title: Microphthalmia-associated transcription factor suppresses invasion by reducing intracellular GTP pools.
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.
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bianchi-Smiraglia
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bagati
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Fink
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Moparthy
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Wawrzyniak
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: E K
authors.initials: EK
authors.lastname: Marvin
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Battaglia
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: P
authors.initials: P
authors.lastname: Jowdy
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kolesnikova
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Foley
authors.affiliation: Orekhovich Institute of Biomedical Chemistry, Moscow, Russia.
authors.forename: A E
authors.initials: AE
authors.lastname: Berman
authors.affiliation: Orekhovich Institute of Biomedical Chemistry, Moscow, Russia.
authors.forename: N I
authors.initials: NI
authors.lastname: Kozlova
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Lipchick
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Paul-Rosner
authors.affiliation: Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: W
authors.initials: W
authors.lastname: Bshara
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Ackroyd
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Shewach
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Nikiforov
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D000066630:Ectopic Gene Expression; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D050899:GMP Reductase / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006160:Guanosine Triphosphate / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D051739:Microphthalmia-Associated Transcription Factor; D006160:Guanosine Triphosphate; D050899:GMP Reductase; D020741:rho GTP-Binding Proteins