Placental transforming growth factor beta: Regulation byp53 and downstream target genes.
Published: 2005
Language: eng
Number of pages: 218
Description: This thesis explores the DNA transcriptional regulatory elements involved in the response of P&barbelow;lacental T&barbelow;ransforming G&barbelow;rowth F&barbelow;actor beta (PTGF-beta) to p53-dependent DNA damage signals, and examines alterations in gene expression brought about by elevated levels of PTGF-beta that contribute to its downstream effects on human tumour cells. Previous work has shown that expression of PTGF-beta, a divergent member of the T&barbelow;ransforming G&barbelow;rowth F&barbelow;actor-beta (TGF-beta) superfamily, is upregulated after DNA damage in human breast cancer cells largely via p53. In studies presented here, a search for  cis-acting regulatory elements between +49 and -966 bp led to the identification of two functional p53-binding sites, denoted p53-1 (+29 bp) and p53-2 (-850 bp), and a novel p53 suppressor element, denoted the p53 T&barbelow;ranscriptional R&barbelow;epressor E&barbelow;lement (p53TRE: -242 bp), that down-regulates the response to p53 (Chapter 2). These analyses were extended to include an additional 7 451 bp of PTGF-beta genomic sequence upstream of -966 bp. Two additional p53-binding sites, designated p53-6 (-7 562 bp) and p53-7 (-8 318 bp), were identified that interact synergistically with sites p53-1 and p53-2 to augment the transcriptional response to p53 (Chapter 3). Consistent with its role as a downstream effector of p53, elevated levels of PTGF-beta protein were shown to reduce tumour cell growth and viability. However, similar to TGF-beta, PTGF-beta was subsequently shown to suppress tumour growth in some cases, and contribute to malignant progression in others. Studies presented here explore changes in gene expression associated with elevated levels of PTGF-beta in human breast and prostate cancer cells (Chapter 4). Microarray studies are described that identify nine genes that are upregulated in both cell types. The anti- and pro-oncogenic effects associated with two of these genes---the receptor kinase, c-kit, and the transcription factor, ELL---may contribute to the dual nature of PTGF-beta action in human tumours. Findings presented in this thesis (1) clearly define the mechanisms by which p53 regulates PTGF-beta transcription and (2) provide a molecular basis for the downstream consequences of PTGF-beta signaling.
Notes: Thesis (Ph.D.)--University of Toronto, 2005.

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Source: Dissertation Abstracts International, Volume: 66-06, Section: B, page: 2976.