Ras and Rac1, Frequently Mutated in Melanomas, Are Activated by Superoxide Anion, Modulate Dnmt1 Level and Are Causally Related to Melanocyte Malignant Transformation

Autor(es)

Molognoni, Fernanda ^[1] ; Machado de Melo, Fabiana Henriques ^{[1, 2]} ; da Silva, Camila Tainah ^[1] ; Jasiulionis, Miriam Galvonas ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Dept Farmacol, UNIFESP, Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Dept Microbiol Imunol & Parasitol, UNIFESP, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 8, n. 12 DEC 16 2013.
• Citações Web of Science: 15

Resumo

A melanocyte malignant transformation model was developed in our laboratory, in which different melanoma cell lines were obtained after submitting the non-tumorigenic melanocyte lineage melan-a to sequential cycles of anchorage impediment. Our group has already showed that increased superoxide level leads to global DNA hypermemethylation as well increased Dnmt1 expression few hours after melanocyte anchorage blockade. Here, we showed that Ras/Rac1/ERK signaling pathway is activated in melanocytes submitted to anchorage impediment, regulating superoxide levels, global DNA methylation, and Dnmt1 expression. Interestingly, Ras and Rac1 activation is not related to codon mutations, but instead regulated by superoxide. Moreover, the malignant transformation was drastically compromised when melan-a melanocytes were submitted to sequential cycles of anchorage blockage in the presence of a superoxide scavenger. This aberrant signaling pathway associated with a sustained stressful condition, which might be similar to conditions such as UV radiation and inflammation, seems to be an early step in malignant transformation and to contribute to an epigenetic reprogramming and the melanoma development. (AU)

• Processo FAPESP: 09/51462-9 - Assinaturas moleculares da progressao do melanoma.
• Beneficiário: Camila Ferreira de Souza
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 11/12306-1 - Mecanismos epigenéticos como mediadores da transformação maligna de melanócitos associada a condições sustentadas de estresse
• Beneficiário: Miriam Galvonas Jasiulionis
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 11/09676-1 - Regulação transcricional do gene dnmt1 pelo estresse oxidativo causado pelo bloqueio de ancoragem de melanócitos
• Beneficiário: Camila Tainah da Silva
• Modalidade de apoio: Bolsas no Brasil - Doutorado