Identifying a role for the scaffolding protein IQGAP1 in liver health and disease

Erickson, Hanna Lynne

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https://hdl.handle.net/2142/105795 Copy

Description

Title

Identifying a role for the scaffolding protein IQGAP1 in liver health and disease

Author(s)

Erickson, Hanna Lynne

Issue Date

2019-07-09

Director of Research (if dissertation) or Advisor (if thesis)

Anakk, Sayeepriyadarshini

Doctoral Committee Chair(s)

Anakk, Sayeepriyadarshini

Committee Member(s)

• Katzenellenbogen, Benita
• Nelson, Erik
• Shapiro, David

Department of Study

Molecular & Integrative Physl

Discipline

Molecular & Integrative Physi

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Liver disease
• scaffolding protein

Abstract

Chronic liver diseases contribute to approximately 4% of deaths worldwide. The high mortality associated with liver disease is partially due to 1) difficulty diagnosing liver disease until a later stage and 2) difficulty treating liver disease once diagnosed. Therefore, there is an urgent need to better understand the biological mechanisms underlying liver disease. This dissertation is focused on understanding the role of the scaffolding protein IQ motif-containing GTPase-Activating Protein 1 (IQGAP1), an evolutionarily conserved scaffolding protein that is frequently up-regulated in liver disease, in the liver’s response to nutritional and cholestatic stress as well as in liver tumorigenesis. In chapter 2, I review how IQGAP1’s complex structure relates to its dynamic function in cells. In chapter 3, I show that hepatic IQGAP1 expression is increased after a 24-hour fast and that deletion of IQGAP1 blunts the ketogenic response to fasting and ketogenic diet feeding, which is associated with impaired PPARα activation and hyperactive mTORC1 signaling. Furthermore, in chapter 4 I show that IQGAP1 is upregulated at a transcriptional level by bile acid signaling and its deletion results in increased toxin-induced liver injury and bile acid accumulation. E-cadherin, which is important for maintaining adherens junctions, has reduced expression in the absence of IQGAP1, suggesting that IQGAP1 may protect against liver injury by stabilizing E-cadherin and maintaining bile canaliculi integrity. Lastly, in chapter 5 I show that both overexpression and deletion of IQGAP1 can result in increased tumor burden. In these tumors, overexpression of IQGAP1 was associated with increased β-catenin activation while deletion of IQGAP1 increased cell proliferation and MET activation. Together, these results show that while IQGAP1 normally has low expression in the liver of adult mice, its expression increases in response to physiological stresses to maintain nutrient availability and protect against excess damage. However, in the long-term, both too much and too little IQGAP1 can have negative consequences on tumor burden.

Graduation Semester

2019-08

Type of Resource

text

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Copyright and License Information

Copyright 2019 Hanna Erickson

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