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The Protein Arginine Methyltransferase PRMT5 Regulates Proliferation and the Expression of MITF and p27Kip1 in Human Melanoma

Nicholas, Courtney
http://rave.ohiolink.edu/etdc/view?acc_num=osu1343078125

Abstract Details

2012, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
The protein arginine methyltransferase-5 (PRMT5) enzyme is a Type II arginine methyltransferase that can regulate a variety of cellular functions. We hypothesized that PRMT5 plays a unique role in regulating the growth of human melanoma cells. Immunohistochemical analysis indicated significant upregulation of PRMT5 in human melanocytic nevi (88% of specimens positive for PRMT5), malignant melanomas (90% positive) and metastatic melanomas (88% positive) as compared to normal epidermis (5% of specimens positive for PRMT5; p<0.001, Fisher’s exact test). Furthermore, nuclear PRMT5 was significantly decreased in metastatic melanomas as compared to primary cutaneous melanomas (p<0.001, Wilcoxon rank sum test). Human metastatic melanoma cell lines in culture expressed PRMT5 predominantly in the cytoplasm. PRMT5 was found to be associated with its enzymatic cofactor Mep50, but not associated with STAT3 or cyclin D1. However, histologic examination of tumor xenografts from athymic mice revealed a heterogeneous pattern of nuclear and cytoplasmic PRMT5 expression. siRNA mediated depletion of PRMT5 inhibited proliferation in a subset of melanoma cell lines, while it accelerated the growth of others. Loss of PRMT5 also led to reduced expression of MITF (microphthalmia-associated transcription factor), a melanocyte lineage specific oncogene, and increased expression of the cell cycle regulator p27Kip1. These results represent the first characterization of PRMT5 expression in clinical melanoma specimens and indicate this protein can regulate melanoma cell growth via pathways involving MITF and p27. Taken together, these data suggest that PRMT5 may play a role in melanocytic proliferation and expression of the major cellular proteins MITF and p27Kip1.
Gregory B. Lesinski, PhD (Advisor)
Jiayuh Lin, PhD (Committee Member)
Amanda E. Toland, PhD (Committee Member)
Susheela Tridandapani, PhD (Committee Member)
101 p.
Molecular Biology; Oncology
melanoma; methyltransferase; PRMT; MITF; p27; proliferation; skin cancer

Recommended Citations

Citations

  • Nicholas, C. (2012). The Protein Arginine Methyltransferase PRMT5 Regulates Proliferation and the Expression of MITF and p27Kip1 in Human Melanoma [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1343078125

    APA Style (7th edition)

  • Nicholas, Courtney. The Protein Arginine Methyltransferase PRMT5 Regulates Proliferation and the Expression of MITF and p27Kip1 in Human Melanoma. 2012. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1343078125.

    MLA Style (8th edition)

  • Nicholas, Courtney. "The Protein Arginine Methyltransferase PRMT5 Regulates Proliferation and the Expression of MITF and p27Kip1 in Human Melanoma." Doctoral dissertation, Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1343078125

    Chicago Manual of Style (17th edition)

osu1343078125
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© 2012, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.