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.
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Acknowledgements
We thank E. Holland, A.C. Koff and J. Huse for helpful advice. S.T. was a recipient of a US National Institutes of Health T32 grant (5T32CA160001).This work was supported by the US National Institutes of Health (RO1 NS086875-01) (T.A.C.), the Memorial Sloan-Kettering Cancer Center Brain Tumor Center (T.A.C.), the Sontag Foundation (T.A.C.) and the Frederick Adler Fund (T.A.C.).
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T.A.C., Y.G., T.I.Z. and R.B. designed the experiments. Y.G., T.I.Z., K.L., I.-L.T., S.T., S.V., S.M., A.V., S.E.S. and P.P. performed the experiments. Y.G., T.A.C., R.B., T.I.Z. and L.G.T.M. analyzed the data. E.H. and R.R. contributed new reagents. T.A.C., Y.G., T.I.Z. and R.B. wrote the manuscript.
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Integrated supplementary information
Supplementary Figure 1 Examples of PARK2 locus profiles from distinct cancer lineages.
Copy number data from TCGA. Representative types of malignancy are shown. SCNA profiles of chromosome 6 (left) and a 5-Mb region surrounding PARK2 (right) are shown in the three lineages that had the highest frequency of PARK2 deletions: ovarian cancer (a), breast cancer (b) and bladder cancer (c).
Supplementary Figure 2 PARK2 regulates cell cycle progression.
FACS data from three cell lines as indicated. Cells were transfected with scrambled siRNA control or with PARK2 siRNAs. DNA content and BrdU incorporation were measured after PARK2 knockdown. Representative results are shown from triplicate experiments.
Supplementary Figure 3 PARK2 knockdown results in alterations in gene expression.
The indicated cells were treated with scrambled siRNA or with PARK2 siRNA as shown. The heat map shows the top 50 genes with increased expression.
Supplementary Figure 4 Pathway analyses of 2,698 genes differentially expressed across 2 cell lines transfected with PARK2 siRNAs.
Significant enrichment is shown in transcriptional programs governing cell growth, proliferation, protein ubiquitination and cell cycle control.
Supplementary Figure 5 Gene expression does not change for cyclin D1 and cyclin E1 after PARK2 knockdown.
Two independent PARK2 siRNAs were used. Experiments were repeated five times. Error bars, 1 s.d. NS, not significant.
Supplementary Figure 6 PARK2 knockdown causes accumulation of cyclin D2 and cyclin D3.
T202 cells were transfected with scrambled siRNA control or with PARK2 siRNAs, and protein blots were performed with antibodies specific for each cyclin type as indicated. Representative results are shown from triplicate experiments.
Supplementary Figure 7 Immunoprecipitation assays show binding of wild-type PARK2 to endogenous cyclin D2 and cyclin D3.
HEK 293T cells were transfected with either vector only (pcDNA3.1) or with vector encoding wild-type PARK2. Assays were performed as described in the Online Methods.
Supplementary Figure 8 Patterns of genetic alteration of FBXW7 and PARK2 in colorectal cancer.
In colorectal cancer, FBXW7 is primarily mutated, whereas PARK2 is deleted and mutated. Shown are data from The Cancer Genome Atlas Project (http://www.cbioportal.org/public-portal/). Point mutations are noted in green, and deletions are noted in blue. Percentages denote total numbers of tumors with alterations in the gene. p, not significant.
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Supplementary Text and Figures
Supplementary Figures 1–8 and Supplementary Tables 1, 2 and 5 (PDF 1314 kb)
Supplementary Table 3
Gene expression changes after PARK2 knockdown. (XLS 654 kb)
Supplementary Table 4
Pathway analyses, based on genes differentially expressed after PARK2 knockdown. (XLSX 22 kb)
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Gong, Y., Zack, T., Morris, L. et al. Pan-cancer genetic analysis identifies PARK2 as a master regulator of G1/S cyclins. Nat Genet 46, 588–594 (2014). https://doi.org/10.1038/ng.2981
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DOI: https://doi.org/10.1038/ng.2981
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