PARK2 Coordinately Controls Cyclin D and Cyclin E

Cell-cycle progression is driven by a series of coordinated events that are tightly controlled by cyclin-dependent kinase (CDK) activity. Activation of CDKs is finely tuned by CDK inhibitor proteins and oscillating levels of their cognate cyclins, which are regulated at the level of protein stability. Disruption of these processes can lead to aberrant cell-cycle dynamics and is frequently observed in cancer. The G₁/S-phase transition is controlled by sequential activation of cyclin D–CDK4, cyclin D–CDK6 and cyclin E–CDK2. Degradation of cyclin D and cyclin E is mediated by SKP/cullin/F-box (SCF) E3 ubiquitin ligase complexes, but it is unclear how cyclin D and cyclin E stability is connected. In an analysis of almost 5,000 tumors across 11 tumor types, Gong and colleagues found that the PARK2 ubiquitin ligase gene is deleted or lost in 30% of tumors, with deletions occurring most often in serous ovarian, breast, and bladder carcinomas. Interestingly, PARK2 deletion was mutually exclusive with cyclin D1 (CCND1), cyclin E (CCNE1), and CDK4 amplifications, suggestive of functional redundancy. Consistent with this possibility, depletion of PARK2 stimulated cell proliferation, enhanced cyclin D–CDK activity, and increased cyclin D and cyclin E protein levels. Conversely, overexpression of wild-type PARK2, but not cancer-associated PARK2 mutants, led to decreased cyclin D and cyclin E levels in a proteasome- and SCF-dependent manner. PARK2 was found to associate with cullin-1 and F-box proteins as part of a previously uncharacterized class of SCF-like E3 ubiquitin ligase complexes; PARK2 synergized with F-box protein 4 (FBX4) to promote cyclin D degradation and cooperated with F-Box and WD repeat domain containing 7 (FBXW7) to target cyclin E for destruction. Together, these results increase our understanding of how cyclins are controlled and highlight a role for PARK2 loss in cell-cycle deregulation and oncogenesis.

Gong Y, Zack TI, Morris LG, Lin K, Hukkelhoven E, Raheja R, et al. Pan-cancer genetic analysis identifies PARK2 as a master regulator of G1/S cyclins. Nat Genet 2014 May 4 [Epub ahead of print].