The aim of this work was to investigate the role of TGFbeta family members in the induction of cell growth arrest and apoptosis in immune cell types. The TGFbeta superfamily is a large group of evolutionary conserved polypeptide growth factors, involved in different physiological processes. Any deregulation of the different components of the TGFbeta signaling pathway, has been largely implicated in multiple human critical disorders including cancer. Activin, originally isolated from gonadal fluid, and more recently described as an antiproliferative and proapoptotic factor in different cell types has been implicated in different immune functions. In particular, activin and TGFbeta play an important role in the haematopoietic tissue. They are critical death inducers in the immune system contributing to the elimination of different activated immune cell types. Control of immune cell proliferation, activation and subsequent elimination of activated cell populations by cell growth arrest and apoptosis are critical events for controlling infections and preventing autoimmune disease. However, very limited information about the downstream target genes and their signaling mechanism that relay on the inhibitory effects on cell growth by activin and TGFbeta ligands. Using a screen for genes that are differentially regulated by activin and TGFbeta in haematopoietic cells, we found that the phospholipids phosphatase SHIP-1 was strongly upregulated by activin and TGFbeta. Thus, we hypothesized that TGFbeta and activin induce cell growth arrest in immune cells through up-regulation of SHIP-1 with a significant and subsequent decrease in PtdIns 3,4,5-P3 levels affecting cell survival. Furthermore, we attempted to characterize the different intracellular signalling pathways downstream of these serine/threonine kinase receptors that lead to SHIP-1 overexpression as well as the transcription factors involved in the mediation of transcriptional regulation of the SHIP-1 gene promoter. / Chapter 1 provides a broad introduction to the field of TGFbeta signaling focusing on TGFbeta-induced apoptosis in immune cell types and the biology of inositol phosphatases involved in phospholipide metabolism, mainly focused on SHIP-1. Chapter 2 contains data demonstrating that the activin/TGFbeta-induced cell growth arrests and apoptosis through expression of SHIP-1. Data in chapter 3 proved evidences about the cross-talk between the Smad and JNK MAP kinase signalling pathways and their role in the transcriptional regulation of the SHIP-1 gene promoter. Finally, chapter 4, is focused on the discussion and the propose model of how activin/TGFbeta-induced SHIP-1 expression blocks induction of cell survival signals. As a dynamic cellular and molecular process the induction of SHIP-1 by TGFbeta ligands might be in co-association with other apoptosis molecules leading to cell growth arrest and apoptosis in different cell populations of the immune system.

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