Date of Graduation

5-2016

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Hui-Kuan Lin

Committee Member

Shiaw-Yih Lin

Committee Member

Gary E. Gallick

Committee Member

Jianping Jin

Committee Member

Angabin Matin

Abstract

AMPK plays a central role in controlling cellular and whole body energy level. Increasing studies have also discovered the diverse function of AMPK in cancer, such as autophagy and mitochondria biogenesis. However, how AMPK promotes cancer progression is still not clear. Here, we show that AMPK is essential for EGF-induced Akt activation, Glut1 expression, and glucose uptake. AMPK is also required for various stresses induced Akt activation and promote cell survival, including hypoxia and glucose deprivation. In addition, we found glucose deprivation-induced VEGF expression and secretion is also depend on AMPK, which may contribute to angiogenesis of surrounding endothelial cell in the tumor microenvironment. We also discovered that AMPK directly phosphorylates Skp2 at S256 residue and this phosphorylation is essential for Skp2 SCF complex integrity and E3 ligase activity to ubiquitinate Akt, which is critical for Akt activation. Also, Skp2 S256 phosphorylation can be induced by many stress and EGF. The phosphorylation status is necessary for breast cancer tumor progression and correlated with poor survival of breast cancer patient.

Keywords

Ubiquitination, AMPK, Akt, Skp2, breast cancer, stress

Available for download on Tuesday, May 02, 2017

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