Pan-cancer genetic analysis identifies PARK2 as a master regulator of G1/S cyclins

Abstract

Coordinate control of different classes of cyclins is fundamentally important for cell cycle regulation and tumor suppression, yet the underlying mechanisms are incompletely understood. Here we show that the PARK2 tumor suppressor mediates this coordination. The PARK2 E3 ubiquitin ligase coordinately controls the stability of both cyclin D and cyclin E. Analysis of approximately 5,000 tumor genomes shows that PARK2 is a very frequently deleted gene in human cancer and uncovers a striking pattern of mutual exclusivity between PARK2 deletion and amplification of CCND1, CCNE1 or CDK4—implicating these genes in a common pathway. Inactivation of PARK2 results in the accumulation of cyclin D and acceleration of cell cycle progression. Furthermore, PARK2 is a component of a new class of cullin-RING-containing ubiquitin ligases targeting both cyclin D and cyclin E for degradation. Thus, PARK2 regulates cyclin-CDK complexes, as does the CDK inhibitor p16, but acts as a master regulator of the stability of G1/S cyclins.

Mitophagy: In sickness and in health

“…3 Notably, the human Parkin gene, PARK2, maps to a chromosome 6 site that is commonly deleted in several types of cancer. 4 In C. elegans, inhibition of mitophagy increases mitochondrial mass, uncouples respiration from ATP production, enhances mitochondrial ROS production and raises cytoplasmic calcium levels. These phenotypes are commonly observed in aged animals, across large evolutionary distance.…”

Pathologic and therapeutic implications for the cell biology of parkin

“…Parkin was thought to act as a tumor-suppressor gene because of its location in chromosome 6, implicated as a hotspot in several human cancers (Garber 2010), and deletions in the PARK2 locus and parkin mutations were found in a wide variety of tumors (Cesari, Martin et al 2003, Veeriah, Taylor et al 2010). Recently, a vast study of about 5000 tumors showed that deletions in parkin were the most commonly occurring deletions, comprising of almost 30% of all tumors studied (Bartek and Hodny 2014, Gong, Zack et al 2014). On the surface, these results do seem counterintuitive to the anti-apoptotic and mitochondrial quality control functions of parkin.…”

Parkin induces G2/M cell cycle arrest in TNF-α-treated HeLa cells

“…However, the role of parkin in cell cycle regulation was not examined in our previous study. Recently, several reports have suggested that parkin is implicated in cell cycle control [5,23]. Parkin ubiquitinates cyclin D and cyclin E, resulting in proteasome-mediated degradation with subsequent cell cycle arrest in colon cancer, glioma and human embryonic kidney cell lines.…”