title: MicroRNA-149*, a p53-responsive microRNA, functions as an oncogenic regulator in human melanoma.
abstract: The tumor suppressor p53 is activated in response to cellular stress to prevent malignant transformation by activation of the DNA repair machinery to preserve the cell, or by induction of apoptosis to eliminate the cell should the damage prove irrevocable. The gene encoding p53 frequently undergoes inactivating mutations in many human cancers, but WT p53 is often expressed at high levels in melanoma, which, as judged from the malignant nature of the disease, fails to act as an effective tumor suppressor. Here we show that p53 directly up-regulates microRNA-149* (miR-149*) that in turn targets glycogen synthase kinase-3α, resulting in increased expression of Mcl-1 and resistance to apoptosis in melanoma cells. Although deficiency in miR-149* undermined survival of melanoma cells and inhibited melanoma growth in a mouse xenograft model, elevated expression of miR-149* was found in fresh human metastatic melanoma isolates, which was associated with decreased glycogen synthase kinase-3α and increased Mcl-1. These results reveal a p53-dependent, miR-149*-mediated pathway that contributes to survival of melanoma cells, provides a rational explanation for the ineffectiveness of p53 to suppress melanoma, and identifies the expression of miR-149* as a mechanism involved in the increased expression of Mcl-1 in melanoma cells.
authors: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei 230027, People's Republic of China.
authors: Lei
authors: L
authors: Jin
authors: Wang Lai
authors: WL
authors: Hu
authors: Chen Chen
authors: CC
authors: Jiang
authors: Jia Xu
authors: JX
authors: Wang
authors: Chuan Chun
authors: CC
authors: Han
authors: Ping
authors: P
authors: Chu
authors: Lin Jie
authors: LJ
authors: Zhang
authors: Rick F
authors: RF
authors: Thorne
authors: James
authors: J
authors: Wilmott
authors: Richard A
authors: RA
authors: Scolyer
authors: Peter
authors: P
authors: Hersey
authors: Xu Dong
authors: XD
authors: Zhang
authors: Mian
authors: M
authors: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009368:Neoplasm Transplantation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011519:Proto-Oncogenes / Q000235:genetics*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C551557:MIRN149 microRNA, human; C579094:Mcl1 protein, mouse; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha