Date of Award

2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Youhai H. Chen

Second Advisor

Xiaolu Yang

Abstract

TIPE2 is a recently discovered regulator of immunity and inflammation. Here we describe a new function of TIPE2 in the regulation of Ras signaling and Tumorigenesis. By using various stimuli and inhibitors in T Cells and macrophages we discovered that TIPE2 is regulated at both the message and protein level by inflammatory stimuli. TIPE2 mRNA is regulated in the short to intermediate term by an NF-Kappa B induced micro RNA, and TIPE2 is also ubiquitylated and degraded, possibly by SCF-Beta TRCP. Mechanistically TIPE2 interacts with and inhibits the Ras-interacting domain of the RalGDS family of Ras effectors, leading to a loss of downstream Ral and AKT activity. TIPE2 deficiency led to increased activation of Ral and AKT, resulting in resistance to cell death, increased migration, and dysregulated exocyst complex formation. Overexpression of TIPE2 conversely induced cell death, affected actin polymerization, and reduced exocyst complex assembly. TIPE2 was able to dramatically slow the growth of Ras-induced tumors in mice, and the tumors were required to silence TIPE2 before they were licensed to grow. TIPE2 additionally negatively regulates effectors of the mTOR pathway, including S6K and 4EBP1, possibly via an interaction with, and destabilization of the mTORC2 complex. Crucially TIPE2 expression is either completely lost or heavily down-regulated by human hepatocellular carcinoma. Thus, via its simultaneous role as a regulator of inflammation and cancer, TIPE2 provides a mechanistic link between these two disease states, and may be a potential drug target for both inflammatory and neoplastic disease.

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