Pan-Cancer Analysis Links PARK2 to BCL-XL-Dependent Control of Apoptosis.

Abstract:

:Mutation of the PARK2 gene can promote both Parkinson's Disease and cancer, yet the underlying mechanisms of how PARK2 controls cellular physiology is incompletely understood. Here, we show that the PARK2 tumor suppressor controls the apoptotic regulator BCL-XL and modulates programmed cell death. Analysis of approximately 10,000 tumor genomes uncovers a striking pattern of mutual exclusivity between PARK2 genetic loss and amplification of BCL2L1, implicating these genes in a common pathway. PARK2 directly binds to and ubiquitinates BCL-XL. Inactivation of PARK2 leads to aberrant accumulation of BCL-XL both in vitro and in vivo, and cancer-specific mutations in PARK2 abrogate the ability of the ubiquitin E3 ligase to target BCL-XL for degradation. Furthermore, PARK2 modulates mitochondrial depolarization and apoptosis in a BCL-XL-dependent manner. Thus, like genes at the nodal points of growth arrest pathways such as p53, the PARK2 tumor suppressor is able to exert its antiproliferative effects by regulating both cell cycle progression and programmed cell death.

journal_name

Neoplasia

authors

Gong Y,Schumacher SE,Wu WH,Tang F,Beroukhim R,Chan TA

doi

10.1016/j.neo.2016.12.006

subject

Has Abstract

pub_date

2017-02-01 00:00:00

pages

75-83

issue

2

eissn

1522-8002

issn

1476-5586

pii

S1476-5586(16)30152-X

journal_volume

19

pub_type

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