A chemical biology approach identifies AMPK as a modulator of melanoma oncogene MITF. 2014

V Borgdorff, and U Rix, and G E Winter, and M Gridling, and A C Müller, and F P Breitwieser, and C Wagner, and J Colinge, and K L Bennett, and G Superti-Furga, and S N Wagner
1] Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria [2] CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

The microphthalmia-associated transcription factor (MITF) is indispensable for the viability of melanocytic cells, is an oncogene in melanoma and has a cell type-specific expression pattern. As the modulation of MITF activity by direct chemical targeting remains a challenge, we assessed a panel of drugs for their ability to downregulate MITF expression or activity by targeting its upstream modulators. We found that the multi-kinase inhibitors midostaurin and sunitinib downregulate MITF protein levels. To identify the target molecules shared by both the drugs in melanocytic cells, a chemical proteomic approach was applied and AMP-activated kinase (AMPK) was identified as the relevant target for the observed phenotype. RNA interference and chemical inhibition of AMPK led to a decrease in MITF protein levels. Reduction of MITF protein levels was the result of proteasomal degradation, which was preceded by enhanced phosphorylation of MITF mediated by ERK. As expected, downregulation of MITF protein levels by AMPK inhibition was associated with decreased viability. Together, these results identify AMPK as an important regulator for the maintenance of MITF protein levels in melanocytic cells.

UI MeSH Term Description Entries
D007211 Indoles Benzopyrroles with the nitrogen at the number one carbon adjacent to the benzyl portion, in contrast to ISOINDOLES which have the nitrogen away from the six-membered ring.
D008544 Melanocytes Mammalian pigment cells that produce MELANINS, pigments found mainly in the EPIDERMIS, but also in the eyes and the hair, by a process called melanogenesis. Coloration can be altered by the number of melanocytes or the amount of pigment produced and stored in the organelles called MELANOSOMES. The large non-mammalian melanin-containing cells are called MELANOPHORES. Melanocyte
D008545 Melanoma A malignant neoplasm derived from cells that are capable of forming melanin, which may occur in the skin of any part of the body, in the eye, or, rarely, in the mucous membranes of the genitalia, anus, oral cavity, or other sites. It occurs mostly in adults and may originate de novo or from a pigmented nevus or malignant lentigo. Melanomas frequently metastasize widely, and the regional lymph nodes, liver, lungs, and brain are likely to be involved. The incidence of malignant skin melanomas is rising rapidly in all parts of the world. (Stedman, 25th ed; from Rook et al., Textbook of Dermatology, 4th ed, p2445) Malignant Melanoma,Malignant Melanomas,Melanoma, Malignant,Melanomas,Melanomas, Malignant
D009857 Oncogenes Genes whose gain-of-function alterations lead to NEOPLASTIC CELL TRANSFORMATION. They include, for example, genes for activators or stimulators of CELL PROLIFERATION such as growth factors, growth factor receptors, protein kinases, signal transducers, nuclear phosphoproteins, and transcription factors. A prefix of "v-" before oncogene symbols indicates oncogenes captured and transmitted by RETROVIRUSES; the prefix "c-" before the gene symbol of an oncogene indicates it is the cellular homolog (PROTO-ONCOGENES) of a v-oncogene. Transforming Genes,Oncogene,Transforming Gene,Gene, Transforming,Genes, Transforming
D011758 Pyrroles Azoles of one NITROGEN and two double bonds that have aromatic chemical properties. Pyrrole
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D002470 Cell Survival The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D002853 Chromatography, Liquid Chromatographic techniques in which the mobile phase is a liquid. Liquid Chromatography
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D005455 Fluorescent Antibody Technique Test for tissue antigen using either a direct method, by conjugation of antibody with fluorescent dye (FLUORESCENT ANTIBODY TECHNIQUE, DIRECT) or an indirect method, by formation of antigen-antibody complex which is then labeled with fluorescein-conjugated anti-immunoglobulin antibody (FLUORESCENT ANTIBODY TECHNIQUE, INDIRECT). The tissue is then examined by fluorescence microscopy. Antinuclear Antibody Test, Fluorescent,Coon's Technique,Fluorescent Antinuclear Antibody Test,Fluorescent Protein Tracing,Immunofluorescence Technique,Coon's Technic,Fluorescent Antibody Technic,Immunofluorescence,Immunofluorescence Technic,Antibody Technic, Fluorescent,Antibody Technics, Fluorescent,Antibody Technique, Fluorescent,Antibody Techniques, Fluorescent,Coon Technic,Coon Technique,Coons Technic,Coons Technique,Fluorescent Antibody Technics,Fluorescent Antibody Techniques,Fluorescent Protein Tracings,Immunofluorescence Technics,Immunofluorescence Techniques,Protein Tracing, Fluorescent,Protein Tracings, Fluorescent,Technic, Coon's,Technic, Fluorescent Antibody,Technic, Immunofluorescence,Technics, Fluorescent Antibody,Technics, Immunofluorescence,Technique, Coon's,Technique, Fluorescent Antibody,Technique, Immunofluorescence,Techniques, Fluorescent Antibody,Techniques, Immunofluorescence,Tracing, Fluorescent Protein,Tracings, Fluorescent Protein

Related Publications

V Borgdorff, and U Rix, and G E Winter, and M Gridling, and A C Müller, and F P Breitwieser, and C Wagner, and J Colinge, and K L Bennett, and G Superti-Furga, and S N Wagner
June 2017, Cancer cell,
V Borgdorff, and U Rix, and G E Winter, and M Gridling, and A C Müller, and F P Breitwieser, and C Wagner, and J Colinge, and K L Bennett, and G Superti-Furga, and S N Wagner
October 2009, Proceedings of the National Academy of Sciences of the United States of America,
V Borgdorff, and U Rix, and G E Winter, and M Gridling, and A C Müller, and F P Breitwieser, and C Wagner, and J Colinge, and K L Bennett, and G Superti-Furga, and S N Wagner
September 2006, Trends in molecular medicine,
V Borgdorff, and U Rix, and G E Winter, and M Gridling, and A C Müller, and F P Breitwieser, and C Wagner, and J Colinge, and K L Bennett, and G Superti-Furga, and S N Wagner
July 2005, Nature,
V Borgdorff, and U Rix, and G E Winter, and M Gridling, and A C Müller, and F P Breitwieser, and C Wagner, and J Colinge, and K L Bennett, and G Superti-Furga, and S N Wagner
October 2011, Proceedings of the National Academy of Sciences of the United States of America,
V Borgdorff, and U Rix, and G E Winter, and M Gridling, and A C Müller, and F P Breitwieser, and C Wagner, and J Colinge, and K L Bennett, and G Superti-Furga, and S N Wagner
June 2012, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology,
V Borgdorff, and U Rix, and G E Winter, and M Gridling, and A C Müller, and F P Breitwieser, and C Wagner, and J Colinge, and K L Bennett, and G Superti-Furga, and S N Wagner
March 2022, European journal of immunology,
V Borgdorff, and U Rix, and G E Winter, and M Gridling, and A C Müller, and F P Breitwieser, and C Wagner, and J Colinge, and K L Bennett, and G Superti-Furga, and S N Wagner
March 2008, Apoptosis : an international journal on programmed cell death,
V Borgdorff, and U Rix, and G E Winter, and M Gridling, and A C Müller, and F P Breitwieser, and C Wagner, and J Colinge, and K L Bennett, and G Superti-Furga, and S N Wagner
June 1971, Biochemical and biophysical research communications,
V Borgdorff, and U Rix, and G E Winter, and M Gridling, and A C Müller, and F P Breitwieser, and C Wagner, and J Colinge, and K L Bennett, and G Superti-Furga, and S N Wagner
January 2022, Frontiers in cell and developmental biology,
Copied contents to your clipboard!