p73 shares many structural and functional similarities with its homologue, the p53 tumour suppressor. Many p73 protein isoforms result from both alternative splicing and differential promoter utilization. Transcriptionally active (TA) isoforms are pro-apoptotic, while N-terminally truncated (dN) variants are anti-apoptotic and act as dominant-negative inhibitors of TAp73 and p53. p73 has been shown to activate the transcription of genes involved in cell cycle arrest and apoptosis in response to DNA damaging agents, including chemotherapies. We hypothesize that the activity of p73, like many transcription factors, may be modulated by binding to regulatory proteins. A novel p73-binding protein that we have identified is special AT-rich sequence binding protein 2 (SATB2), which is a nuclear matrix attachment region (MAR)-binding protein. It has important functions in the regulation of gene transcription, neuronal and osteoblast (OB) differentiation, and craniofacial patterning. The SATB2 family member, SATB1, has been implicated in breast tumour growth and metastasis. Here, I describe the initial characterization of the p73-SATB2 interaction. SATB2 binds to and stabilizes TAp73a, leading to the enhancement of TAp73a-mediated induction of p53-upregulated modulator of apoptosis (PUMA; apoptotic gene) and p21 (cell cycle gene). Conversely, SATB2 does not bind to but decreases TAp73b levels, resulting in inhibition of TAp73b-mediated transcription. Thus, our findings reveal a role for SATB2 in the regulation of p73 stability and function. Moreover, we demonstrate that SATB2 is overexpressed in osteosarcoma (OS), while it is undetectable in other sarcomas, thereby suggesting that SATB2 may be a potential biomarker that can distinguish OS from other sarcomas. Loss of SATB2 also inhibits the migration and invasion capabilities of OS cells, and suggests that SATB2 promotes both migration and invasion in OS. Therefore, I present work showing that SATB2 is a novel p73-binding partner that differentially regulates the stability and function of the C-terminal isoforms of p73, as well as the novel involvement of SATB2 in OS invasion.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/35734 |
| Date | 24 July 2013 |
| Creators | Lau, Joanne |
| Contributors | Irwin, Meredith |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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