RESUMEN
Periostin (POSTN), an osteoblast-specific secreted protein known to be associated with cell adhesion activity for bone formation and development by the epithelial cell-derived tumors, leads to a significant enhancement in angiogenesis and tumorigenesis. At present, little is known about the mechanisms underlying its transcriptional control either in physiological or neoplastic conditions. In this study we demonstrate that the ability of the human POSTN promoter to drive transcription mostly depends on the activity of YingYang-1 (YY1) zinc finger transcription factor. YY1, whose regulatory role in biology includes, besides transcriptional control, also chromatin remodeling, DNA damage repair and tumorigenesis, acts as a strong negative modulator of the POSTN expression. We retain that the identification of the functional role of YY1 in the transcriptional control of the human POSTN gene adds new insights in the studies focused on gene expression in normal and transformed cells.
Asunto(s)
Moléculas de Adhesión Celular/genética , Transcripción Genética , Factor de Transcripción YY1/fisiología , Secuencia de Bases , Sitios de Unión/genética , Moléculas de Adhesión Celular/metabolismo , Células Cultivadas , Regulación hacia Abajo/genética , Silenciador del Gen/fisiología , Células HeLa , Humanos , Datos de Secuencia Molecular , Regiones Promotoras Genéticas , Unión Proteica/fisiología , Transcripción Genética/genética , Transfección , Factor de Transcripción YY1/genética , Factor de Transcripción YY1/metabolismoRESUMEN
The Akt/protein kinase B serine/threonine kinase is a downstream effector of phosphoinositide 3-kinase (PI3K). Akt is an important component of mitogenic and antiapoptotic signaling pathways and is implicated in neoplastic transformation. Thyroid cells in culture retain a differentiated phenotype consisting of epithelial cell morphology and the expression of several tissue-specific genes. The survival and proliferation of these cells depend on thyrotropin and a mixture of five additional hormones that includes insulin. The regulation of proliferation and the expression of the thyroid differentiation program are intimately connected processes. As a result, oncogenes that induce hormone-independent proliferation invariably impair the expression of the thyroid-specific differentiation markers. Given that thyrotropin and insulin stimulate Akt activation in thyroid cells, we set out to determine the effects of Akt on thyroid cell proliferation, survival, and differentiation. To this end, we expressed constitutively active myristylated Akt (myrAkt) in PC Cl 3 thyroid cells. The myrAkt-expressing cells continued to proliferate, even in the absence of hormones, and they were resistant to programmed cell death induced by starvation. These effects were paralleled by the induction of the G1 cyclins D3 and E and by the inhibition of induction of the proapoptotic Fas, Fas ligand, and BAD genes in starved cells. However, in marked contrast with several other oncogenes, myrAkt did not interfere with the expression of thyroid differentiation functions. These results unveil the existence of an Akt-triggered thyroid cell pathway that modulates proliferation and survival without affecting the expression of the thyroid cell differentiated phenotype.
Asunto(s)
Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/fisiología , Glándula Tiroides/citología , Animales , Apoptosis/genética , Proteínas Portadoras/metabolismo , División Celular/genética , Línea Celular , Supervivencia Celular/genética , Transformación Celular Neoplásica , Ciclina D3 , Ciclinas/metabolismo , Fragmentación del ADN , ADN Complementario/metabolismo , Proteína Ligando Fas , Etiquetado Corte-Fin in Situ , Glicoproteínas de Membrana/metabolismo , Fenotipo , Plásmidos , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-akt , Ratas , Ratas Endogámicas F344 , Transducción de Señal , Transfección , Proteína Letal Asociada a bcl , Receptor fas/metabolismoRESUMEN
We have isolated a rat thyroid cDNA encoding a novel rat receptor-type tyrosine phosphatase protein. This gene, on the basis of its homology to another tyrosine phosphatase, the recently isolated human DEP-1/HPTPeta, has been named r-PTPeta. In rat thyroid cells the r-PTPeta gene acts as a differentiation marker. Indeed, the block of thyroid cell differentiation induced by viral and cellular oncogenes is associated with the inhibition or marked reduction of the expression of this gene, and its expression is positively regulated by thyrotropin, the physiological stimulator of thyroid cell growth.