6hr2

Structural highlights

Disease

[SMCA4_HUMAN] Defects in SMARCA4 are the cause of rhabdoid tumor predisposition syndrome type 2 (RTPS2) [MIM:613325]. RTPS2 is a familial cancer syndrome predisposing to renal or extrarenal malignant rhabdoid tumors and to a variety of tumors of the central nervous system, including choroid plexus carcinoma, medulloblastoma, and central primitive neuroectodermal tumors. Rhabdoid tumors are the most aggressive and lethal malignancies occurring in early childhood.^[1] Defects in SMARCA4 are the cause of mental retardation autosomal dominant type 16 (MRD16) [MIM:614609]. A disease characterized by multiple congenital anomalies and mental retardation. Mental retardation is defined by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. MRD16 patients manifest developmental delay, absent or hypoplastic fifth fingernails or toenails, thick eyebrows and long eyelashes, hirsutism. Additional findings include hypotonia, microcephaly, seizures, a Dandy-Walker malformation, and vision and hearing problems.^[2] [VHL_HUMAN] Defects in VHL are a cause of susceptibility to pheochromocytoma (PCC) [MIM:171300]. A catecholamine-producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent. Defects in VHL are the cause of von Hippel-Lindau disease (VHLD) [MIM:193300]. VHLD is a dominantly inherited familial cancer syndrome characterized by the development of retinal angiomatosis, cerebellar and spinal hemangioblastoma, renal cell carcinoma (RCC), phaeochromocytoma and pancreatic tumors. VHL type 1 is without pheochromocytoma, type 2 is with pheochromocytoma. VHL type 2 is further subdivided into types 2A (pheochromocytoma, retinal angioma, and hemangioblastomas without renal cell carcinoma and pancreatic cyst) and 2B (pheochromocytoma, retinal angioma, and hemangioblastomas with renal cell carcinoma and pancreatic cyst). VHL type 2C refers to patients with isolated pheochromocytoma without hemangioblastoma or renal cell carcinoma. The estimated incidence is 3/100000 births per year and penetrance is 97% by age 60 years.^{[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]} [:]^{[17] [18] [19]} Defects in VHL are the cause of familial erythrocytosis type 2 (ECYT2) [MIM:263400]; also called VHL-dependent polycythemia or Chuvash type polycythemia. ECYT2 is an autosomal recessive disorder characterized by an increase in serum red blood cell mass, hypersensitivity of erythroid progenitors to erythropoietin, increased erythropoietin serum levels, and normal oxygen affinity. Patients with ECYT2 carry a high risk for peripheral thrombosis and cerebrovascular events.^{[20] [21]} Defects in VHL are a cause of renal cell carcinoma (RCC) [MIM:144700]. Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into clear cell renal carcinoma (non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma.^[22]

Function

[ELOB_HUMAN] SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A is transcriptionally active and its transcription activity is strongly enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex).^{[23] [24]} The elongin BC complex seems to be involved as an adapter protein in the proteasomal degradation of target proteins via different E3 ubiquitin ligase complexes, including the von Hippel-Lindau ubiquitination complex CBC(VHL). By binding to BC-box motifs it seems to link target recruitment subunits, like VHL and members of the SOCS box family, to Cullin/RBX1 modules that activate E2 ubiquitination enzymes.^{[25] [26]} [SMCA4_HUMAN] Transcriptional coactivator cooperating with nuclear hormone receptors to potentiate transcriptional activation. Component of the CREST-BRG1 complex, a multiprotein complex that regulates promoter activation by orchestrating a calcium-dependent release of a repressor complex and a recruitment of an activator complex. In resting neurons, transcription of the c-FOS promoter is inhibited by BRG1-dependent recruitment of a phospho-RB1-HDAC repressor complex. Upon calcium influx, RB1 is dephosphorylated by calcineurin, which leads to release of the repressor complex. At the same time, there is increased recruitment of CREBBP to the promoter by a CREST-dependent mechanism, which leads to transcriptional activation. The CREST-BRG1 complex also binds to the NR2B promoter, and activity-dependent induction of NR2B expression involves a release of HDAC1 and recruitment of CREBBP. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a post-mitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to post-mitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth. SMARCA4/BAF190A may promote neural stem cell self-renewal/proliferation by enhancing Notch-dependent proliferative signals, while concurrently making the neural stem cell insensitive to SHH-dependent differentiating cues (By similarity). Also involved in vitamin D-coupled transcription regulation via its association with the WINAC complex, a chromatin-remodeling complex recruited by vitamin D receptor (VDR), which is required for the ligand-bound VDR-mediated transrepression of the CYP27B1 gene. Acts as a corepressor of ZEB1 to regulate E-cadherin transcription and is required for induction of epithelial-mesenchymal transition (EMT) by ZEB1.^{[27] [28] [29]} [ELOC_HUMAN] SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A is transcriptionally active and its transcription activity is strongly enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex).^[30] The elongin BC complex seems to be involved as an adapter protein in the proteasomal degradation of target proteins via different E3 ubiquitin ligase complexes, including the von Hippel-Lindau ubiquitination complex CBC(VHL). By binding to BC-box motifs it seems to link target recruitment subunits, like VHL and members of the SOCS box family, to Cullin/RBX1 modules that activate E2 ubiquitination enzymes.^[31] [VHL_HUMAN] Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Seems to act as target recruitment subunit in the E3 ubiquitin ligase complex and recruits hydroxylated hypoxia-inducible factor (HIF) under normoxic conditions. Involved in transcriptional repression through interaction with HIF1A, HIF1AN and histone deacetylases. Ubiquitinates, in an oxygen-responsive manner, ADRB2.^{[32] [33] [34]}

References

1. ↑ Schneppenheim R, Fruhwald MC, Gesk S, Hasselblatt M, Jeibmann A, Kordes U, Kreuz M, Leuschner I, Martin Subero JI, Obser T, Oyen F, Vater I, Siebert R. Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. Am J Hum Genet. 2010 Feb 12;86(2):279-84. Epub 2010 Feb 4. PMID:20137775 doi:S0002-9297(10)00016-9
2. ↑ Tsurusaki Y, Okamoto N, Ohashi H, Kosho T, Imai Y, Hibi-Ko Y, Kaname T, Naritomi K, Kawame H, Wakui K, Fukushima Y, Homma T, Kato M, Hiraki Y, Yamagata T, Yano S, Mizuno S, Sakazume S, Ishii T, Nagai T, Shiina M, Ogata K, Ohta T, Niikawa N, Miyatake S, Okada I, Mizuguchi T, Doi H, Saitsu H, Miyake N, Matsumoto N. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nat Genet. 2012 Mar 18;44(4):376-8. doi: 10.1038/ng.2219. PMID:22426308 doi:10.1038/ng.2219
3. ↑ 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 Dec;4(6):1051-61. PMID:10635329
4. ↑ Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, et al.. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993 May 28;260(5112):1317-20. PMID:8493574
5. ↑ Crossey PA, Richards FM, Foster K, Green JS, Prowse A, Latif F, Lerman MI, Zbar B, Affara NA, Ferguson-Smith MA, et al.. Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. Hum Mol Genet. 1994 Aug;3(8):1303-8. PMID:7987306
6. ↑ Chen F, Kishida T, Yao M, Hustad T, Glavac D, Dean M, Gnarra JR, Orcutt ML, Duh FM, Glenn G, et al.. Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. Hum Mutat. 1995;5(1):66-75. PMID:7728151 doi:http://dx.doi.org/10.1002/humu.1380050109
7. ↑ . Germline mutations in the von Hippel-Lindau disease (VHL) gene in Japanese VHL. Clinical Research Group for VHL in Japan. Hum Mol Genet. 1995 Dec;4(12):2233-7. PMID:8634692
8. ↑ Crossey PA, Eng C, Ginalska-Malinowska M, Lennard TW, Wheeler DC, Ponder BA, Maher ER. Molecular genetic diagnosis of von Hippel-Lindau disease in familial phaeochromocytoma. J Med Genet. 1995 Nov;32(11):885-6. PMID:8592333
9. ↑ Eng C, Crossey PA, Mulligan LM, Healey CS, Houghton C, Prowse A, Chew SL, Dahia PL, O'Riordan JL, Toledo SP, et al.. Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas. J Med Genet. 1995 Dec;32(12):934-7. PMID:8825918
10. ↑ Maher ER, Webster AR, Richards FM, Green JS, Crossey PA, Payne SJ, Moore AT. Phenotypic expression in von Hippel-Lindau disease: correlations with germline VHL gene mutations. J Med Genet. 1996 Apr;33(4):328-32. PMID:8730290
11. ↑ Zbar B, Kishida T, Chen F, Schmidt L, Maher ER, Richards FM, Crossey PA, Webster AR, Affara NA, Ferguson-Smith MA, Brauch H, Glavac D, Neumann HP, Tisherman S, Mulvihill JJ, Gross DJ, Shuin T, Whaley J, Seizinger B, Kley N, Olschwang S, Boisson C, Richard S, Lips CH, Lerman M, et al.. Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat. 1996;8(4):348-57. PMID:8956040 doi:<348::AID-HUMU8>3.0.CO;2-3 10.1002/(SICI)1098-1004(1996)8:4<348::AID-HUMU8>3.0.CO;2-3
12. ↑ Li C, Weber G, Ekman P, Lagercrantz J, Norlen BJ, Akerstrom G, Nordenskjold M, Bergerheim US. Germline mutations detected in the von Hippel-Lindau disease tumor suppressor gene by Southern blot and direct genomic DNA sequencing. Hum Mutat. 1998;Suppl 1:S31-3. PMID:9452032
13. ↑ Mandich P, Montera M, Bellone E, Trojani A, Daniele S, Ajmar F. Three novel mutations in the Von Hippel-Lindau tumour suppressor gene in Italian patients. Hum Mutat. 1998;Suppl 1:S268-70. PMID:9452106
14. ↑ Martin R, Hockey A, Walpole I, Goldblatt J. Variable penetrance of familial pheochromocytoma associated with the von Hipple Lindau gene mutation, S68W. Mutations in brief no. 150. Online. Hum Mutat. 1998;12(1):71. PMID:10627136 doi:<71::AID-HUMU14>3.0.CO;2-A 10.1002/(SICI)1098-1004(1998)12:1<71::AID-HUMU14>3.0.CO;2-A
15. ↑ Stolle C, Glenn G, Zbar B, Humphrey JS, Choyke P, Walther M, Pack S, Hurley K, Andrey C, Klausner R, Linehan WM. Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat. 1998;12(6):417-23. PMID:9829911 doi:<417::AID-HUMU8>3.0.CO;2-K 10.1002/(SICI)1098-1004(1998)12:6<417::AID-HUMU8>3.0.CO;2-K
16. ↑ Olschwang S, Richard S, Boisson C, Giraud S, Laurent-Puig P, Resche F, Thomas G. Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma. Hum Mutat. 1998;12(6):424-30. PMID:9829912 doi:<424::AID-HUMU9>3.0.CO;2-H 10.1002/(SICI)1098-1004(1998)12:6<424::AID-HUMU9>3.0.CO;2-H
17. ↑ Bradley JF, Collins DL, Schimke RN, Parrott HN, Rothberg PG. Two distinct phenotypes caused by two different missense mutations in the same codon of the VHL gene. Am J Med Genet. 1999 Nov 19;87(2):163-7. PMID:10533030
18. ↑ Gallou C, Joly D, Mejean A, Staroz F, Martin N, Tarlet G, Orfanelli MT, Bouvier R, Droz D, Chretien Y, Marechal JM, Richard S, Junien C, Beroud C. Mutations of the VHL gene in sporadic renal cell carcinoma: definition of a risk factor for VHL patients to develop an RCC. Hum Mutat. 1999;13(6):464-75. PMID:10408776 doi:<464::AID-HUMU6>3.0.CO;2-A 10.1002/(SICI)1098-1004(1999)13:6<464::AID-HUMU6>3.0.CO;2-A
19. ↑ Abbott MA, Nathanson KL, Nightingale S, Maher ER, Greenstein RM. The von Hippel-Lindau (VHL) germline mutation V84L manifests as early-onset bilateral pheochromocytoma. Am J Med Genet A. 2006 Apr 1;140(7):685-90. PMID:16502427 doi:10.1002/ajmg.a.31116
20. ↑ Pastore Y, Jedlickova K, Guan Y, Liu E, Fahner J, Hasle H, Prchal JF, Prchal JT. Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia. Am J Hum Genet. 2003 Aug;73(2):412-9. Epub 2003 Jul 3. PMID:12844285 doi:S0002-9297(07)61930-2
21. ↑ Pastore YD, Jelinek J, Ang S, Guan Y, Liu E, Jedlickova K, Krishnamurti L, Prchal JT. Mutations in the VHL gene in sporadic apparently congenital polycythemia. Blood. 2003 Feb 15;101(4):1591-5. Epub 2002 Oct 10. PMID:12393546 doi:10.1182/blood-2002-06-1843
22. ↑ Wiesener MS, Seyfarth M, Warnecke C, Jurgensen JS, Rosenberger C, Morgan NV, Maher ER, Frei U, Eckardt KU. Paraneoplastic erythrocytosis associated with an inactivating point mutation of the von Hippel-Lindau gene in a renal cell carcinoma. Blood. 2002 May 15;99(10):3562-5. PMID:11986208
23. ↑ Garrett KP, Aso T, Bradsher JN, Foundling SI, Lane WS, Conaway RC, Conaway JW. Positive regulation of general transcription factor SIII by a tailed ubiquitin homolog. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7172-6. PMID:7638163
24. ↑ Kario E, Marmor MD, Adamsky K, Citri A, Amit I, Amariglio N, Rechavi G, Yarden Y. Suppressors of cytokine signaling 4 and 5 regulate epidermal growth factor receptor signaling. J Biol Chem. 2005 Feb 25;280(8):7038-48. Epub 2004 Dec 7. PMID:15590694 doi:10.1074/jbc.M408575200
25. ↑ Garrett KP, Aso T, Bradsher JN, Foundling SI, Lane WS, Conaway RC, Conaway JW. Positive regulation of general transcription factor SIII by a tailed ubiquitin homolog. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7172-6. PMID:7638163
26. ↑ Kario E, Marmor MD, Adamsky K, Citri A, Amit I, Amariglio N, Rechavi G, Yarden Y. Suppressors of cytokine signaling 4 and 5 regulate epidermal growth factor receptor signaling. J Biol Chem. 2005 Feb 25;280(8):7038-48. Epub 2004 Dec 7. PMID:15590694 doi:10.1074/jbc.M408575200
27. ↑ Kitagawa H, Fujiki R, Yoshimura K, Mezaki Y, Uematsu Y, Matsui D, Ogawa S, Unno K, Okubo M, Tokita A, Nakagawa T, Ito T, Ishimi Y, Nagasawa H, Matsumoto T, Yanagisawa J, Kato S. The chromatin-remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in Williams syndrome. Cell. 2003 Jun 27;113(7):905-17. PMID:12837248
28. ↑ Park JI, Venteicher AS, Hong JY, Choi J, Jun S, Shkreli M, Chang W, Meng Z, Cheung P, Ji H, McLaughlin M, Veenstra TD, Nusse R, McCrea PD, Artandi SE. Telomerase modulates Wnt signalling by association with target gene chromatin. Nature. 2009 Jul 2;460(7251):66-72. doi: 10.1038/nature08137. PMID:19571879 doi:10.1038/nature08137
29. ↑ Sanchez-Tillo E, Lazaro A, Torrent R, Cuatrecasas M, Vaquero EC, Castells A, Engel P, Postigo A. ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1. Oncogene. 2010 Jun 17;29(24):3490-500. doi: 10.1038/onc.2010.102. Epub 2010 Apr, 26. PMID:20418909 doi:10.1038/onc.2010.102
30. ↑ Kario E, Marmor MD, Adamsky K, Citri A, Amit I, Amariglio N, Rechavi G, Yarden Y. Suppressors of cytokine signaling 4 and 5 regulate epidermal growth factor receptor signaling. J Biol Chem. 2005 Feb 25;280(8):7038-48. Epub 2004 Dec 7. PMID:15590694 doi:10.1074/jbc.M408575200
31. ↑ Kario E, Marmor MD, Adamsky K, Citri A, Amit I, Amariglio N, Rechavi G, Yarden Y. Suppressors of cytokine signaling 4 and 5 regulate epidermal growth factor receptor signaling. J Biol Chem. 2005 Feb 25;280(8):7038-48. Epub 2004 Dec 7. PMID:15590694 doi:10.1074/jbc.M408575200
32. ↑ Iliopoulos O, Ohh M, Kaelin WG Jr. pVHL19 is a biologically active product of the von Hippel-Lindau gene arising from internal translation initiation. Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11661-6. PMID:9751722
33. ↑ Tanimoto K, Makino Y, Pereira T, Poellinger L. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J. 2000 Aug 15;19(16):4298-309. PMID:10944113 doi:10.1093/emboj/19.16.4298
34. ↑ Xie L, Xiao K, Whalen EJ, Forrester MT, Freeman RS, Fong G, Gygi SP, Lefkowitz RJ, Stamler JS. Oxygen-regulated beta(2)-adrenergic receptor hydroxylation by EGLN3 and ubiquitylation by pVHL. Sci Signal. 2009 Jul 7;2(78):ra33. doi: 10.1126/scisignal.2000444. PMID:19584355 doi:10.1126/scisignal.2000444