This proposal investigates the hypothesis that the disintegration of activin anti-proliferation signaling pathways plays an important role in an pituitary tumorigenesis. Activin is a member of the transforming growth factor beta (TGFbeta) superfamily of cytokines. It has anti-proliferative effects in a variety of cell types. Activin signals are mediated by type I and type II serine/threonine kinase receptors. Several truncated activin type I receptors lacking the intact cytoplasmic kinase domains, generated by alternative RNA splicing, are found exclusively in human pituitary tumors. We propose that these truncated type I receptors may act as dominant negative receptors to interfere activin signaling and block activin anti- proliferative function in pituitary tumors. Firstly, we will investigate whether truncated type I activin receptor isoforms act in a dominant negative manner interfering with activin signaling. To achieve this, we will examine whether truncated type I receptor isoforms suppress activin-induced gene transcription. In addition, we will examine whether these truncated receptor isoforms assert their dominant negative effects by forming functionally inactive complexes with type II activin receptor. Secondly, we will investigate whether truncated activin receptor isoforms block activin anti- proliferation function. To achieve this we will examine expression of truncated receptor isoforms desensitizes cells to activin-induced growth arrest and cellular differentiation. Furthermore, we will investigate whether these truncated receptor isoforms block activin-induced growth arrest by inhibiting activin-induced activation of Rb protein. This proposed research is critical to understand how activin signaling pathway is involved in development of human pituitary tumors.
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| Zhou, Yunli; Mehta, Kshama R; Choi, Andrew P et al. (2003) DNA damage-induced inhibition of securin expression is mediated by p53. J Biol Chem 278:462-70 |
