1. Inicio
  2. Atrás
Título: Molecular mechanisms and signaling pathways induced by TGF [beta] for transcriptional repression of target genes
Autores: Lacerte, Annie.
Fecha: 2006
Publicador: McGill University - MCGILL
Fuente:
Tipo: Electronic Thesis or Dissertation
Tema: Biology, Molecular.
Descripción: Signaling by growth factors from the TGFbeta/activin has a profound impact on cancer development. They can either negatively regulate tumor development by their ability to inhibit cell growth, induce apoptosis and limit the number of cell divisions through inhibition of telomerase activity, or positively promote cancer through the induction of angiogenesis, epithelial to mesenchymal transition, and the suppression of the immune response. These ligands bind to serine-threonine kinase receptors that phosphorylate the Smad proteins: Smad2 and Smad3. Once phosphorylated, Smad2/3 cooperate with Smad4 to activate or repress expression of TGFbeta and activin target genes. It is the combined expression/repression of the numerous target genes that determine the physiological outcome of TGFbeta and activin signaling. In this thesis, we have characterized the molecular mechanisms by which TGFbeta and activin repress two target genes that are often overexpressed in human tumors. First, we studied the inhibitory effects of TGFbeta/activin on cell growth and prolactin (PRL) production in pituitary lactotroph tumor cells, as prolactinomas are tumors that secrete large amounts of PRL, causing endocrine and reproductive disorders. We showed that activin represses PRL expression through the Smad pathway and the tumor suppressor menin by downregulating the expression of Pit-1, a pituitary transcription factor essential for PRL expression. Second, we wanted to understand how TGFbeta inhibits hTERT gene expression, the gene encoding for the protein component of telomerase. In 90% of cancers, telomerase is reactivated through the induction of hTERT, allowing cancer cells to become immortal. Using the keratinocyte HaCaT cell line, we showed that TGFbeta rapidly increased E2F-1 expression, through the Smad pathway, Erk and p38 kinases. We identify four binding sites for E2F as critical for hTERT inhibition by TGFbeta. Moreover, interfering with E2F activity also abolishes hTERT inhibition by TGFbeta. These data identify E2F-1 as the intermediate factor required by TGFbeta to repress hTERT expression. Understanding the mechanisms used by TGFbeta and activin to regulate their target genes is important to improve our basic knowledge on how cancers progress. More importantly, it can create new avenues for cancer therapy development.
Idioma: en