{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:40:22Z","timestamp":1787002822088,"version":"build-2736575974"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"38","license":[{"start":{"date-parts":[[2016,3,14]],"date-time":"2016-03-14T00:00:00Z","timestamp":1457913600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2016,3,14]],"date-time":"2016-03-14T00:00:00Z","timestamp":1457913600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Oncogene"],"published-print":{"date-parts":[[2016,9,22]]},"DOI":"10.1038\/onc.2016.40","type":"journal-article","created":{"date-parts":[[2016,3,14]],"date-time":"2016-03-14T08:26:49Z","timestamp":1457944009000},"page":"4973-4980","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Phosphorylation-dependent cleavage regulates von Hippel Lindau proteostasis and function"],"prefix":"10.1038","volume":"35","author":[{"given":"P","family":"German","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X-D","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Kalra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Minelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K L","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G B","family":"Mills","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Jonasch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,3,14]]},"reference":[{"key":"BFonc201640_CR1","doi-asserted-by":"publisher","first-page":"2059","DOI":"10.1016\/S0140-6736(03)13643-4","volume":"361","author":"RR Lonser","year":"2003","unstructured":"Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM et al. von Hippel-Lindau disease. Lancet 2003; 361: 2059\u20132067.","journal-title":"Lancet"},{"key":"BFonc201640_CR2","doi-asserted-by":"publisher","first-page":"g4797","DOI":"10.1136\/bmj.g4797","volume":"349","author":"E Jonasch","year":"2014","unstructured":"Jonasch E, Gao J, Rathmell WK . Renal cell carcinoma. BMJ 2014; 349: g4797.","journal-title":"BMJ"},{"key":"BFonc201640_CR3","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/nrc3844","volume":"15","author":"L Gossage","year":"2015","unstructured":"Gossage L, Eisen T, Maher ER . VHL, the story of a tumour suppressor gene. Nat Rev Cancer 2015; 15: 55\u201364.","journal-title":"Nat Rev Cancer"},{"key":"BFonc201640_CR4","doi-asserted-by":"publisher","first-page":"4726","DOI":"10.1158\/1078-0432.CCR-07-4921","volume":"14","author":"ML Nickerson","year":"2008","unstructured":"Nickerson ML, Jaeger E, Shi Y, Durocher JA, Mahurkar S, Zaridze D et al. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res 2008; 14: 4726\u20134734.","journal-title":"Clin Cancer Res"},{"key":"BFonc201640_CR5","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1056\/NEJMoa1113205","volume":"366","author":"M Gerlinger","year":"2012","unstructured":"Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366: 883\u2013892.","journal-title":"N Engl J Med"},{"key":"BFonc201640_CR6","doi-asserted-by":"publisher","first-page":"1444","DOI":"10.1126\/science.7660130","volume":"269","author":"A Kibel","year":"1995","unstructured":"Kibel A, Iliopoulos O, DeCaprio JA, Kaelin WG Jr . Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C. Science 1995; 269: 1444\u20131446.","journal-title":"Science"},{"key":"BFonc201640_CR7","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1128\/MCB.18.2.732","volume":"18","author":"KM Lonergan","year":"1998","unstructured":"Lonergan KM, Iliopoulos O, Ohh M, Kamura T, Conaway RC, Conaway JW et al. Regulation of hypoxia-inducible mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding to complexes containing elongins B\/C and Cul2. Mol Cell Biol 1998; 18: 732\u2013741.","journal-title":"Mol Cell Biol"},{"key":"BFonc201640_CR8","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1038\/20459","volume":"399","author":"PH Maxwell","year":"1999","unstructured":"Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999; 399: 271\u2013275.","journal-title":"Nature"},{"key":"BFonc201640_CR9","doi-asserted-by":"publisher","first-page":"E83","DOI":"10.1371\/journal.pbio.0000083","volume":"1","author":"K Kondo","year":"2003","unstructured":"Kondo K, Kim WY, Lechpammer M, Kaelin WG . Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth. PLoS Biol 2003; 1: E83.","journal-title":"PLoS Biol"},{"key":"BFonc201640_CR10","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/S1535-6108(02)00043-0","volume":"1","author":"K Kondo","year":"2002","unstructured":"Kondo K, Klco J, Nakamura E, Lechpammer M, Kaelin WG . Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 2002; 1: 237\u2013246.","journal-title":"Cancer Cell"},{"key":"BFonc201640_CR11","doi-asserted-by":"publisher","first-page":"3127","DOI":"10.1158\/0008-5472.CAN-13-3213","volume":"74","author":"Z Ding","year":"2014","unstructured":"Ding Z, German P, Bai S, Reddy AS, Liu XD, Sun M et al. Genetic and pharmacological strategies to refunctionalize the von Hippel Lindau R167Q mutant protein. Cancer Res 2014; 74: 3127\u20133136.","journal-title":"Cancer Res"},{"key":"BFonc201640_CR12","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.1016\/S1097-2765(00)80233-6","volume":"4","author":"DE Feldman","year":"1999","unstructured":"Feldman DE, Thulasiraman V, Ferreyra RG, Frydman J . Formation of the VHL-elongin BC tumor suppressor complex is mediated by the chaperonin TRiC. Mol Cell 1999; 4: 1051\u20131061.","journal-title":"Mol Cell"},{"key":"BFonc201640_CR13","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1016\/S1097-2765(03)00423-4","volume":"12","author":"DE Feldman","year":"2003","unstructured":"Feldman DE, Spiess C, Howard DE, Frydman J . Tumorigenic mutations in VHL disrupt folding in vivo by interfering with chaperonin binding. Mol Cell 2003; 12: 1213\u20131224.","journal-title":"Mol Cell"},{"key":"BFonc201640_CR14","doi-asserted-by":"publisher","first-page":"8507","DOI":"10.1073\/pnas.97.15.8507","volume":"97","author":"AR Schoenfeld","year":"2000","unstructured":"Schoenfeld AR, Davidowitz EJ, Burk RD, Elongin BC . Complex prevents degradation of von Hippel-Lindau tumor suppressor gene products. Proc Natl Acad Sci USA 2000; 97: 8507\u20138512.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFonc201640_CR15","doi-asserted-by":"publisher","first-page":"2000","DOI":"10.1158\/0008-5472.CAN-05-3074","volume":"66","author":"RE Banks","year":"2006","unstructured":"Banks RE, Tirukonda P, Taylor C, Hornigold N, Astuti D, Cohen D et al. Genetic and epigenetic analysis of von Hippel-Lindau (VHL) gene alterations and relationship with clinical variables in sporadic renal cancer. Cancer Res 2006; 66: 2000\u20132011.","journal-title":"Cancer Res"},{"key":"BFonc201640_CR16","doi-asserted-by":"publisher","first-page":"5500","DOI":"10.1158\/0008-5472.CAN-11-0757","volume":"71","author":"MP Rechsteiner","year":"2011","unstructured":"Rechsteiner MP, von Teichman A, Nowicka A, Sulser T, Schraml P, Moch H . VHL gene mutations and their effects on hypoxia inducible factor HIF\u03b1: identification of potential driver and passenger mutations. Cancer Res 2011; 71: 5500\u20135511.","journal-title":"Cancer Res"},{"key":"BFonc201640_CR17","doi-asserted-by":"publisher","first-page":"1694","DOI":"10.1038\/onc.2009.12","volume":"28","author":"CM Lee","year":"2009","unstructured":"Lee CM, Hickey MM, Sanford CA, McGuire CG, Cowey CL, Simon MC et al. VHL Type 2B gene mutation moderates HIF dosage in vitro and in vivo. Oncogene 2009; 28: 1694\u20131705.","journal-title":"Oncogene"},{"key":"BFonc201640_CR18","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.celrep.2012.12.007","volume":"3","author":"C Yang","year":"2013","unstructured":"Yang C, Huntoon K, Ksendzovsky A, Zhuang Z, Lonser RR . Proteostasis modulators prolong missense VHL protein activity and halt tumor progression. Cell Rep 2013; 3: 52\u201359.","journal-title":"Cell Rep"},{"key":"BFonc201640_CR19","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1177\/1087057112436557","volume":"17","author":"Z Ding","year":"2012","unstructured":"Ding Z, German P, Bai S, Feng Z, Gao M, Si W et al. Agents that stabilize mutated von Hippel-Lindau (VHL) protein: results of a high-throughput screen to identify compounds that modulate VHL proteostasis. J Biomol Screen 2012; 17: 572\u2013580.","journal-title":"J Biomol Screen"},{"key":"BFonc201640_CR20","doi-asserted-by":"publisher","first-page":"8817","DOI":"10.1073\/pnas.95.15.8817","volume":"95","author":"A Schoenfeld","year":"1998","unstructured":"Schoenfeld A, Davidowitz EJ, Burk RD . A second major native von Hippel-Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor. Proc Natl Acad Sci USA 1998; 95: 8817\u20138822.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFonc201640_CR21","doi-asserted-by":"publisher","first-page":"11661","DOI":"10.1073\/pnas.95.20.11661","volume":"95","author":"O Iliopoulos","year":"1998","unstructured":"Iliopoulos O, Ohh M, Kaelin WG . pVHL19 is a biologically active product of the von Hippel\u2013Lindau gene arising from internal translation initiation. Proc Natl Acad Sci 1998; 95: 11661\u201311666.","journal-title":"Proc Natl Acad Sci"},{"key":"BFonc201640_CR22","doi-asserted-by":"publisher","first-page":"6459","DOI":"10.1073\/pnas.92.14.6459","volume":"92","author":"DR Duan","year":"1995","unstructured":"Duan DR, Humphrey JS, Chen DY, Weng Y, Sukegawa J, Lee S et al. Characterization of the VHL tumor suppressor gene product: localization, complex formation, and the effect of natural inactivating mutations. Proc Natl Acad Sci 1995; 92: 6459\u20136463.","journal-title":"Proc Natl Acad Sci"},{"key":"BFonc201640_CR23","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.cell.2006.05.041","volume":"126","author":"PP Scaglioni","year":"2006","unstructured":"Scaglioni PP, Yung TM, Cai LF, Erdjument-Bromage H, Kaufman AJ, Singh B et al. A CK2-dependent mechanism for degradation of the PML tumor suppressor. Cell 2006; 126: 269\u2013283.","journal-title":"Cell"},{"key":"BFonc201640_CR24","doi-asserted-by":"publisher","first-page":"1729","DOI":"10.1016\/j.biocel.2010.07.008","volume":"42","author":"E Ampofo","year":"2010","unstructured":"Ampofo E, Kietzmann T, Zimmer A, Jakupovic M, Montenarh M, Gotz C . Phosphorylation of the von Hippel-Lindau protein (VHL) by protein kinase CK2 reduces its protein stability and affects p53 and HIF-1alpha mediated transcription. Int J Biochem Cell Biol 2010; 42: 1729\u20131735.","journal-title":"Int J Biochem Cell Biol"},{"key":"BFonc201640_CR25","doi-asserted-by":"publisher","first-page":"22205","DOI":"10.1074\/jbc.M503220200","volume":"280","author":"MP Lolkema","year":"2005","unstructured":"Lolkema MP, Gervais ML, Snijckers CM, Hill RP, Giles RH, Voest EE et al. Tumor suppression by the von Hippel-Lindau protein requires phosphorylation of the acidic domain. J Biol Chem 2005; 280: 22205\u201322211.","journal-title":"J Biol Chem"},{"key":"BFonc201640_CR26","doi-asserted-by":"publisher","first-page":"4639","DOI":"10.1021\/cr010182v","volume":"102","author":"JC Powers","year":"2002","unstructured":"Powers JC, Asgian JL, Ekici \u00d6D, James KE . Irreversible inhibitors of serine, cysteine, and threonine proteases. Chem Rev 2002; 102: 4639\u20134750.","journal-title":"Chem Rev"},{"key":"BFonc201640_CR27","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1006\/bbrc.1994.1904","volume":"202","author":"G Stalter","year":"1994","unstructured":"Stalter G, Siemer S, Becht E, Ziegler M, Remberger K, Issinger OG . Asymmetric expression of protein kinase CK2 subunits in human kidney tumors. Biochem Biophys Res Commun 1994; 202: 141\u2013147.","journal-title":"Biochem Biophys Res Commun"},{"key":"BFonc201640_CR28","doi-asserted-by":"publisher","first-page":"3247","DOI":"10.1038\/sj.onc.1204411","volume":"20","author":"E Landesman-Bollag","year":"2001","unstructured":"Landesman-Bollag E, Romieu-Mourez R, Song DH, Sonenshein GE, Cardiff RD, Seldin DC . Protein kinase CK2 in mammary gland tumorigenesis. Oncogene 2001; 20: 3247\u20133257.","journal-title":"Oncogene"},{"key":"BFonc201640_CR29","doi-asserted-by":"publisher","first-page":"6544","DOI":"10.18632\/oncotarget.3446","volume":"6","author":"M Pizzi","year":"2015","unstructured":"Pizzi M, Piazza F, Agostinelli C, Fuligni F, Benvenuti P, Mandato E et al. Protein kinase CK2 is widely expressed in follicular, Burkitt and diffuse large B-cell lymphomas and propels malignant B-cell growth. Oncotarget 2015; 6: 6544\u20136552.","journal-title":"Oncotarget"},{"key":"BFonc201640_CR30","doi-asserted-by":"publisher","first-page":"153","DOI":"10.17219\/acem\/37040","volume":"23","author":"M Montenarh","year":"2014","unstructured":"Montenarh M . Protein kinase CK2 and angiogenesis. Adv Clin Exp Med 2014; 23: 153\u2013158.","journal-title":"Adv Clin Exp Med"},{"key":"BFonc201640_CR31","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1016\/j.canlet.2014.10.026","volume":"356","author":"B Guerra","year":"2014","unstructured":"Guerra B, Rasmussen TDL, Schnitzler A, Jensen HH, Boldyreff BS, Miyata Y et al. Protein kinase CK2 inhibition is associated with the destabilization of HIF-1\u03b1 in human cancer cells. Cancer Lett 2014; 356: 751\u2013761.","journal-title":"Cancer Lett"},{"key":"BFonc201640_CR32","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1002\/ijc.21268","volume":"117","author":"D Mottet","year":"2005","unstructured":"Mottet D, Ruys SP, Demazy C, Raes M, Michiels C . Role for casein kinase 2 in the regulation of HIF-1 activity. Int J Cancer 2005; 117: 764\u2013774.","journal-title":"Int J Cancer"},{"key":"BFonc201640_CR33","doi-asserted-by":"publisher","first-page":"15014","DOI":"10.1073\/pnas.0606917103","volume":"103","author":"Z Ding","year":"2006","unstructured":"Ding Z, Liang J, Lu Y, Yu Q, Songyang Z, Lin SY et al. A retrovirus-based protein complementation assay screen reveals functional AKT1-binding partners. Proc Natl Acad Sci USA 2006; 103: 15014\u201315019.","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["Oncogene"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/onc201640.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/onc201640","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/onc201640.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,21]],"date-time":"2022-03-21T16:21:32Z","timestamp":1647879692000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/onc201640"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,3,14]]},"references-count":33,"journal-issue":{"issue":"38","published-print":{"date-parts":[[2016,9,22]]}},"alternative-id":["BFonc201640"],"URL":"https:\/\/doi.org\/10.1038\/onc.2016.40","relation":{},"ISSN":["0950-9232","1476-5594"],"issn-type":[{"value":"0950-9232","type":"print"},{"value":"1476-5594","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,3,14]]},"assertion":[{"value":"27 May 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 December 2015","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 January 2016","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 March 2016","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}