A MYC-Driven Change in Mitochondrial Dynamics Limits YAP/TAZ Function in Mammary Epithelial Cells and Breast Cancer

Publication date: 14 December 2015
Source:Cancer Cell, Volume 28, Issue 6
Author(s): Björn von Eyss, Laura A. Jaenicke, Roderik M. Kortlever, Nadine Royla, Katrin E. Wiese, Sebastian Letschert, Leigh-Anne McDuffus, Markus Sauer, Andreas Rosenwald, Gerard I. Evan, Stefan Kempa, Martin Eilers
In several developmental lineages, an increase in MYC expression drives the transition from quiescent stem cells to transit-amplifying cells. We show that MYC activates a stereotypic transcriptional program of genes involved in cell growth in mammary epithelial cells. This change in gene expression indirectly inhibits the YAP/TAZ co-activators, which maintain the clonogenic potential of these cells. We identify a phospholipase of the mitochondrial outer membrane, PLD6, as the mediator of MYC activity. MYC-dependent growth strains cellular energy resources and stimulates AMP-activated kinase (AMPK). PLD6 alters mitochondrial fusion and fission dynamics downstream of MYC. This change activates AMPK, which in turn inhibits YAP/TAZ. Mouse models and human pathological data show that MYC enhances AMPK and suppresses YAP/TAZ activity in mammary tumors.

Graphical abstract

Teaser

Von Eyss et al. show that MYC induces PLD6 expression to promote mitochondrial fusion, leading to stimulation of AMPK. Activated AMPK then phosphorylates YAP to inhibit YAP/TAZ function. Both high MYC activity and elevated PLD6 expression correlate with poor prognosis of breast cancer patients.


from Cancer via ola Kala on Inoreader http://ift.tt/1Za6V7p
via IFTTT