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

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.

The ability of TRIM3 to induce growth arrest depends on RING-dependent E3 ligase activity.

Mutation of the TRIM (tripartite motif)-NHL family members brat and mei-P26 perturb the differentiation of transit-amplifying progenitor cells resulting in tumour-like phenotypes. The NHL (named after the NCL1, HT2A and LIN41 repeat) domain is essential for their growth suppressive activity, and they can induce cell-cycle exit in a RING-independent manner. TRIM3 is the only bona fide tumour suppressor in the mammalian TRIM-NHL subfamily and similar to the other members of this family, its ability to inhibit cell proliferation depends on the NHL domain. However, whether the RING domain was required for TRIM3-dependent cell-cycle exit had not been investigated. In the present study, we establish that the RING domain is required for TRIM3-induced growth suppression. Furthermore, we show that this domain is necessary to promote ubiquitination of p21 in a reconstituted in vitro system where UbcH5a is the preferred E2. Thus the ability of TRIM3 to suppress growth is associated with its ability to ubiquitinate proteins.

Tyrosine phosphorylation of the p21 cyclin-dependent kinase inhibitor facilitates the development of proneural glioma.

Phosphorylation of Tyr-88/Tyr-89 in the 3(10) helix of p27 reduces its cyclin-dependent kinase (CDK) inhibitory activity. This modification does not affect the interaction of p27 with cyclin-CDK complexes but does interfere with van der Waals and hydrogen bond contacts between p27 and amino acids in the catalytic cleft of the CDK. Thus, it had been suggested that phosphorylation of this site could switch the tumor-suppressive CDK inhibitory activity to an oncogenic activity. Here, we examined this hypothesis in the RCAS-PDGF-HA/nestin-TvA proneural glioma mouse model, in which p21 facilitates accumulation of nuclear cyclin D1-CDK4 and promotes tumor development. In these tumor cells, approximately one-third of the p21 is phosphorylated at Tyr-76 in the 3(10) helix. Mutation of this residue to glutamate reduced inhibitory activity in vitro. Mutation of this residue to phenylalanine reduced the tumor-promoting activity of p21 in the animal model, whereas glutamate or alanine substitution allowed tumor formation. Consequently, we conclude that tyrosine phosphorylation contributes to the conversion of CDK inhibitors from tumor-suppressive roles to oncogenic roles.