NDRG2 gene expression in B16F10 melanoma cells restrains melanogenesis via inhibition of Mitf expression.
NDRG2 (N-myc downstream-regulated gene 2) is a candidate tumor suppressor implicated in control of glioblastoma proliferation and dendritic cell differentiation. The microphthalmia-associated transcription factor (Mitf) plays a crucial role in the melanocyte lineage and in melanoma by controlling survival, differentiation, cell cycle entry and exit, and melanoma metastasis. Identifying upstream regulators of Mitf expression, therefore, remains a key issue. In this study, we aimed to assess whether the candidate tumor suppressor NDRG2 can modulate Mitf expression. Here, we show that NDRG2 acts to prevent cAMP and beta-catenin-mediated activation of the Mitf promoter, thereby blocking melanogenesis via the downstream Mitf target genes Tyrosinase, Tyrp1 and Dct. The data suggest that NDRG2 impairs melanogenesis by interfering with both the TCF/beta-catenin and cAMP/CREB pathways that are known to stimulate Mitf expression in melanocytes and have major implications for the role of NDRG2 in pigmentation and melanoma progression. Taken together, the results not only identify NDRG2 as a novel regulator of pigmentation, but also potentially a key factor in regulating melanoma progression via Mitf.
Kim
Aeyung
A
Department of Biological Science and the Research Center for Women's Diseases, Sookmyung Women's University, Seoul, Korea.
Yang
Young
Y
Lee
Myeong-Sok
MS
Yoo
Young Do
YD
Lee
Hee Gu
HG
Lim
Jong-Seok
JS
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015153:Blotting, Western; D000242:Cyclic AMP / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006728:Hormones / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008543:Melanins / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology* / Q000378:metabolism; D008546:Melanoma, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051820:TCF Transcription Factors / Q000378:metabolism; D000521:alpha-MSH / Q000494:pharmacology; D051176:beta Catenin / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D006728:Hormones; D008543:Melanins; D008562:Membrane Glycoproteins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; C485172:Ndr2 protein, mouse; D010726:Phosphodiesterase Inhibitors; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051820:TCF Transcription Factors; D051176:beta Catenin; D000521:alpha-MSH; D000242:Cyclic AMP; D010088:Oxidoreductases; D008156:Luciferases; C079621:Tyrp1 protein, mouse; D014442:Monophenol Monooxygenase; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase; D015056:1-Methyl-3-isobutylxanthine