Tubedown in neuroblastic tumors

Martin, Darryl (2009) Tubedown in neuroblastic tumors. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Tubedown (Tbdn), a developmentally regulated gene, is a subunit of the N-terminal acetyltransferase Arrest Defective-1 (Ardl) complex that is conserved from yeast to human. The role of the Tbdn gene product was examined in the development and progression of pediatric neuroblastic tumors (ganglioneuroma, ganglioneuroblastoma, and neuroblastoma) that result from a blockage during normal sympathetic development. -- Currently, very few markers have been proven useful to distinguish the various states of neuroblastic differentiation. Therefore, the use of a neuroblastic tissue microarray was essential in determining the importance of Tbdn expression as a novel biomarker. High levels of Tbdn expression correlated with advanced tumor stages (stage 3 and 4), high-risk group status, unfavorable histology, and poor outcome. -- In addition, the functional relationship between the NatA complex (Tbdn and Ardl) and the MycN gene product was investigated. MYCN gene amplification strongly correlates with advanced tumor stage and treatment failure. Although, MYCN gene amplification usually results in high MycN mRNA and protein expression there are subsets of neuroblastomas that have high MycN expression without MYCN gene amplification. I have demonstrated a co-regulation between Tbdn, Ardl, and MycN, using an in vitro human neuroblastoma LA-N-5 cell model. Subsequently, a conditional in vitro MycN-inducible system demonstrated an over-expression of MycN that resulted in increased expression of both Tbdn and Ardl. These results suggested that MycN may regulate the NatA complex. Promoter region analysis of TBDN and ARD1 revealed a MycN consensus binding site within the TBDN promoter region, indicating a possible direct target for MycN. However, no MycN consensus sequence was detected within the ARD1 promoter. The binding of MycN to TBDN was confirmed by chromatin immunoprecipitation potentially providing a mechanistic role for poor outcome in neuroblastoma. Finding functional links between MycN and TBDN will provide further validation for Tbdn as a novel biomarker that may possibly be used in diagnosis and/or prognosis.

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