Dataset Information

PRMT5 is upregulated in malignant and metastatic melanoma and regulates expression of MITF and p27(Kip1.).

ABSTRACT: Protein arginine methyltransferase-5 (PRMT5) is a Type II arginine methyltransferase that regulates various cellular functions. We hypothesized that PRMT5 plays a role in regulating the growth of human melanoma cells. Immunohistochemical analysis indicated significant upregulation of PRMT5 in human melanocytic nevi, malignant melanomas and metastatic melanomas as compared to normal epidermis. Furthermore, nuclear PRMT5 was significantly decreased in metastatic melanomas as compared to primary cutaneous melanomas. In human metastatic melanoma cell lines, PRMT5 was predominantly cytoplasmic, and associated with its enzymatic cofactor Mep50, but not STAT3 or cyclin D1. However, histologic examination of tumor xenografts from athymic mice revealed heterogeneous nuclear and cytoplasmic PRMT5 expression. Depletion of PRMT5 via siRNA inhibited proliferation in a subset of melanoma cell lines, while it accelerated 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 p27(Kip1). These results are the first to report elevated PRMT5 expression in human melanoma specimens and indicate this protein may regulate MITF and p27(Kip1) expression in human melanoma cells.

SUBMITTER: Nicholas C

PROVIDER: S-EPMC3786975 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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PRMT5 is upregulated in malignant and metastatic melanoma and regulates expression of MITF and p27(Kip1.).

Nicholas Courtney C Yang Jennifer J Peters Sara B SB Bill Matthew A MA Baiocchi Robert A RA Yan Fengting F Sïf Saïd S Tae Sookil S Gaudio Eugenio E Wu Xin X Grever Michael R MR Young Gregory S GS Lesinski Gregory B GB

PloS one 20130930 9

Protein arginine methyltransferase-5 (PRMT5) is a Type II arginine methyltransferase that regulates various cellular functions. We hypothesized that PRMT5 plays a role in regulating the growth of human melanoma cells. Immunohistochemical analysis indicated significant upregulation of PRMT5 in human melanocytic nevi, malignant melanomas and metastatic melanomas as compared to normal epidermis. Furthermore, nuclear PRMT5 was significantly decreased in metastatic melanomas as compared to primary cu ...[more]

PMID: 24098663

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Project description:BackgroundExcessive growth of keratinocytes is the critical event in the etiology of psoriasis. However, the underlying molecular mechanism of psoriatic keratinocyte hyperproliferation is still unclear.ObjectiveThis study aimed to figure out the potential contributory role of S-phase kinase-associated protein 2 (SKP2) in promoting the hyperproliferation of keratinocytes in psoriasis.MethodsWe analyzed microarray data (GSE41662) to investigate the gene expression of SKP2 in psoriatic lesion skins compared with their adjacent non-lesional skin. Then, we further confirmed the mRNA and protein expression of SKP2 in human psoriatic skin tissues, imiquimod (IMQ)-induced psoriatic mice back skins and tumor necrosis factor α (TNF-α), interleukin (IL)-17A and IL-6-stimulated keratinocytes by using real-time quantitative polymerase chain reaction and western blot (WB). Furthermore, we explored the potential pathogenic role and its underlying cellular mechanism of SKP2 in promoting keratinocytes hyperproliferation through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell cycle detection, 5-ethynyl-2'-deoxyuridine staining and WB. Finally, we determined whether inhibition of SKP2 can effectively alleviate the keratinocytes hyperproliferation in vivo.ResultsWe identified that SKP2 is aberrantly upregulated in the psoriatic lesion skin and cytokines-stimulated keratinocytes. Moreover, upregulated SKP2 augments cytokines-induced keratinocytes hyperproliferation. Mechanistically, enhanced SKP2 increased the S phase ratio through inhibiting Cyclin-Dependent Kinase Inhibitor p27 (P27 Kip1) expression. Correspondingly, suppression of SKP2 with SMIP004 can significantly ease the epidermis hyperplasia in vivo.ConclusionOur results suggest that elevated SKP2 can empower keratinocytes proliferation and psoriasis-like epidermis hyperplasia via downregulation of P27 Kip1. Therefore, targeting SKP2-P27 Kip1 axis might be a promising therapeutic strategy for the treatment of psoriasis in future.

Dataset Information

PRMT5 is upregulated in malignant and metastatic melanoma and regulates expression of MITF and p27(Kip1.).

Publications

PRMT5 is upregulated in malignant and metastatic melanoma and regulates expression of MITF and p27(Kip1.).

Similar Datasets

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