Understanding of the mechanisms of melanocytic transformation is a continuing challenge. An in- depth knowledge of the genetic controls of cellular proliferation and cell division may provide critical information regarding the conversion of a normal melanocyte to its neoplastic phenotype. Polo-like kinases (Plks) are a family of highly conserved mitotic serine/threonine kinases that have been shown to play critical roles in cell division and cycle progression. Plk1 is the most widely studied member of the Plk family that contributes to multiple mitotic processes including the activation of the Cdk1/Cyclin B1 cascade, centrosome maturation, bipolar spindle formation and the regulation of Emi1 degradation at mitotic exit. Plk1 has been shown to be over-expressed in several cancers and a forced over-expression of Plk1 in normal cells has been found to cause a transformed phenotype and increased tumorigenicity. However, the functional role of Plk1 in melanocytic transformation is not well understood. In a recent study (J Invest Dermatol, In Press;Appendix-1), we have found that, i) Plk1 was over-expressed in both clinical tissue specimens and cultured human melanoma cells when compared to normal skin tissues and cultured normal melanocytes, respectively;and ii) genetic as well as chemical inhibition of Plk1 resulted in a significant decrease in the viability and growth of melanoma cells without affecting the normal human melanocytes. This study suggested that Plk1 may have an important role in melanoma survival and/or progression. However, additional studies are needed to determine the functional significance of Plk1 in melanocytic transformation and to define its molecular mechanism(s). In this study, we propose to challenge our novel hypothesis that Plk1 plays a critical role in melanocytic transformation and melanoma survival through modulation of Notch signaling. To test the hypothesis, the following specific aims are proposed: 1) To determine the expression pattern of Plk1, Notch and Numb during melanocytic transformation and melanoma development;2) To determine the involvement of Notch signaling as a downstream target of Plk1 in normal melanocytes and melanoma cells;3) To define the mechanism by which Plk1 regulates Notch1 signaling;and 4) To determine the functional and therapeutic significance of Plk1 in vivo in athymic nude mice xenografts. The outcome of proposed studies may define i) the role of Plk1 in melanocytic transformation and melanoma progression, ii) a novel connection between a key mitotic regulator (Plk1) with an important signaling pathway (Notch) involved in multiple cellular processes, including melanoma development.

Public Health Relevance

Understanding of the mechanisms of melanocytic transformation is a continuing challenge. An in depth knowledge of the genetic controls of cellular proliferation and cell division may provide critical information regarding the conversion of a normal melanocyte to its neoplastic phenotype. In this study, we will conduct pre-clinical studies to define the molecular mechanism of melanocytic transformation. Specifically, we will challenge our novel hypothesis that Plk1 plays a critical role in melanocytic transformation and melanoma survival through modulation of Notch signaling. The outcome of proposed studies may define i) the role of Plk1 in melanocytic transformation and melanoma progression, ii) a novel connection between a key mitotic regulator (Plk1) with an important signaling pathway (Notch) involved in multiple cellular processes, including melanoma development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR059130-05
Application #
8685888
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Tseng, Hung H
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Dermatology
Type
Schools of Medicine
DUNS #
City
Madison
State
WI
Country
United States
Zip Code
53715
Chhabra, Gagan; Garvey, Debra R; Singh, Chandra K et al. (2018) Effects and Mechanism of Nicotinamide Against UVA- and/or UVB-mediated DNA Damages in Normal Melanocytes. Photochem Photobiol :
Singh, Chandra K; Chhabra, Gagan; Ndiaye, Mary Ann et al. (2018) The Role of Sirtuins in Antioxidant and Redox Signaling. Antioxid Redox Signal 28:643-661
Denu, Ryan A; Shabbir, Maria; Nihal, Minakshi et al. (2018) Centriole Overduplication is the Predominant Mechanism Leading to Centrosome Amplification in Melanoma. Mol Cancer Res 16:517-527
Kong, Yifan; Cheng, Lijun; Mao, Fengyi et al. (2018) Inhibition of cholesterol biosynthesis overcomes enzalutamide resistance in castration-resistant prostate cancer (CRPC). J Biol Chem 293:14328-14341
Chhabra, Gagan; Singh, Chandra K; Ndiaye, Mary Ann et al. (2018) Prostate cancer chemoprevention by natural agents: Clinical evidence and potential implications. Cancer Lett 422:9-18
Wilking-Busch, Melissa J; Ndiaye, Mary A; Liu, Xiaoqi et al. (2018) RNA interference-mediated knockdown of SIRT1 and/or SIRT2 in melanoma: Identification of downstream targets by large-scale proteomics analysis. J Proteomics 170:99-109
Garcia-Peterson, Liz Mariely; Wilking-Busch, Melissa Jean; Ndiaye, Mary Ann et al. (2017) Sirtuins in Skin and Skin Cancers. Skin Pharmacol Physiol 30:216-224
Li, Zhiguo; Li, Jie; Kong, Yifan et al. (2017) Plk1 Phosphorylation of Mre11 Antagonizes the DNA Damage Response. Cancer Res 77:3169-3180
Shao, Chen; Li, Zhiguo; Ahmad, Nihal et al. (2017) Regulation of PTEN degradation and NEDD4-1 E3 ligase activity by Numb. Cell Cycle 16:957-967
Garcia-Peterson, Liz Mariely; Ndiaye, Mary Ann; Singh, Chandra K et al. (2017) SIRT6 histone deacetylase functions as a potential oncogene in human melanoma. Genes Cancer 8:701-712

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