Regulation of TGF-beta the inner nuclear membrane protein MAN1, Ski and SnoN: A genomic approach to understand their functions. by Luis Daniel Estevez Salmeron

ISBN: 9781109097986

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NOOKstudy eTextbook

144 pages


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Regulation of TGF-beta  by  the inner nuclear membrane protein MAN1, Ski and SnoN: A genomic approach to understand their functions. by Luis Daniel Estevez Salmeron

Regulation of TGF-beta by the inner nuclear membrane protein MAN1, Ski and SnoN: A genomic approach to understand their functions. by Luis Daniel Estevez Salmeron
| NOOKstudy eTextbook | PDF, EPUB, FB2, DjVu, AUDIO, mp3, ZIP | 144 pages | ISBN: 9781109097986 | 8.56 Mb

TGF-beta signaling plays a prominent role in the regulation of embryonic patterning, organ development, adult tissue homeostasis, and immune regulation in metazoans. The canonical pathway is activated when TGF-beta superfamily ligands bind to theirMoreTGF-beta signaling plays a prominent role in the regulation of embryonic patterning, organ development, adult tissue homeostasis, and immune regulation in metazoans.

The canonical pathway is activated when TGF-beta superfamily ligands bind to their receptors leading to the phosphorylation of the receptor activated Smads. The activated R-Smads oligomerize with co-Smad4 and translocate into the nucleus, leading to the activation or repression of TGF-beta responsive genes. The outcome of the pathway is determined by the interacting partners of this complex in the nucleus. This thesis has two major goals: first, to elucidate the role of the inner membrane protein MAN1 in the regulation of TGF-beta superfamily signaling- and second, to understand the genes regulated by Ski and Son, two important TGF-beta signaling repressors.-MAN1 is an inner nuclear membrane protein that was initially found to interact with Smad3 in pulldown experiments.

In Chapter 3, the interaction of MAN1 and Smad proteins is characterized and the function of this interaction assessed. MAN1 interacts with all R-Smads tested, but not co-Smad4 and this interaction is mediated by the RNA recognition motif of MAN1 and the C-terminus of R-Smads. MAN1 colocalizes with the R-Smads at the nuclear membrane and this interaction exerts a negative effect on TGF-beta superfamily signaling. Several experiments to investigate the mechanism by which MAN1 regulates TGF-beta signaling were performed. MAN1 was shown to be able to interfere with R-Smad phosphorylation estate, R-Smad-co-Smad interaction and nuclear translocation of the R-Smad-co-Smad4 complex.

Additionally, MAN1 was found to be an important negative regulator of the TGF-beta superfamily signaling.-MAN1 interaction with R-Smad leads to the dephosphorylation of the R-Smads. This helps explain why overexpression of MAN1 interferes with R-Smad-co-Smad interaction and with the localization of the R-Smads.

In Chapter 4, the possibility of MAN1 serving as a regulatory subunit of a protein phosphatase for the dephosphorylation of R-Smads was tested. MAN1 was shown to interact with the protein phosphatase 1 (PP1) and this interaction was shown to be affected by R-Smad binding to MAN1. The interaction of MAN1 and PP1 was characterized and the proteins were shown to colocalize at the nuclear periphery. Finally, it was shown that inhibition of PP1 leads to the accumulation of R-Smad at the nucleus and that PP1 can dephosphorylate Smad3 in vitro.-In chapter 5, a genomic approach was taken to study the genes regulated by Ski and SnoN.

Ski and SnoN are proto-oncoproteins that can cause oncogenic transformation and may also induce muscle differentiation. Ski and SnoN are important regulators of the TGF-beta superfamily signaling. Interestingly, the levels of these proteins have been shown to be elevated in tumors. In this chapter, a microarray approach was implemented to understand Ski and SnoN function in a cancer cell context both in the presence and absence of TGF-beta signaling activation.

Results from these analyses reveal that Ski and SnoN regulate different groups of genes, that their effects are cell-/tissue-specific and that in TGF-beta stimulated cells, they can affect the kinetics of the signaling response.



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