Degradation of AMPK by a cancer-specific ubiquitin ligase.

Cell 2015 Feb;160(4):715-728

Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Departments of Pharmacology and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

AMP-activated protein kinase (AMPK) is a master sensor and regulator of cellular energy status. Upon metabolic stress, AMPK suppresses anabolic and promotes catabolic processes to regain energy homeostasis. Cancer cells can occasionally suppress the growth-restrictive AMPK pathway by mutation of an upstream regulatory kinase. Here, we describe a widespread mechanism to suppress AMPK through its ubiquitination and degradation by the cancer-specific MAGE-A3/6-TRIM28 ubiquitin ligase. MAGE-A3 and MAGE-A6 are highly similar proteins normally expressed only in the male germline but frequently re-activated in human cancers. MAGE-A3/6 are necessary for cancer cell viability and are sufficient to drive tumorigenic properties of non-cancerous cells. Screening for targets of MAGE-A3/6-TRIM28 revealed that it ubiquitinates and degrades AMPKα1. This leads to inhibition of autophagy, activation of mTOR signaling, and hypersensitization to AMPK agonists, such as metformin. These findings elucidate a germline mechanism commonly hijacked in cancer to suppress AMPK.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2015.01.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629913PMC
February 2015
25 Reads

Publication Analysis

Top Keywords

suppress ampk
8
ubiquitin ligase
8
ampk
6
ampk ubiquitination
4
mage-a6 highly
4
widespread mechanism
4
ubiquitination degradation
4
mechanism suppress
4
degradation cancer-specific
4
ligase mage-a3
4
inhibition autophagy
4
mage-a3/6-trim28 ubiquitin
4
cancer-specific mage-a3/6-trim28
4
describe widespread
4
mage-a3 mage-a6
4
autophagy activation
4
ampk pathway
4
cells screening
4
growth-restrictive ampk
4
suppress growth-restrictive
4

Similar Publications