title: Oncogenic BRAF induces melanoma cell invasion by downregulating the cGMP-specific phosphodiesterase PDE5A.
abstract: We show that in melanoma cells oncogenic BRAF, acting through MEK and the transcription factor BRN2, downregulates the cGMP-specific phosphodiesterase PDE5A. Although PDE5A downregulation causes a small decrease in proliferation, its major impact is to stimulate a dramatic increase in melanoma cell invasion. This is because PDE5A downregulation leads to an increase in cGMP, which induces an increase in cytosolic Ca(2+), stimulating increased contractility and inducing invasion. PDE5A downregulation also this leads to an increase in short-term and long-term colonization of the lungs by melanoma cells. We do not observe this pathway in NRAS mutant melanoma or BRAF mutant colorectal cells. Thus, we show that in melanoma cells oncogenic BRAF induces invasion through downregulation of PDE5A.
authors.affiliation: The Institute of Cancer Research, Signal Transduction Team, Section of Cell and Molecular Biology, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Imanol
authors.initials: I
authors.lastname: Arozarena
authors.forename: Berta
authors.initials: B
authors.lastname: Sanchez-Laorden
authors.forename: Leisl
authors.initials: L
authors.lastname: Packer
authors.forename: Cristina
authors.initials: C
authors.lastname: Hidalgo-Carcedo
authors.forename: Robert
authors.initials: R
authors.lastname: Hayward
authors.forename: Amaya
authors.initials: A
authors.lastname: Viros
authors.forename: Erik
authors.initials: E
authors.lastname: Sahai
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
mesh_terms: D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism; D024722:Cardiac Myosins / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000517:prevention & control / Q000556:secondary; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D018994:Myosin Light Chains / Q000037:antagonists & inhibitors / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control; D050809:POU Domain Factors / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D014183:Transplantation, Heterologous / Q000473:pathology
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D018398:Homeodomain Proteins; D018994:Myosin Light Chains; D050809:POU Domain Factors; D058986:Phosphodiesterase 5 Inhibitors; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C107184:myosin light chain 2; C085076:transcription factor Brn-2; C472645:blebbistatin; D000001:Calcimycin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; D024722:Cardiac Myosins; D006152:Cyclic GMP; D002118:Calcium