RESUMEN
Tumor progression locus 2 (Tpl2) is a serine/threonine kinase in the mitogen-activated protein kinase signal transduction cascade known to regulate inflammatory pathways. Previously identified as an oncogene, its mutation or overexpression is reported in a variety of human cancers. To address its role in skin carcinogenesis, Tpl2(-/-) or wild-type (WT) C57BL/6 mice were subjected to a two-stage dimethylbenzanthracene/12-O-tetradecanoylphorbol-13-acetate (TPA) mouse skin carcinogenesis model. Tpl2(-/-) mice developed a significantly higher incidence of tumors (80%) than WT mice (17%), as well as a reduced tumor latency and a significantly higher number of total tumors (113 vs 6). Moreover, Tpl2(-/-) mice treated with TPA experienced significantly higher nuclear factor kappaB (NF-κB) activation, edema, infiltrating neutrophils and production of proinflammatory cytokines than did WT mice. We investigated the role of the p38, JNK, MEK and NF-κB signaling pathways both in vitro and in vivo in WT and Tpl2(-/-) mice by using inhibitors for each of these pathways. We confirmed that the proinflammatory effect in Tpl2(-/-) mice was due to heightened activity of the NF-κB pathway. These studies indicate that Tpl2 may serve more as a tumor suppressor than as an oncogene in chemically induced skin carcinogenesis, with its absence contributing to both tumorigenesis and inflammation.
Asunto(s)
Transformación Celular Neoplásica/metabolismo , Inflamación/metabolismo , Quinasas Quinasa Quinasa PAM/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Transducción de Señal/fisiología , Neoplasias Cutáneas/metabolismo , Animales , Carcinógenos/toxicidad , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/patología , Citocinas/biosíntesis , Femenino , Immunoblotting , Inmunohistoquímica , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/patología , Acetato de Tetradecanoilforbol/toxicidadRESUMEN
Calcium channels play important roles in cellular signalling. TRP (transient receptor potential) channels form a superfamily of calcium channels through which Ca(2+) enters the cell. TRPs have six transmembrane segments with a putative pore between the fifth and the sixth segments, and assemble in tetrameric complexes to form functional Ca(2+) channels. They are thus similar to K(V) (voltage-gated potassium channel) channels in terms of structure and molecular determinants that promote subunit assembly. In this review, the molecular determinants mediating the assembly of Drosophila TRP, TRPC (TRP canonical), TRPV (TRP vanilloid) and K(V) channels are described.