RESUMEN
The human tumor suppressor gene PTEN encodes a putative cytoskeleton-associated molecule with both protein phosphatase and phosphatidylinositol 3,4,5-trisphosphate (PIP3) 3-phosphatase activities. In cell culture, the lipid phosphatase activity of this protein is involved in regulating cell proliferation and survival, but the mechanism by which PTEN inhibits tumorigenesis in vivo is not fully established. Here we show that the highly evolutionarily conserved Drosophila PTEN homolog, DPTEN, suppresses hyperplastic growth in flies by reducing cell size and number. We demonstrate that DPTEN modulates tissue mass by acting antagonistically to the Drosophila Class I phosphatidylinositol 3-kinase, Dp110, and its upstream activator Chico, an insulin receptor substrate homolog. Surprisingly, although DPTEN does not generally affect cell fate determination, it does appear to regulate the subcellular organization of the actin cytoskeleton in multiple cell types. From these data, we propose that DPTEN has a complex role in regulating tissue and body size. It acts in opposition to Dp110 to control cell number and growth, while coordinately influencing events at the cell periphery via its effects on the actin cytoskeleton.
Asunto(s)
Proteínas Portadoras , Proteínas de Drosophila , Drosophila melanogaster/genética , Ojo/crecimiento & desarrollo , Proteínas de Insectos/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Fosfatidilinositol 3-Quinasas/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Proteínas Supresoras de Tumor , Secuencia de Aminoácidos , Animales , Secuencia de Bases , División Celular , Tamaño de la Célula , Mapeo Cromosómico , Citoesqueleto/fisiología , Drosophila melanogaster/crecimiento & desarrollo , Metanosulfonato de Etilo , Ojo/citología , Genes Supresores de Tumor , Biblioteca Genómica , Mutación de Línea Germinal , Homocigoto , Humanos , Proteínas Sustrato del Receptor de Insulina , Datos de Secuencia Molecular , Mutagénesis , Fosfohidrolasa PTEN , Monoéster Fosfórico Hidrolasas/genética , Transducción de Señal/fisiología , Transcripción Genética , Alas de Animales/citología , Alas de Animales/crecimiento & desarrolloRESUMEN
Calcitonin gene-related peptide (CGRP) is a 37 amino acid peptide encoded in the calcitonin gene. Its expression is dependent on tissue-specific alternative RNA processing: mRNA for CGRP predominates in the brain, whilst calcitonin (CT) mRNA predominates in thyroid C cells. The existence of this hitherto unsuspected peptide was predicted by mRNA analysis and demonstrated using antibodies raised against a synthetic peptide corresponding to the predicted C-terminal sequence of CGRP. The distribution of CGRP in the central and peripheral nervous system and its co-localization in some neurons with substance P (SP) or acetylcholine suggests several possible roles in autonomic, sensory and motor functions. Its actions appear to depend on the existence of specific CGRP receptors in target tissues, distinct from the receptors for CT but bearing some resemblance to them.