PF-4708671 activates AMPK independently of p70S6K1 inhibition

Gilad W Vainer; Ann Saada; Juliane Kania-Almog; Adir Amartely; Jacob Bar-Tana; Rachel Hertz

doi:10.1371/journal.pone.0107364

PF-4708671 activates AMPK independently of p70S6K1 inhibition

PLoS One. 2014 Sep 9;9(9):e107364. doi: 10.1371/journal.pone.0107364. eCollection 2014.

Authors

Gilad W Vainer¹, Ann Saada², Juliane Kania-Almog¹, Adir Amartely³, Jacob Bar-Tana⁴, Rachel Hertz⁴

Affiliations

¹ Department of Pathology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
² Monique and Jacques Roboh Department of Genetic Research, and Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
³ Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
⁴ Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel.

Abstract

The P70 ribosomal protein S6 kinase 1 (P70S6K1) is activated by the mammalian target of rapamycin (mTORC1) and regulates proliferation, growth, and metabolism. PF-4708671 is a novel, cell-permeable, has been proposed to be a highly specific inhibitor of p70S6K1. It is used in micromolar concentration range to dissect signaling pathways downstream of mTORC1 and to study the function of p70S6K1. Here we show that PF-4708671 induces AMP-activated protein kinase (AMPK) phosphorylation and activation in immortalized mouse embryonic fibroblasts (MEF) independently of p70S6K1, due to specific inhibition of mitochondrial respiratory chain Complex I.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / metabolism*
Animals
Cells, Cultured
Fibroblasts / drug effects
Fibroblasts / metabolism
Imidazoles / pharmacology*
Mechanistic Target of Rapamycin Complex 1
Mice
Multiprotein Complexes / metabolism
Phosphorylation / drug effects
Piperazines / pharmacology*
Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors*
Ribosomal Protein S6 Kinases, 70-kDa / metabolism
Signal Transduction / drug effects
TOR Serine-Threonine Kinases / metabolism

Substances

Imidazoles
Multiprotein Complexes
PF-4708671
Piperazines
Mechanistic Target of Rapamycin Complex 1
Ribosomal Protein S6 Kinases, 70-kDa
TOR Serine-Threonine Kinases
AMP-Activated Protein Kinases

Grants and funding

This work was financed in part by the Tel-Aviv Sourasky Medical Center and Mr. Daniel Levin donation (GWV); the Israeli Ministry of Health grant #5938 (GWV); The Israeli Cancer Association (GWV); and Israeli Science Foundation (ISF) grant #1462 (AS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.