Biomedical Sciences ETDs

Author

Brian Reinert

Publication Date

5-1-2010

Abstract

Ski and SnoN are two highly related transcription factors that are transcribed from two separate genes named SKI and SKIL, respectively. They are both co-repressors of the Smad-mediated transforming growth factor beta (TGFβ) signaling pathway. Originally they were classified as oncogenes as they have the ability to transform quail fibroblasts. However, they have also been found to have anti-proliferative properties so they are also considered tumor suppressors. They are involved in normal growth and development and thought to be essential as there is evidence that a homozygous mouse knockout of either SKI or SKIL is embryonic lethal. Both Ski and SnoN have been found to be overexpressed in some cancers. This overexpression has been found to be prognostic in some cases. Another prognostic factor in certain cancers is the cytoplasmic localization of these normally nuclear proteins. Other than with the TGFβ signaling pathway, Ski and SnoN are known to have interactions with retinoic acid receptor signaling and the retinoblastoma protein. In order to obtain a better understanding of Ski and SnoN we have studied several aspects of the proteins. First, we identified the nuclear localization signal (NLS) of Ski and proved that this sequence was both necessary and sufficient for nuclear localization. Next, we looked into the correlation of Ski subcellular location and serine phosphorylation status. Here we found that serine phosphorylated Ski is found predominately in the cytoplasm. Finally, we looked at possible involvement of Ski and SnoN in the pediatric cancer rhabdomyosarcoma (RMS). We found there was expression of both of these proteins in cell lines derived from the cancer and in tumor tissue samples. We also found that Ski protein levels in RMS tumor tissue are negatively correlated with RMS tumor group. The data from the Ski phosphorylation studies suggest that this modification may work with the NLS to regulate the subcellular location of Ski. Misregulation of this process may be responsible for the cytoplasmic localization of Ski that we found in RMS.

Keywords

Ski

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Bear, David

First Committee Member (Chair)

Larson, Richard

Second Committee Member

Winter, Stuart

Third Committee Member

Hartley, Rebecca

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