VHL

VHL
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	4WQO, 1LM8, 1LQB, 1VCB, 3ZRC, 3ZRF, 3ZTC, 3ZTD, 3ZUN, 4AJY, 4AWJ, 4B95, 4B9K, 4BKS, 4BKT, 4W9C, 4W9D, 4W9E, 4W9F, 4W9G, 4W9H, 4W9I, 4W9J, 4W9K, 4W9L
Identifikatori
Aliasi	VHL
Vanjski ID-jevi	OMIM: 608537 MGI: 103223 HomoloGene: 465 GeneCards: VHL
Lokacija gena (čovjek)
Hrom.	Hromosom 3 (čovjek)
Kraj	10,153,667 bp
Lokacija gena (miš)
Hrom.	Hromosom 6 (miš)
Kraj	113,608,594 bp
Obrazac RNK ekspresije
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• GO:1904264, GO:1904822, GO:0090622, GO:0090302 ubiquitin protein ligase activity; • transcription factor binding; • GO:0050372 aktivnost sa transferazom ubikvitina; • GO:0001948, GO:0016582 vezivanje za proteine; • vezivanje enzima;
Ćelijska komponenta	• citoplazma; • citosol; • VCB complex; • membrana; • nukleoplazma; • Endoplazmatski retikulum; • mitohondrija; • jedro;
Biološki proces	• GO:0009373 regulation of transcription, DNA-templated; • protein stabilization; • negative regulation of apoptotic process; • GO:1901227 negative regulation of transcription by RNA polymerase II; • Proteoliza; • GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated; • positive regulation of cell differentiation; • GO:0000767 cell morphogenesis; • regulation of transcription from RNA polymerase II promoter in response to hypoxia; • negative regulation of transcription from RNA polymerase II promoter in response to hypoxia; • negative regulation of cell population proliferation; • negative regulation of gene expression; • protein ubiquitination; • Posttranslacione modifikacije; • negative regulation of receptor signaling pathway via JAK-STAT;
	Izvori:Amigo / QuickGO
Ortolozi
	7428
	22346
	ENSG00000134086
	ENSMUSG00000033933
	P40337
	P40338
	NM_000551; NM_198156; NM_001354723
	NM_009507
	NP_000542; NP_937799; NP_001341652; NP_000542.1
	NP_033533
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Supresor Von Hippel–Lindauovog tumora znan i kao pVHL jest protein koji je kod ljudi kodiran genom VHL sa hromosoma 3. Mutacije VHL gena povezuju se sa Von Hippel-Lindauovom bolešću.^[5]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 213 aminokiselina, а molekulska težina 24.153 Da.^[6]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MPRRAENWDE	AEVGAEEAGV	EEYGPEEDGG	EESGAEESGP	EESGPEELGA
EEEMEAGRPR	PVLRSVNSRE	PSQVIFCNRS	PRVVLPVWLN	FDGEPQPYPT
LPPGTGRRIH	SYRGHLWLFR	DAGTHDGLLV	NQTELFVPSL	NVDGQPIFAN
ITLPVYTLKE	RCLQVVRSLV	KPENYRRLDI	VRSLYEDLED	HPNVQKDLER
LTQERIAHQR	MGD

Funkcija

Protein kodiran VHL genom je komponenta za prepoznavanje supstrata proteinskog kompleksa koji uključuje elongin B, elongin C i kulin-2 i posjeduje E3 ubikvitin-ligaznu aktivnost. Ovaj kompleks uključen je u ubikvitinaciju i kasniju degradaciju hipoksija-inducibilnih faktora (HIFs), koji su faktori transkripcije sa centralnom ulogom u regulaciji ekspresije gena. kao odgovor na promjenjive nivoe kisika. Podjedinica [[RNK-polimeraza II|RNK-polimeraze II POLR2G/RPB7 također je navodna meta ovog proteina. Uočene su alternativno prerađene varijante transkripta koje kodiraju različite izoforme.^[7]

Regulacija HIF1α pomoću pVHL-a. Pod normalnim nivoima kisika, HIF1α vezuje pVHL preko dva hidroksilovana ostatka prolina i poliubikvitinira se pVHL. To dovodi do njegove degradacije preko proteasoma. Tokom hipoksije, ostaci prolina nisu hidroksilirani i pVHL se ne može vezati. HIF1α uzrokuje transkripciju gena koji sadrže element odgovora na hipoksiju. Kod VHL bolesti, mutacije uzrokuju promjene na pVHL proteinu, obično na mjestu vezivanja HIF1α.

Dobijeni protein se proizvodi u dva oblika, protein od 18 kDa i protein od 30 kDa koji funkcioniše kao tumorski supresor. Smatra se da je glavno djelovanje VHL proteina njegova E3 ubikvitin ligazna aktivnost koja rezultira time da su specifični ciljni proteini 'označeni' za razgradnju.

Najistraženiji od ovih ciljeva je faktor induciran hipoksijom 1a (HIF1a), transkripcijski faktor koji inducira ekspresiju brojnih faktora povezanih sa angiogenezom.^[8]

Pored interakcije sa HIF, VHL protein se takođe može povezati sa tubulinom.^[9] Tada je sposoban stabilizirati i tako produžiti mikrotubule. Ova funkcija ima ključnu ulogu u stabilizaciji vretena tokom mitoze. Delecija VHL uzrokuje drastičan porast dezorijentisanih i rotirajućih vretena tokom mitoze. Preko još nepoznatog mehanizma, VHL također povećava koncentraciju MAD2, važnog proteina kontrolne tačke vretena. Tako gubitak VHL-a dovodi do oslabljene kontrolne tačke i posljedično do pogrešne segregacije hromozoma i aneuploidija.

Klinički značaj

Von Hippel-Lindauov sindrom (VHL) je dominantno nasljedni sindrom raka koji predisponira niz malignih i benignih tumora oka, mozga, kičmene moždine, bubrega, pankreasa i nadbubrežnih žlijezda. Mutacija zametne linije ovog gena je osnova porodičnog nasljeđivanja VHL sindroma. Osobe s VHL sindromom nasljeđuju jednu mutaciju u VHL proteinu koja uzrokuje gubitak ili promjenu normalne funkcije proteina. S vremenom, sporadične mutacije u drugoj kopiji VHL proteina mogu dovesti do karcinoma, posebno hemangioblastoma koji zahvataju jetru i bubrege, bubrežnih (i vaginskih) bistroćelijskih adenokarcinoma.

Gubitak aktivnosti VHL proteina rezultira povećanom količinom HIF1a, a time i povećanim nivoima angiogenih faktora, uključujući VEGF i PDGF. Zauzvrat, to dovodi do nereguliranog rasta krvnih sudova, jednog od preduslova tumora. Osim toga, VHL je bio uključen u održavanje diferenciranog fenotipa u bubrežnim čelijama. Nadalje, eksperimenti kulture ćelija sa VHL –/– ćelijama su pokazali da dodatak pVHL može inducirati mezenhimski u epitelni prijelaz. Ovi dokazi sugeriraju da VHL ima centralnu ulogu u održavanju diferenciranog fenotipa u ćeliji.

Dodatno, pVHL je važan za formiranje vanćelijskog matriksa.^[10] Ovaj protein također može biti važan u inhibiciji matriksnih metaloproteinaza. Ove akcije su izuzetno važne u metastazama ćelijama sa nedostatkom VHL-a. U klasičnoj VHL bolesti čini se da je jedan alel divljeg tipa u VHL dovoljan za održavanje normalne kardioplućne funkcije.^[11]

Interakcije

Pokazalo se da supresor Von Hippel-Lindauovog tumora ima reakcije sa:

CCDC82,
CUL2,^[12]^[13]^[14]^[15]^[16]
Filamin,^[17]^[18]
HIF1AN,^[19]
HIF1A,^[19]^[20]^[21]^[22]^[23]^[24]^[25]^[26]^[27]^[28]
Nervni faktor rasta IB,^[20]
PHF17,^[17]
PSMC3,^[22]
SAP130,^[12]
TCEB1,^[13]^[14]^[15]^[18]^[20]^[21]^[29]
TCEB2,^[12]^[13]^[14]^[15]^[21] i
USP33.^[29]

Također pogledajte

Von Hippel-Lindauova bolest

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000134086 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000033933 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Ben-Skowronek I, Kozaczuk S (2015). "Von Hippel–Lindau Syndrome". Hormone Research in Paediatrics. 84 (3): 145–52. doi:10.1159/000431323. PMID 26279462.
^ "UniProt, P40337" (jezik: engleski). Pristupljeno 6. 11. 2021.
^ "Entrez Gene: VHL von Hippel–Lindau tumor suppressor".
^ Czyzyk-Krzeska MF, Meller J (april 2004). "von Hippel–Lindau tumor suppressor: not only HIF's executioner". Trends in Molecular Medicine. 10 (4): 146–9. doi:10.1016/j.molmed.2004.02.004. PMID 15162797.
^ Lolkema MP, Mehra N, Jorna AS, van Beest M, Giles RH, Voest EE (decembar 2004). "The von Hippel–Lindau tumor suppressor protein influences microtubule dynamics at the cell periphery". Experimental Cell Research. 301 (2): 139–46. doi:10.1016/j.yexcr.2004.07.016. PMID 15530850.
^ Kaelin WG (septembar 2002). "Molecular basis of the VHL hereditary cancer syndrome". Nature Reviews. Cancer. 2 (9): 673–82. doi:10.1038/nrc885. PMID 12209156. S2CID 20186415.
^ Formenti F, Beer PA, Croft QP, Dorrington KL, Gale DP, Lappin TR, Lucas GS, Maher ER, Maxwell PH, McMullin MF, O'Connor DF, Percy MJ, Pugh CW, Ratcliffe PJ, Smith TG, Talbot NP, Robbins PA (juni 2011). "Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel–Lindau disease and HIF-2alpha gain-of-function mutation". FASEB Journal. 25 (6): 2001–11. doi:10.1096/fj.10-177378. PMC 3159892. PMID 21389259.
^ ^a ^b ^c Menon S, Tsuge T, Dohmae N, Takio K, Wei N (2008). "Association of SAP130/SF3b-3 with Cullin-RING ubiquitin ligase complexes and its regulation by the COP9 signalosome". BMC Biochemistry. 9: 1. doi:10.1186/1471-2091-9-1. PMC 2265268. PMID 18173839.
^ ^a ^b ^c Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, et al. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3: 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.
^ ^a ^b ^c Ohh M, Takagi Y, Aso T, Stebbins CE, Pavletich NP, Zbar B, Conaway RC, Conaway JW, Kaelin WG (decembar 1999). "Synthetic peptides define critical contacts between elongin C, elongin B, and the von Hippel–Lindau protein". The Journal of Clinical Investigation. 104 (11): 1583–91. doi:10.1172/JCI8161. PMC 481054. PMID 10587522.
^ ^a ^b ^c Hacker KE, Lee CM, Rathmell WK (2008). Zhang B (ured.). "VHL type 2B mutations retain VBC complex form and function". PLOS ONE. 3 (11): e3801. doi:10.1371/journal.pone.0003801. PMC 2583047. PMID 19030229.
^ Kamura T, Burian D, Yan Q, Schmidt SL, Lane WS, Querido E, Branton PE, Shilatifard A, Conaway RC, Conaway JW (august 2001). "Muf1, a novel Elongin BC-interacting leucine-rich repeat protein that can assemble with Cul5 and Rbx1 to reconstitute a ubiquitin ligase". The Journal of Biological Chemistry. 276 (32): 29748–53. doi:10.1074/jbc.M103093200. PMID 11384984.
^ ^a ^b Zhou MI, Wang H, Ross JJ, Kuzmin I, Xu C, Cohen HT (oktobar 2002). "The von Hippel–Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1". The Journal of Biological Chemistry. 277 (42): 39887–98. doi:10.1074/jbc.M205040200. PMID 12169691.
^ ^a ^b Tsuchiya H, Iseda T, Hino O (juli 1996). "Identification of a novel protein (VBP-1) binding to the von Hippel–Lindau (VHL) tumor suppressor gene product". Cancer Research. 56 (13): 2881–5. PMID 8674032.
^ ^a ^b Mahon PC, Hirota K, Semenza GL (oktobar 2001). "FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity". Genes & Development. 15 (20): 2675–86. doi:10.1101/gad.924501. PMC 312814. PMID 11641274.
^ ^a ^b ^c Kim BY, Kim H, Cho EJ, Youn HD (februar 2008). "Nur77 upregulates HIF-alpha by inhibiting pVHL-mediated degradation". Experimental & Molecular Medicine. 40 (1): 71–83. doi:10.3858/emm.2008.40.1.71. PMC 2679322. PMID 18305400.
^ ^a ^b ^c Min JH, Yang H, Ivan M, Gertler F, Kaelin WG, Pavletich NP (juni 2002). "Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling". Science. 296 (5574): 1886–9. doi:10.1126/science.1073440. PMID 12004076. S2CID 19641938.
^ ^a ^b Corn PG, McDonald ER, Herman JG, El-Deiry WS (novembar 2003). "Tat-binding protein-1, a component of the 26S proteasome, contributes to the E3 ubiquitin ligase function of the von Hippel–Lindau protein". Nature Genetics. 35 (3): 229–37. doi:10.1038/ng1254. PMID 14556007. S2CID 22798700.
^ Li Z, Wang D, Na X, Schoen SR, Messing EM, Wu G (april 2003). "The VHL protein recruits a novel KRAB-A domain protein to repress HIF-1alpha transcriptional activity". The EMBO Journal. 22 (8): 1857–67. doi:10.1093/emboj/cdg173. PMC 154465. PMID 12682018.
^ Tanimoto K, Makino Y, Pereira T, Poellinger L (august 2000). "Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel–Lindau tumor suppressor protein". The EMBO Journal. 19 (16): 4298–309. doi:10.1093/emboj/19.16.4298. PMC 302039. PMID 10944113.
^ Yu F, White SB, Zhao Q, Lee FS (august 2001). "HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation". Proceedings of the National Academy of Sciences of the United States of America. 98 (17): 9630–5. doi:10.1073/pnas.181341498. PMC 55503. PMID 11504942.
^ Jung JE, Kim HS, Lee CS, Shin YJ, Kim YN, Kang GH, Kim TY, Juhnn YS, Kim SJ, Park JW, Ye SK, Chung MH (oktobar 2008). "STAT3 inhibits the degradation of HIF-1alpha by pVHL-mediated ubiquitination". Experimental & Molecular Medicine. 40 (5): 479–85. doi:10.3858/emm.2008.40.5.479. PMC 2679355. PMID 18985005.
^ André H, Pereira TS (oktobar 2008). "Identification of an alternative mechanism of degradation of the hypoxia-inducible factor-1alpha". The Journal of Biological Chemistry. 283 (43): 29375–84. doi:10.1074/jbc.M805919200. PMC 2662024. PMID 18694926.
^ Park YK, Ahn DR, Oh M, Lee T, Yang EG, Son M, Park H (juli 2008). "Nitric oxide donor, (+/-)-S-nitroso-N-acetylpenicillamine, stabilizes transactive hypoxia-inducible factor-1alpha by inhibiting von Hippel–Lindau recruitment and asparagine hydroxylation". Molecular Pharmacology. 74 (1): 236–45. doi:10.1124/mol.108.045278. PMID 18426857. S2CID 31675735.
^ ^a ^b Li Z, Na X, Wang D, Schoen SR, Messing EM, Wu G (februar 2002). "Ubiquitination of a novel deubiquitinating enzyme requires direct binding to von Hippel–Lindau tumor suppressor protein". The Journal of Biological Chemistry. 277 (7): 4656–62. doi:10.1074/jbc.M108269200. PMID 11739384.

Dopunska literatura

Conaway RC, Conaway JW (2003). The von Hippel–Lindau tumor suppressor complex and regulation of hypoxia-inducible transcription. Advances in Cancer Research. 85. str. 1–12. doi:10.1016/S0065-230X(02)85001-1. ISBN 978-0120066858. PMID 12374282.
Czyzyk-Krzeska MF, Meller J (april 2004). "von Hippel–Lindau tumor suppressor: not only HIF's executioner". Trends in Molecular Medicine. 10 (4): 146–9. doi:10.1016/j.molmed.2004.02.004. PMID 15162797.
Esteban MA, Harten SK, Tran MG, Maxwell PH (juli 2006). "Formation of primary cilia in the renal epithelium is regulated by the von Hippel–Lindau tumor suppressor protein". Journal of the American Society of Nephrology. 17 (7): 1801–6. doi:10.1681/ASN.2006020181. PMID 16775032.
Hoebeeck J, Vandesompele J, Nilsson H, De Preter K, Van Roy N, De Smet E, Yigit N, De Paepe A, Laureys G, Påhlman S, Speleman F (august 2006). "The von Hippel–Lindau tumor suppressor gene expression level has prognostic value in neuroblastoma". International Journal of Cancer. 119 (3): 624–9. doi:10.1002/ijc.21888. PMID 16506218. S2CID 632377.
Kaelin WG (septembar 2004). "The von Hippel–Lindau tumor suppressor gene and kidney cancer". Clinical Cancer Research. 10 (18 Pt 2): 6290S–5S. doi:10.1158/1078-0432.CCR-sup-040025. PMID 15448019.
Kaelin WG (januar 2007). "The von Hippel–Lindau tumor suppressor protein and clear cell renal carcinoma". Clinical Cancer Research. 13 (2 Pt 2): 680s–684s. doi:10.1158/1078-0432.CCR-06-1865. PMID 17255293.
Kamura T, Conaway JW, Conaway RC (2002). "Roles of SCF and VHL ubiquitin ligases in regulation of cell growth". Protein Degradation in Health and Disease. Progress in Molecular and Subcellular Biology. 29. str. 1–15. doi:10.1007/978-3-642-56373-7_1. ISBN 978-3-642-62714-9. PMID 11908068.
Kralovics R, Skoda RC (januar 2005). "Molecular pathogenesis of Philadelphia chromosome negative myeloproliferative disorders". Blood Reviews. 19 (1): 1–13. doi:10.1016/j.blre.2004.02.002. PMID 15572213.
Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH (juni 2003). "von Hippel–Lindau disease". Lancet. 361 (9374): 2059–67. doi:10.1016/S0140-6736(03)13643-4. PMID 12814730. S2CID 13783714.
Neumann HP, Wiestler OD (maj 1991). "Clustering of features of von Hippel–Lindau syndrome: evidence for a complex genetic locus". Lancet. 337 (8749): 1052–4. doi:10.1016/0140-6736(91)91705-Y. PMID 1673491. S2CID 24022884.
Russell RC, Ohh M (januar 2007). "The role of VHL in the regulation of E-cadherin: a new connection in an old pathway". Cell Cycle. 6 (1): 56–9. doi:10.4161/cc.6.1.3668. PMID 17245122.
Schipani E (2006). "Hypoxia and HIF-1 alpha in chondrogenesis". Seminars in Cell & Developmental Biology. 16 (4–5): 539–46. doi:10.1016/j.semcdb.2005.03.003. PMID 16144691.
Takahashi K, Iida K, Okimura Y, Takahashi Y, Naito J, Nishikawa S, Kadowaki S, Iguchi G, Kaji H, Chihara K (2006). "A novel mutation in the von Hippel–Lindau tumor suppressor gene identified in a Japanese family with pheochromocytoma and hepatic hemangioma". Internal Medicine. 45 (5): 265–9. doi:10.2169/internalmedicine.45.1547. PMID 16595991.
Graff JW (2005). "The VHL Handbook: What You Need to Know about VHL". VHL Family Alliance. 12 (1): 1–56.

Vanjski linkovi

VHL Alliance
GeneReviews/NCBI/NIH/UW entry on Von Hippel–Lindau Syndrome or Angiomatosis Retinae, VHL Syndrome, von Hippel–Lindau Disease
Von Hippel–Lindau Tumor Suppressor Protein na US National Library of Medicine Medical Subject Headings (MeSH)

Portal Biologija

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000134086 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000033933 - Ensembl, maj 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[Ben-SkowronekKozaczuk2015-5] Ben-Skowronek I, Kozaczuk S (2015). "Von Hippel–Lindau Syndrome". Hormone Research in Paediatrics. 84 (3): 145–52. doi:10.1159/000431323. PMID 26279462.

[UniProt-6] "UniProt, P40337" (jezik: engleski). Pristupljeno 6. 11. 2021.

[7] "Entrez Gene: VHL von Hippel–Lindau tumor suppressor".

[8] Czyzyk-Krzeska MF, Meller J (april 2004). "von Hippel–Lindau tumor suppressor: not only HIF's executioner". Trends in Molecular Medicine. 10 (4): 146–9. doi:10.1016/j.molmed.2004.02.004. PMID 15162797.

[pmid15530850-9] Lolkema MP, Mehra N, Jorna AS, van Beest M, Giles RH, Voest EE (decembar 2004). "The von Hippel–Lindau tumor suppressor protein influences microtubule dynamics at the cell periphery". Experimental Cell Research. 301 (2): 139–46. doi:10.1016/j.yexcr.2004.07.016. PMID 15530850.

[Kaelin_2002-10] Kaelin WG (septembar 2002). "Molecular basis of the VHL hereditary cancer syndrome". Nature Reviews. Cancer. 2 (9): 673–82. doi:10.1038/nrc885. PMID 12209156. S2CID 20186415.

[pmid21389259-11] Formenti F, Beer PA, Croft QP, Dorrington KL, Gale DP, Lappin TR, Lucas GS, Maher ER, Maxwell PH, McMullin MF, O'Connor DF, Percy MJ, Pugh CW, Ratcliffe PJ, Smith TG, Talbot NP, Robbins PA (juni 2011). "Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel–Lindau disease and HIF-2alpha gain-of-function mutation". FASEB Journal. 25 (6): 2001–11. doi:10.1096/fj.10-177378. PMC 3159892. PMID 21389259.

[pmid18173839-12] Menon S, Tsuge T, Dohmae N, Takio K, Wei N (2008). "Association of SAP130/SF3b-3 with Cullin-RING ubiquitin ligase complexes and its regulation by the COP9 signalosome". BMC Biochemistry. 9: 1. doi:10.1186/1471-2091-9-1. PMC 2265268. PMID 18173839.

[pmid17353931-13] Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, et al. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3: 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.

[pmid10587522-14] Ohh M, Takagi Y, Aso T, Stebbins CE, Pavletich NP, Zbar B, Conaway RC, Conaway JW, Kaelin WG (decembar 1999). "Synthetic peptides define critical contacts between elongin C, elongin B, and the von Hippel–Lindau protein". The Journal of Clinical Investigation. 104 (11): 1583–91. doi:10.1172/JCI8161. PMC 481054. PMID 10587522.

[pmid19030229-15] Hacker KE, Lee CM, Rathmell WK (2008). Zhang B (ured.). "VHL type 2B mutations retain VBC complex form and function". PLOS ONE. 3 (11): e3801. doi:10.1371/journal.pone.0003801. PMC 2583047. PMID 19030229.

[pmid11384984-16] Kamura T, Burian D, Yan Q, Schmidt SL, Lane WS, Querido E, Branton PE, Shilatifard A, Conaway RC, Conaway JW (august 2001). "Muf1, a novel Elongin BC-interacting leucine-rich repeat protein that can assemble with Cul5 and Rbx1 to reconstitute a ubiquitin ligase". The Journal of Biological Chemistry. 276 (32): 29748–53. doi:10.1074/jbc.M103093200. PMID 11384984.

[pmid12169691-17] Zhou MI, Wang H, Ross JJ, Kuzmin I, Xu C, Cohen HT (oktobar 2002). "The von Hippel–Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1". The Journal of Biological Chemistry. 277 (42): 39887–98. doi:10.1074/jbc.M205040200. PMID 12169691.

[pmid8674032-18] Tsuchiya H, Iseda T, Hino O (juli 1996). "Identification of a novel protein (VBP-1) binding to the von Hippel–Lindau (VHL) tumor suppressor gene product". Cancer Research. 56 (13): 2881–5. PMID 8674032.

[pmid11641274-19] Mahon PC, Hirota K, Semenza GL (oktobar 2001). "FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity". Genes & Development. 15 (20): 2675–86. doi:10.1101/gad.924501. PMC 312814. PMID 11641274.

[pmid18305400-20] Kim BY, Kim H, Cho EJ, Youn HD (februar 2008). "Nur77 upregulates HIF-alpha by inhibiting pVHL-mediated degradation". Experimental & Molecular Medicine. 40 (1): 71–83. doi:10.3858/emm.2008.40.1.71. PMC 2679322. PMID 18305400.

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