Date of Award

2011

Document Type

Campus Access Dissertation

Department

Biological Sciences

First Advisor

DAN A DIXON

Abstract

Messenger RNA decay is a critical mechanism to control the expression of many inflammation- and cancer-associated genes. These transcripts are targeted for rapid degradation through AU-rich element (ARE) motifs present in the mRNA 3' untranslated region (3'UTR). Tristetraprolin (TTP) is an RNA-binding protein that plays a significant role in regulating the expression of ARE-containing mRNAs. Through its ability to bind AREs and target the bound mRNA for rapid degradation, TTP can limit the expression of a number of critical genes frequently overexpressed in inflammation and cancer. For this reason, loss of TTP expression is a consistent feature associated with many human malignancies that serves as a critical mechanism for allowing overexpression of oncogenic transcripts.

In chapter I, we demonstrate that TTP expression is lost in cervical cancer, and ectopic expression of TTP acts in an anti-proliferative capacity in cervical cancer cells through p53 stabilization and telomerase inhibition leading to cellular senescence. This growth-suppressive phenotype is the functional consequence of TTP's ability to promote rapid ARE-mRNA decay of the cellular ubiquitin ligase E6-AP, which is a key player in human papillomavirus (HPV)-mediated cellular transformation and tumorigenesis.

In Chapter II we describe that loss of TTP is observed during early stages of human colon carcinogenesis and TTP expression in colon cancer cell model dramatically inhibits cell growth and tumorigenecity. We show that the anti-tumor effects of TTP expression in colon cancer cells are, at least in part, a result of delayed cell cycle progression and an increase in cellular doubling time.

Finally, we demonstrate in Chapter III that apparent lack of TTP in colon cancer is attributable to epigenetic control of gene expression via chromatin remodeling, and treatment with histone deacetylase (HDAC) inhibitors relieves this repression leading to activation of TTP expression. Taken together, our novel findings provide strong evidence for the protective role of TTP in cervical and intestinal epithelium that originates from its ability to control pathogenic expression of various ARE-mRNAs coding for growth and inflammation promoting factors. Conversely, loss of TTP expression as evidenced in tumors, promotes selective enrichment of oncogenic factors through aberrant mRNA stabilization and directly contributes to tumor development.

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