1. Microphthalmia-associated transcription factor suppresses invasion by reducing intracellular GTP pools
- Author
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Joseph A. Wawrzyniak, Jeffrey J. Ackroyd, C E Foley, L M Paul-Rosner, Sebastiano Battaglia, Emily E. Fink, Archis Bagati, Brittany C. Lipchick, Masha Kolesnikova, Nadezhda I. Kozlova, Wiam Bshara, Anna Bianchi-Smiraglia, A. E. Berman, Sudha Moparthy, Donna S. Shewach, Mikhail A. Nikiforov, Peter Jowdy, and E K Marvin
- Subjects
rho GTP-Binding Proteins ,0301 basic medicine ,Cancer Research ,Intracellular Space ,Melanoma, Experimental ,Ectopic Gene Expression ,Mice ,Transactivation ,Neoplasms ,microphtalmia-associated transcription factor (MITF) ,Neoplasm Metastasis ,Melanoma ,integumentary system ,invasion ,Microphthalmia-associated transcription factor ,Extracellular Matrix ,3. Good health ,Cell biology ,Gene Expression Regulation, Neoplastic ,GMP Reductase ,Invadopodia ,Disease Progression ,Heterografts ,Melanocytes ,Female ,Guanosine Triphosphate ,vemurafenib-resistance ,RAC1 ,guanosine monophosphate reductase (GMPR) ,Biology ,Article ,03 medical and health sciences ,Downregulation and upregulation ,Growth factor receptor ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Molecular Biology ,Transcription factor ,Microphthalmia-Associated Transcription Factor ,medicine.disease ,Molecular biology ,body regions ,Disease Models, Animal ,030104 developmental biology ,GTP - Abstract
Melanoma progression is associated with increased invasion and, often, decreased levels of microphthalmia-associated transcription factor (MITF). Accordingly, downregulation of MITF induces invasion in melanoma cells, however little is known about the underlying mechanisms. Here, we report for the first time that depletion of MITF results in elevation of intracellular GTP levels and increased amounts of active (GTP-bound) RAC1, RHO-A and RHO-C. Concomitantly, MITF-depleted cells display larger number of invadopodia and increased invasion. We further demonstrate that the gene for guanosine monophosphate reductase (GMPR) is a direct MITF target, and that the partial repression of GMPR accounts mostly for the above phenotypes in MITF-depleted cells. Reciprocally, transactivation of GMPR is required for MITF-dependent suppression of melanoma cell invasion, tumorigenicity, and lung colonization. Moreover, loss of GMPR accompanies downregulation of MITF in vemurafenib-resistant BRAFV600E-melanoma cells and underlies the increased invasion in these cells. Our data uncover novel mechanisms linking MITF-dependent inhibition of invasion to suppression of guanylate metabolism.
- Published
- 2016
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