Oncotarget

Priority Research Papers:

Loss of p16INK4A stimulates aberrant mitochondrial biogenesis through a CDK4/Rb-independent pathway

Ethika Tyagi, Bin Liu, Chelsea Li, Tong Liu, Jared Rutter and Douglas Grossman _

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Oncotarget. 2017; 8:55848-55862. https://doi.org/10.18632/oncotarget.19862

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Abstract

Ethika Tyagi1,*, Bin Liu1,*, Chelsea Li1, Tong Liu1, Jared Rutter3,4 and Douglas Grossman1,2

1 The Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake, Utah, USA

2 The Department of Dermatology, University of Utah Health Sciences Center, Salt Lake, Utah, USA

3 The Department of Biochemistry, University of Utah Health Sciences Center, Salt Lake, Utah, USA

4 The Howard Hughes Medical Institute, University of Utah Health Sciences Center, Salt Lake, Utah, USA

* These authors have contributed equally to this work

Correspondence to:

Douglas Grossman, email:

Keywords: p16, mitochondria, CDK4, migration, fibroblast

Received: May 24, 2017 Accepted: July 09, 2017 Published: August 03, 2017

Abstract

The tumor suppressor p16INK4A (p16) inhibits cell cycle progression through the CDK4/Rb pathway. We have previously shown that p16 regulates cellular oxidative stress, independent of its role in cell cycle control. We investigated whether loss of p16 had a direct impact on the mitochondria. We found that p16-null primary mouse fibroblasts (PMFs) displayed increased mitochondrial mass and expression of mitochondrial respiratory subunit proteins compared to wild-type (WT) PMFs. These findings in p16-null PMFs were associated with increased expression of the mitochondrial biogenesis transcription factors PRC and TFAM. On the other hand, p16-deficient PMFs demonstrated reduced mitochondrial respiration capacity consistent with electron microscopy findings showing that mitochondria in p16-deficient PMFs have abnormal morphology. Consistent with increased mitochondrial mass and reduced respiratory capacity, p16-deficient PMFs generated increased mitochondrial superoxide. One biological consequence of elevated ROS in p16-deficient PMFs was enhanced migration, which was reduced by the ROS scavenger N-acetylcysteine. Finally, p16-deficient PMFs displayed increased mitochondrial membrane potential, which was also required for their enhanced migration. The mitochondrial and migration phenotype was restored in p16-deficient PMFs by forced expression of p16. Similarly, over-expression of p16 in human melanocytes and A375 melanoma cells led to decreased expression of some mitochondrial respiratory proteins, enhanced respiration, and decreased migration. Inhibition of Rb phosphorylation in melanocytes and melanoma cells, either by addition of chemical CDK4 inhibitors or RNAi-mediated knockdown of CDK4, did not mimic the effects of p16 loss. These results suggest that p16 regulates mitochondrial biogenesis and function, which is independent of the canonical CDK4/Rb pathway.


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