المؤلفون: Gong, Yongxing, Zack, Travis Ian, Morris, Luc G T, Lin, Kan, Hukkelhoven, Ellen, Raheja, Radhika, Tan, I-Li, Turcan, Sevin, Veeriah, Selvaraju, Meng, Shasha, Viale, Agnes, Schumacher, Steven E, Palmedo, Perry, Beroukhim, Rameen, Chan, Timothy A

المصدر: Nature Genetics; Jun2014, Vol. 46 Issue 6, p588-594, 7p, 4 Diagrams, 2 Graphs

مصطلحات موضوعية: CANCER genetics, TUMOR suppressor genes, TUMOR suppressor proteins, CANCER, GENOMICS, CYCLINS

مستخلص: 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. [ABSTRACT FROM AUTHOR]

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المؤلفون: Veeriah, Selvaraju¹, Brennan, Cameron², Shasha Meng¹, Singh, Bhuvanesh³, Fagin, James A.^1,4, Solit, David B.^1,4, Paty, Philip B.³, Rohle, Dan¹, Vivanco, Igor¹, Chmielecki, Juliann¹, Pao, William^1,4, Ladanyi, Marc^1,5, Gerald, William L.^1,5, Liau, Linda⁶, Cloughesy, Timothy C.⁶, Mischel, Paul S.⁶, Sander, Chris⁷, Taylor, Barry⁷, Schultz, Nikolaus⁷, Major, John⁷

المصدر: Proceedings of the National Academy of Sciences of the United States of America. 6/9/2009, Vol. 106 Issue 23, p9435-9440. 6p. 1 Chart, 3 Graphs.

مصطلحات موضوعية: *PROTEIN-tyrosine phosphatase, *TUMOR suppressor genes, *GLIOBLASTOMA multiforme, *PHOSPHORYLATION, *CARCINOGENESIS, *TUMORS, *METHYLATION, *GENETIC mutation

مستخلص: Tyrosine phosphorylation plays a critical role in regulating cellular function and is a central feature in signaling cascades involved in oncogenesis. The regulation of tyrosine phosphorylation is coordinately controlled by kinases and phosphatases (PTPs). Whereas activation of tyrosine kinases has been shown to play vital roles in tumor development, the role of PTPs is much less well defined. Here, we show that the receptor protein tyrosine phosphatase delta (PTPRD) is frequently inactivated in glioblastoma multiforme (GBM), a deadly primary neoplasm of the brain. PTPRD is a target of deletion in GBM. often via focal intragenic loss. In GBM tumors that do not possess deletions in PTPRD, the gene is frequently subject to cancer-specific epigenetic silencing via promoter CpG island hypermethylation (37%). Sequencing of the PTPRD gene in GBM and other primary human tumors revealed that the gene is mutated in 6% of GBMs. 13% of head and neck squamous cell carcinomas, and in 9% of lung cancers. These mutations were deleterious. In total, PTPRD inactivation occurs in >50% of GBM tumors, and loss of expression predicts for poor prognosis in glioma patients. Wild-type PTPRD inhibits the growth of GBM and other tumor cells, an effect not observed with PTPRD alleles harboring cancer-specific mutations. Human astrocytes lacking PTPRD exhibited increased growth. PTPRD was found to dephosphorylate the oncoprotein STAT3. These results implicate PTPRD as a tumor suppressor on chromosome 9p that is involved in the development of GBM5 and multiple human cancers. [ABSTRACT FROM AUTHOR]