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GTPBP1 regulates TGF-beta signaling as a co-factor of inhibitory Smads and is essential for embryo development

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dc.contributor.advisor Thomsen, Gerald H en_US
dc.contributor.advisor Sirotkin, Howard I en_US
dc.contributor.author KI, DONG HYUK en_US
dc.contributor.other Department of Molecular and Cellular Biology. en_US
dc.date.accessioned 2017-09-20T16:50:25Z
dc.date.available 2017-09-20T16:50:25Z
dc.date.issued 2015-08-01
dc.identifier.uri http://hdl.handle.net/11401/76492 en_US
dc.description 117 pg. en_US
dc.description.abstract The Transforming Growth Factor Beta (TGF-beta) superfamily of signaling factors regulates various biological processes such as cell growth, survival, differentiation, and development. In early embryonic development, TGF-beta signaling tightly regulates mesodermal induction. Disregulation of TGF-beta superfamily members is implicated in a number of human diseases, including many cancers and heart disease. However, many TGF-beta signaling functions are still undiscovered. Here, I introduce one of the large GTPase family members, GTP Binding Protein 1 (GTPBP1) as a novel regulator of TGF-beta signaling. GTPBP1 is highly conserved across many species, but its function is not fully understood. Interestingly, GTPBP1 interacts with inhibitory Smads (Smad6 and Smad7), which are negative regulators of TGF-beta signaling, rather than receptor Smads. Signaling assays using animal cap explants show that both BMP and Activin/Nodal signaling are increased when GTPBP1 is inhibited with morpholino oligos. Additionally, in animal caps, knockdown of GTPBP1 allows BMP signaling to occur in the presence of overexpressed Smad6, indicating that GTPBP1 is required for Smad6 function. GTPBP1 mRNA is maternal and dynamically expressed during Xenopus development. It is expressed in the head, eyes, somite, notochord, neural tube and neural crest, which are organs that originate from the mesoderm and the ectoderm. GTPBP1 is also required for normal embryonic development, as GTPBP1 knockdown results in ventralized embryos. Although GTPBP1 is necessary for Smad6 to repress BMP signaling, it is still unclear how this is achieved at a mechanistic level. To begin to address this issue, protein interaction analysis was performed using deletion mutants of GTPBP1 and Smad6. Results show that the Smad6 MH2 domain interacts with regions at both the N-terminal GTPase domain and C-terminal domain III of GTPBP1. The present work provides novel insight into the function of GTPBP1, and creates a foundation for investigating the details of its embryonic functions and signaling mechanisms. en_US
dc.description.sponsorship This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. en_US
dc.format Monograph en_US
dc.format.medium Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Developmental biology en_US
dc.subject.other BMP, GTPBP1, Smad6, Xenopus en_US
dc.title GTPBP1 regulates TGF-beta signaling as a co-factor of inhibitory Smads and is essential for embryo development en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US
dc.contributor.committeemember Karzai, A. Wali en_US
dc.contributor.committeemember Takemaru, Ken-Ichi en_US
dc.contributor.committeemember Weinstein, Daniel. en_US


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