Date of Completion

5-6-2014

Embargo Period

11-1-2014

Keywords

TNIP1, HSP, heat shock protein, keratinocyte

Major Advisor

Brian J. Aneskievich

Associate Advisor

Theodore Rasmussen

Associate Advisor

Charlies Giardina

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

The TNFα-induced protein 3-interacting protein 1 (TNIP1) protein, a repressor of transcription factor activation or activity, has been linked to chronic inflammatory diseases, including psoriasis. However, TNIP1’s exact role is not yet been determined. To examine the genes and biological functions regulated by TNIP1, we overexpressed TNIP1 in cultured keratinocytes and performed a gene expression microarray analysis. Reduced expression of most genes was observed, including several heat shock proteins (HSP). However, its exact role in this process and the mechanism of the TNIP1-mediated transcriptional repression is not yet characterized.

We examined the TNIP1 repression of HSPA6 (also named HSP70B’) to model the repression on all HSPs. Since the transcriptional regulation of HSPA6 has not yet been fully characterized, we examined the factors contributing to its promoter activation. We found that a novel AP1 site and heat shock element upstream of previously recognized sites contribute to its basal and stress inducibility, respectively. To determine the mechanism of TNIP1’s repression on HSPA6, we hypothesized that TNIP1 acts on PPAR, RAR or NF-κB to reduce the expression of HSPs. We observed TNIP1 does not act through these transcription factors, but possibly through a novel, yet uncharacterized pathway. Additionally, we assessed the effect of TNIP1 on keratinocyte proliferation and differentiation. We found that a chronic, but not acute, overexpression of TNIP1 blocks keratinocyte cell growth to possibly through decreasing the HSP chaperone function.

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