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Deregulation of Carg-Box Binding Factor-A Contributes to Carcinogenesis

by
Jennifer Tracy Barrett
B.S., Ohio University - 2002

Thesis Advisor: Helmut Zarbl, Ph.D.
Graduate Program in Toxicology

EOHSI Conference Room C
Piscataway

Thursday, September 3, 2015
9:00 a.m.


Abstract

CArG-box binding factor-A (CBF-A) is a member of the heterogeneous nuclear ribonucleoprotein (hnRNPs) family of RNA-binding proteins that are involved in the multiple stages of mRNA metabolism, including transcription, splicing, trafficking, transport and protection of RNA, and translation. hnRNPs are also known to be involved in telomere maintenance, chromatin remodeling, and DNA repair. Since hnRNPs are involved in many aspects of gene regulation, alterations in their function contribute to the pathogenesis of numerous diseases in various cell types. CBF-A is overexpressed in multiple tumor types and is also a key regulator of epithelial-mesenchymal transition (EMT), an important process in cancer progression. CBF-A has two highly conserved isoforms that have opposing effects on promoter activity, suggesting that the ratio of the protein isoforms play a critical role in carcinogenesis. Previously we showed that CBF-A regulated the expression of the Hras oncogene by binding to enhancer elements (ets-like) in the promoter region. It has been shown that CBF-A is a transcriptional inhibitor of osteopontin (OPN), which is implicated in tumor invasion, progression or metastasis in cancer originating in many tissues due to its interaction with cell surface receptors, growth factor/receptor pathways, and proteases. To evaluate the role of CBF-A in carcinogenesis, we generated knock-out mice and then exposed wild-type mice, as well as CBF-A null and heterozygous mice to a single dose of the mutagenic, DNA-alkylating agent N-ethyl-N-nitrosurea (ENU) (10 mg/mL, 9-10 weeks of age). While administration of ENU-decreased the survival rate in all genotypes and sex compared to vehicle control mice, vehicle control
CBF-A null mice had a decreased survival rate compared to the wild-type male mice. CBF-A null mice exposed to ENU had an increased incidence of tumors and decreased latency compared to the wild-type ENU exposed mice. Evaluation of the ENU-induced tumors found in both wild-type and CBF-A null mice resulted in an increase in the expression of OPN in the tumors of CBF-A null mice compared to those in the wild-type mice. Taken in concert, these data suggest CBF-A plays an important role in maintaining normal growth control. In turn, this information provides insight into a mechanism by which deregulation of CBF-A contributes to tumorigenesis.


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