistry 280, 13888-13894. (http://www.ncbi.nlm.nih.gov/pubmed/15805117)

Helen Zhao, Yong Cai, Stacy Santi, Robert Lafrenie and Hoyun Lee. 2005. Chloroquine-mediated radiosensitization is due to the destabilization of the lysosomal membrane and subsequent induction of necrotic cell death. Radiation Research 164, 250-257. (http://www.ncbi.nlm.nih.gov/pubmed/16137197)

Stanislav N. Naryzhny and Hoyun Lee. 2004. The post-translational modifications of proliferating cell nuclear antigen (PCNA): acetylation, not phosphorylation, plays an important role in the regulation of its function. Journal of Biological Chemistry 279, 20194-20199. (http://www.ncbi.nlm.nih.gov/pubmed/14988403)

Bewick, M, M.Conlon, Hoyun Lee, A.M. Parissenti, L. Zhang, S. Gluck, and R. Lafrenie. 2004. An evaluation of the clinical relevance of sICAM-1, sVCAM-1 and sE-selectin levels in patients with metastatic breast cancer. Stem Cells and Development 13, 281-294. (http://www.ncbi.nlm.nih.gov/pubmed/15186724)

Selected Previous Publications

Stanislav N. Naryzhny and Hoyun Lee. 2003. Observation of multiple isoforms and specific proteolysis patterns of PCNA in the context of cell-cycle compartments and sample preparations. Proteomics 3, 930-936. (http://www.ncbi.nlm.nih.gov/pubmed/12833516)

Xing Wu and Hoyun Lee. 2002. Human Dbf4/ASK promoter is activated through the Sp1 and Mlu 1 cell-cycle box (MCB) transcription elements. Oncogene 21 (51), 7786-779621. (http://www.ncbi.nlm.nih.gov/sites/entrez)

Andrew G. Pearce, Tamika M. Segura, Anne C. Rintala, Nina Rintala-Maki, and Hoyun Lee. 2001. The generation and characterization of radioresistant model system to study radioresistance in human breast cancer cells. Radiation Research 156, 739-750. (http://www.ncbi.nlm.nih.gov/sites/entrez)

Baoqing Guo and Hoyun Lee. 2001.Cloning and characterization of Chinese hamster homologue of yeast DBF4 (ChDBF4). Gene 264, 249-256. (http://www.ncbi.nlm.nih.gov/pubmed/11250080)

James M. Larner, Hoyun Lee, Randolf D. Little, P.A. Dijkwel, C. L. Schildkraut, and Joyce L. Hamlin. 1999. Radiation down-regulates replication origin activity throughout the S-phase in mammalian cells.  Nucleic Acids Research 27, 803-809 (http://www.ncbi.nlm.nih.gov/pubmed/9889276)

Hoyun Lee, James M. Larner, and Joyce L. Hamlin. 1997. A p53-independent damage-sensing mechanism that functions as a checkpoint at the G1/S transition in Chinese hamster cells. 1997. Proceeding National Academy of Sciences USA 94, 526-531. (http://www.ncbi.nlm.nih.gov/pubmed/9012817)

Hoyun Lee, James M. Larner, and Joyce L. Hamlin. 1997. Cloning and characterization of Chinese hamster p53. 1997. Gene 184, 177-183. (http://www.ncbi.nlm.nih.gov/pubmed/9031625)

James M. Larner, Hoyun Lee, and Joyce L. Hamlin. 1994. Radiation effects on DNA synthesis in a defined chromosomal replicon. Molecular and Cellular Biology 14, 1901-1908. (http://www.ncbi.nlm.nih.gov/pubmed/8114722)

Book Editing

Current Positions and Duties

Senior Career Scientist, the Regional Cancer Program of the Hôpital Régional de Sudbury Regional Hospital (HRSRH)

Founding Chair, the Northeastern Ontario Cancer Therapeutics Research Initiative (CTRI)

Professor, the Division of Medical Sciences, the Northern Ontario School of Medicine, Sudbury, Ontario

Professor, the Department of Medicine, the University of Ottawa Medical School, Ottawa, Ontario

Professor, the Department of Biochemistry, Microbiology and Immunology (BMI), the University of Ottawa Medical School, Ottawa, Ontario

Professor, the Biomolecular Sciences Ph.D. program, Laurentian University, Sudbury, Ontario

Cross appointed to the Department of Biology, Laurentian University, Sudbury, Ontario

Education/Training

1992-1994 Postdoctoral Fellow, the University of Virginia Medical School, Virginia USA

1992 Ph.D. University of Guelph, Guelph, Ontario

1988 M.Sc. University of Guelph, Guelph, Ontario

Awards

Premier’s Research Excellence award (2001)

Research Funding

Canadian Institutes of Health research (CIHR) – Replication and Cell Cycle research
National Cancer Institute of Canada (NCIC) / Canadian Cancer Society (CCS) – PCNA research
Natural Sciences and Engineering Council of Canada (NSERC) – Cdc7 domain analysis
Ontario Institute of Cancer Research (OICR) & Cancer Care Ontario (CCO) – Cancer Drug Discovery
Northern Cancer Research Foundation (NCRF) – Cancer Research
Canadian Breast cancer Foundation (CBCF) – Cancer Drug Discovery (for breast cancer)
Ontario Research and Challenge Funds – Chair In Cancer Research Initiative
The Cancer Research Society – Cancer Radioresistance
The Northern Ontario Heritage Fund (NOHF) – Stem cell Research

Research Investigations

ASYMMETRIC BIDIRECTIONAL DNA REPLICATION IN MAMMALIAN CELLS
The objective of this research program is to understand the interactions between cis-acting DNA elements and trans-acting factors that regulate the initiation of DNA replication in mammalian cells. Faithful replication of the entire genome once-per-cell cycle is essential for maintaining genetic stability in all living organisms, and the origin of DNA replication (ori) is a key control point of this regulation. Therefore, understanding the mechanism of ori activation is fundamental to gaining insights into the regulation of genome duplication and genetic stability. A short cis-acting genetic element is all that is required for ori function in prokaryotes and simple eukaryotes. However, the chromatin context and gene organizations are critically important in the regulation of mammalian DNA replication. In particular, transcription and replication often interplay in the regulation of mammalian oris, especially for those located at transcription promoters.

DEVELOPING EFFECTIVE AND SPECIFIC ANTICANCER MODALITIES
Effectively and selectively eliminating tumour cells without causing undesirable side-effects to normal cells is one of the most difficult challenges of cancer therapy. Since certain cellular signals are highly elevated in tumour cells (but not in normal cells), blocking these “cancer-specific” signals can be an effective way of controlling cancer. However, this approach is often not very efficient because selectively blocking a signal can usually be achieved only at low concentrations of the blockers, at which doses the efficacy of cancer-cell killing is low. We postulate that this limitation can be largely overcome by combining with effective and safe sensitizers.

We found that chloroquine, an inexpensive and safe anti-malarial and -rheumatoid drug, can effectively sensitize cancer-cell killing by other agents. Importantly, chloroquine does not, in most cases, sensitize normal-cell killing by cancer drugs. We also take repurposing and repositioning approaches to increase drug efficacy and specificity.

THE ROLE OF CDC7-DBF4 KINASE IN THE REGULATION OF DNA REPLICATION AND CELL-CYCLE CONTROL
The Cdc7-Dbf4 serine/threonine kinase activates the initiation of DNA replication by phosphorylating MCM proteins that are bound to the origins of DNA replication. We reported previously that human Cdc7 nuclear import is mediated directly by importin-β through its binding to the Cdc7 nuclear localization sequence (NLS). We also reported that human Cdc7 nuclear localization is regulated by two additional elements: nuclear retention (NRS) and export sequences (NES). Cdc7 proteins imported into the nucleus are retained in the nucleus by associating with chromatin, for which NRS (306-326) is essential. Importantly, this binding appears to be specific to the origin of DNA replication. Furthermore, an NRS-defective Cdc7 mutant could not be retained in the nucleus, although it was imported into the nucleus normally. Together, our data suggest that NRS plays an important role in the activation of DNA replication by Cdc7. The Cdc7 proteins unassociated with chromatin are bound by CRM1 via two NES elements: NES1 at 458-467 within kinase insert III, and NES2 at 545-554 within the kinase IX domain. The primary function of the Cdc7-CRM1 association may be to translocate nuclear Cdc7 to the cytoplasm. However, the binding of CRM1 with Cdc7 at NES2 raises an interesting possibility that CRM1 may also downregulate Cdc7 by masking its kinase domain.  We currently focus our research on the Cdc7 domain-function relation.

MOLECULAR MECHANISMS OF TUMOR CELL RADIATION- AND CHEMO-RESISTANCE
Despite the fact that radiation and chemotherapy have considerably improved during the last several decades, the failure of these treatments is still unacceptably high. This failure is often due to the selection of more radio- or chemo-resistant subpopulations during cancer therapy. We are trying to understand cellular response to radiation and chemotherapeutics at molecular levels and, eventually, to develop effective combined modalities to control cancers. Our research showed that the PI3K-Akt/PKB signal pathway plays a critical role in tumor cell proliferation, survival and resistant to radiation and chemotherapy. We currently examine the detailed mechanism as to how each Akt/PKB isoform is involved in the regulation of tumor cell growth and survival.

THE STRUCTURE-FUNCTION OF PCNA
Proliferating cell nuclear antigen (PCNA), a DNA replication processivity factor, is an essential component for eukaryotic chromosome replication and is often used as a cancer diagnostic and prognostic marker. PCNA is also involved in a wide range of other cellular activities, including DNA damage repair, cell-cycle control, apoptosis and epigenetic inheritance. The diverse function of PCNA may be regulated largely by post-translational modifications and association with different protein partners at a given time and space. We have previously shown by high-resolutional two-dimensional gel electrophoresis that there are three distinct PCNA isoforms that differ in their acetylation status. The Acidic (A), Main (M) and Basic (B) forms are 34 kDa-pI4.52, -pI4.57 and -pI4.62 proteins, respectively. We also found, in contrast to the currently accepted single homotrimer-ring model, that mammalian PCNA trimers exist in a cell as a back-to-back doublet complex. Since the double-trimer complex exposes two front sides, this structure can provide great flexibility in coordinating DNA replication with diverse cellular functions.

Publications

Recent Publications (2004 – 2010)

James W. Knockleby, Julia Romero, Kathleen A. Kylie, and Hoyun Lee. 2010 The role of Dbf4/Drf1-dependent kinase Cdc7. Current Topics in Biochemistry (In press).

Christina Richard, Carita Lanner, Stanislav N. Naryzhny, Levana Sherman, Hoyun Lee, Paul F. Lambert, Ingeborg Zehbe. 2010. The Asian-American E6 variant of human papillomavirus 16 exhibits higher in vitro immortalization and transforming potential than the E6 prototype. Oncogene (in press).

V. Raja Solomon and Hoyun Lee. 2010. Utilization of NMR-Based techniques, In “Anticancer Drug Development, Structure-Activity Relationship Studies in Drug Development by NMR Spectroscopy” (eds., A.U. Rahman and M.I. Choudhary), Bentham Science Publishers (In press).

Stacey Santi and Hoyun Lee. 2010. The Akt isoforms occupy a distinct subcellular localization within cells. Am J Physiology-Cell physiology (Published on-line, December 16, 2009) (doi:10.1152/ajpcell.00375.2009). (http://www.ncbi.nlm.nih.gov/pubmed/20018949)

V. Raja Solomon, Changkun Hu, and Hoyun Lee. 2010. Design and synthesis of anti-breast cancer agents from 4-piperazinylquinoline: A hybrid pharmacophore approach. Bioorganic & Medicinal Chemistry 18, 1563-1572. (http://www.ncbi.nlm.nih.gov/pubmed/20106668)

Changkun Hu, V. Raja Solomon, Pablo Cano, and Hoyun Lee. 2010. A 4-aminoquinoline derivative that markedly sensitizes tumor cell killing by Akt inhibitors with a minimum cytotoxicity to non-cancer cells. European Journal of Medicinal Chemistry 45, 705-709. (http://www.ncbi.nlm.nih.gov/sites/entrez)

V. Raja Solomon and Hoyun Lee. 2009. Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies (invited review). The European Journal of Pharmacology. 625, 220-233.

(http://www.ncbi.nlm.nih.gov/pubmed/19836374)
V. Raja Solomon, Changkun Hu, and Hoyun Lee. 2009. Hybrid Pharmacophore Design and Synthesis of Isatin-Benzothiazole Analogs for their Anti-Breast Cancer Activity. Bioorganic & Medicinal Chemistry 17, 7585-7592. * Identified as a breaking paper by the LeadDiscovery’s  DailyUpdates. (http://www.ncbi.nlm.nih.gov/pubmed/19804979)

Julia Romero and Hoyun Lee. 2008. One-way PCR-based mapping of a replication initiation point (RIP). Nature Protocols 3, 1720-1735. (http://www.ncbi.nlm.nih.gov/pubmed/18927558)

Changkun Hu, V. Raja Solomon, Gerardo Ulibarri, and Hoyun Lee. 2008. The efficacy and selectivity of tumor cell killing by Akt inhibitors are substantially increased by chloroquine. Bioorganic & Medicinal Chemistry 16, 7888-7893. (http://www.ncbi.nlm.nih.gov/pubmed/18691894)

Byung Ju Kim and Hoyun Lee. 2008. Caspase-mediated cleavage of importin-α increases its affinity for MCM and downregulate DNA synthesis. BBA-Molecular Cell Research 1783, 2287-2293. (http://www.ncbi.nlm.nih.gov/pubmed/18761040)

Byung Ju Kim and Hoyun Lee. 2008. Lys-110 is essential for targeting PCNA to replication and repair foci, and the K110A mutant activates apoptosis. Biology of Cell 100, 675-686. (http://www.ncbi.nlm.nih.gov/pubmed/18498247)

Julia Romero and Hoyun Lee. 2008. Asymmetric bidirectional replication (ABR) at the human Dbf4 locus.  Nature Structural and Molecular Biology 15,722-729. (http://www.ncbi.nlm.nih.gov/pubmed/18536724)

Haiwen Zhang, Raja Solomon, Changkun Hu, Gerardo Ulibarri, and Hoyun Lee. 2008. Synthesis and in vitro cytotoxicity evaluation of 4-aminoquinoline derivatives. Biomedicine and Pharmacotherapy 62, 65-69. (http://www.ncbi.nlm.nih.gov/pubmed/17555912)

Stanislav N. Naryzhny and Hoyun Lee. 2007. Characterization of proliferating cell nuclear antigen (PCNA) isoforms in normal and cancer cells: There is no cancer-associated form of PCNA. FEBS Letter 581, 4917-4920. (http://www.ncbi.nlm.nih.gov/pubmed/17900571)

Byung Ju Kim, So-Young Kim, and Hoyun Lee. 2007. Identification and characterization of Cdc7 nuclear retention and export sequences in the context of chromatin binding. Journal of Biological Chemistry 282, 30029-30038. (http://www.ncbi.nlm.nih.gov/pubmed/17711849)

Stanislav N. Naryzhny, Leroi V. DeSouza, K. W. Michael Siu and Hoyun Lee. 2006. Characterization of human proliferating cell nuclear antigen physico-chemical properties: aspects of double trimer stability. Biochemistry and Cell Biology 84, 669-676.(http://www.ncbi.nlm.nih.gov/pubmed/17167529)

Byung-Ju Kim and Hoyun Lee. 2006. Importin-β mediates the nuclear transportation of human Cdc7 by directly binding to its Kinase Insert II domain, which can be antagonized by importin-α. Journal of Biological Chemistry 281, 12041-12049. * This paper is highlighted by the Faculty of 1000 (Biology) in 2006. (http://www.ncbi.nlm.nih.gov/pubmed/16492669)

Baoqing Guo, Julia Romero, Byung-Ju Kim and Hoyun Lee. 2005. High levels of Cdc7 and Dbf4 proteins can arrest cell cycle progression. European Journal of Cell Biology 84, 927-938. (http://www.ncbi.nlm.nih.gov/pubmed/16325502)

Hoyun Lee, Luc Chouinard, Michel Bonin and Robin N. Michel. 2005. NFATc3 deficiency may contribute to the development of mammary gland adenocarcinoma in aging female mice. Molecular Carcinogenesis 44, 219-222. (http://www.ncbi.nlm.nih.gov/pubmed/16167349)

Stanislav N. Naryzhny, Helen Zhao and Hoyun Lee. 2005. Proliferating cell nuclear antigen (PCNA) may function as a double-homotrimer complex in the mammalian cell. Journal of Biological Chemistry 280, 13888-13894. (http://www.ncbi.nlm.nih.gov/pubmed/15805117)

Helen Zhao, Yong Cai, Stacy Santi, Robert Lafrenie and Hoyun Lee. 2005. Chloroquine-mediated radiosensitization is due to the destabilization of the lysosomal membrane and subsequent induction of necrotic cell death. Radiation Research 164, 250-257. (http://www.ncbi.nlm.nih.gov/pubmed/16137197)

Stanislav N. Naryzhny and Hoyun Lee. 2004. The post-translational modifications of proliferating cell nuclear antigen (PCNA): acetylation, not phosphorylation, plays an important role in the regulation of its function. Journal of Biological Chemistry 279, 20194-20199. (http://www.ncbi.nlm.nih.gov/pubmed/14988403)

Bewick, M, M.Conlon, Hoyun Lee, A.M. Parissenti, L. Zhang, S. Gluck, and R. Lafrenie. 2004. An evaluation of the clinical relevance of sICAM-1, sVCAM-1 and sE-selectin levels in patients with metastatic breast cancer. Stem Cells and Development 13, 281-294. (http://www.ncbi.nlm.nih.gov/pubmed/15186724)

Selected Previous Publications

Stanislav N. Naryzhny and Hoyun Lee. 2003. Observation of multiple isoforms and specific proteolysis patterns of PCNA in the context of cell-cycle compartments and sample preparations. Proteomics 3, 930-936. (http://www.ncbi.nlm.nih.gov/pubmed/12833516)

Xing Wu and Hoyun Lee. 2002. Human Dbf4/ASK promoter is activated through the Sp1 and Mlu 1 cell-cycle box (MCB) transcription elements. Oncogene 21 (51), 7786-779621. (http://www.ncbi.nlm.nih.gov/sites/entrez)

Andrew G. Pearce, Tamika M. Segura, Anne C. Rintala, Nina Rintala-Maki, and Hoyun Lee. 2001. The generation and characterization of radioresistant model system to study radioresistance in human breast cancer cells. Radiation Research 156, 739-750. (http://www.ncbi.nlm.nih.gov/sites/entrez)

Baoqing Guo and Hoyun Lee. 2001.Cloning and characterization of Chinese hamster homologue of yeast DBF4 (ChDBF4). Gene 264, 249-256. (http://www.ncbi.nlm.nih.gov/pubmed/11250080)

James M. Larner, Hoyun Lee, Randolf D. Little, P.A. Dijkwel, C. L. Schildkraut, and Joyce L. Hamlin. 1999. Radiation down-regulates replication origin activity throughout the S-phase in mammalian cells.  Nucleic Acids Research 27, 803-809 (http://www.ncbi.nlm.nih.gov/pubmed/9889276)

Hoyun Lee, James M. Larner, and Joyce L. Hamlin. 1997. A p53-independent damage-sensing mechanism that functions as a checkpoint at the G1/S transition in Chinese hamster cells. 1997. Proceeding National Academy of Sciences USA 94, 526-531. (http://www.ncbi.nlm.nih.gov/pubmed/9012817)

Hoyun Lee, James M. Larner, and Joyce L. Hamlin. 1997. Cloning and characterization of Chinese hamster p53. 1997. Gene 184, 177-183. (http://www.ncbi.nlm.nih.gov/pubmed/9031625)

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