Elongin BC complex prevents degradation of von Hippel-Lindau tumor suppressor gene products

Schoenfeld, Alan R.; Davidowitz, Eliot J.; Burk, Robert D.

doi:10.1073/pnas.97.15.8507

Cited by 117 publications

(110 citation statements)

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“…Germline missense mutations of the VHL gene are predominantly detected within the region required for the formation of the multiprotein complex including elongins B and C, which stabilize VHL proteins. (37) Missense VHL mutations disrupting elongin binding have been shown to cause rapid VHL degradation. (37) Another example is a subset of naturally occurring mutant NF2 proteins that have been suggested to act as dominant-negative inhibitors on the wild-type protein.…”

Section: Discussionmentioning

confidence: 99%

Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms

Shimazu¹,

Nagamura²,

Yaguchi

et al. 2011

Cancer Science

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Germline mutations of the tumor suppressor gene MEN1 are found not only in typical multiple endocrine neoplasia type 1 (MEN1) but also in its incomplete forms such as familial isolated hyperparathyroidism (FIHP) and apparently sporadic parathyroid tumor (ASPT). No definitive genotype-phenotype correlation has been established between these clinical forms and MEN1 gene mutations. We previously demonstrated that mutant menin proteins associated with MEN1 are rapidly degraded by the ubiquitin-proteasome pathway. To examine whether the intracellular stability of mutant menin is correlated with clinical phenotypes, we developed a method of evaluating menin stability and examined 20 mutants associated with typical MEN1 (17 missense, two in-frame deletion, one nonsense) and 21 mutants associated with FIHP or ASPT (19 missense, two in-frame deletion). All tested mutants associated with typical MEN1 showed reduced stability. Some missense and in-frame deletion mutants (G28A, R171W, T197I, E255K, E274A, Y353del and E366D) associated with FIHP or ASPT were almost as stable as or only slightly less stable than wild-type menin, while others were as unstable as those associated with typical MEN1. Some stable mutants exhibited substantial biological activities when tested by JunD-dependent transactivation assay. These findings suggest that certain missense and in-frame mutations are fairly stable and retain intrinsic biological activity, and might be specifically associated with incomplete clinical phenotypes. The menin stability test will provide useful information for the management of patients carrying germline MEN1 mutations especially when they have missense or in-frame variants of ambiguous clinical significance. (Cancer Sci 2011; 102: 2097-2102 M enin is a tumor suppressor protein encoded by MEN1, a gene responsible for multiple endocrine neoplasia type 1 (MEN1), a familial cancer syndrome typically characterized by the development of multiple tumors in the pituitary, parathyroid and enteropancreatic endocrine tissues.(1,2) Menin is a nuclear protein having C-terminal nuclear localizing signal sequences, (3) and exhibits modulatory activity on gene expression such as repression of JunD-dependent transcription. (4) Diverse roles have been implicated for menin, including cell cycle control, cell differentiation and DNA repair, which are likely to be conferred by interaction with various menin-binding proteins.(2) Menin is considered to be a scaffold protein tethering such proteins to specific gene loci.(5) Although the mechanism of how menin is involved in gene regulation has been elucidated to some extent, the basis for tissue-specific tumorigenesis in MEN1 remains unknown.Heterozygous germline mutations of the MEN1 gene are found in 70-90% of patients clinically diagnosed as MEN1. (6) More than 500 different loss-of-function mutations have been identified, which are distributed throughout the gene with no apparent hot spot.(2,6,7) Germline MEN1 mutations have also been found in a subset of familial isolated hyperparathy...

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Section: Discussionmentioning

confidence: 99%

Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms

Shimazu¹,

Nagamura²,

Yaguchi

et al. 2011

Cancer Science

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“…We next sought the mechanism behind the decrease of VHL protein. It has been shown that VHL mutants unable to bind EloB/C are prone to degradation (38). The transient expression of BC-box proteins could deplete cellular levels of EloB/C, thus rendering the VHL protein less stable as a consequence.…”

Section: Socs Domain Containing An Intact Bc-box Motif Is Sufficient Tomentioning

confidence: 99%

BC-box protein domain-related mechanism for VHL protein degradation

Pozzebon

Varadaraj

Mattoscio

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The tumor suppressor VHL (von Hippel-Lindau) protein is a substrate receptor for Ubiquitin Cullin Ring Ligase complexes (CRLs), containing a BC-box domain that associates to the adaptor Elongin B/C. VHL targets hypoxia-inducible factor 1α to proteasomedependent degradation. Gam1 is an adenoviral protein, which also possesses a BC-box domain that interacts with the host Elongin B/C, thereby acting as a viral substrate receptor. Gam1 associates with both Cullin2 and Cullin5 to form CRL complexes targeting the host protein SUMO enzyme SAE1 for proteasomal degradation. We show that Gam1 protein expression induces VHL protein degradation leading to hypoxia-inducible factor 1α stabilization and induction of its downstream targets. We also characterize the CRL-dependent mechanism that drives VHL protein degradation via proteasome. Interestingly, expression of Suppressor of Cytokine Signaling (SOCS) domain-containing viral proteins and cellular BC-box proteins leads to VHL protein degradation, in a SOCS domain-containing manner. Our work underscores the exquisite ability of viral domains to uncover new regulatory mechanisms by hijacking key cellular proteins.ubiquitylation | oncoviral proteins | hypoxia U biquitylation is a posttranslational modification that involves the tagging of protein substrates with ubiquitin moieties. Ubiquitin transfer requires the coordinated and subsequent activities of the ubiquitin-activating E1 enzyme, ubiquitin-conjugating E2 enzymes, and ubiquitin E3 ligases. E3 ligases show substrate specificity and can be grouped into three families based on their different E2-docking domains. CRLs (Cullin RING Ligases) are the largest subfamily of RING domain ligases (1). They display the same modular structure: a scaffold subunit (Cullin), a RING subunit, an adaptor, and a substrate-receptor subunit to recruit the specific protein target to be ubiquitylated (2). Each Cullin associates with a specific adaptor subunit, except for Cullin2 and Cullin5, which both interact with the Elongin B and Elongin C (hereafter EloB/C) heterodimer (3). The EloB/C heterodimer is specifically bound by substrate receptors that contain a minimal consensus sequence (called BC-box motif) (4-6) usually included in the SOCS (Suppressor of Cytokine Signaling) domain of several substrate-receptor subunits (7,8). The consensus sequence and the function of the BC-box motif were first described for SOCS proteins (5, 8, 9), a family of downstream effectors of cytokine signaling cascade, involved in the negative feedback regulation of this pathway.Several viruses encode for their own substrate receptors possessing the BC-box motif and are thus able to interact with EloB/ C cellular adaptor, thereby modifying the cellular ubiquitin E3 ligase complex and their target proteins selection (10-17). We have demonstrated that the CELO (Chicken Embryo Lethal Orphan) Adenovirus early protein Gam1 is one of such BC boxcontaining proteins that is able to associate with both Cullin2 and Cullin5 to reconstitute active E3 ligase complexes and tar...

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“…Therefore, loss of pVHL leads to increased HIF levels and transcription of HIF target genes, such as, vascular endothelial growth factor (VEGF) (Iliopoulos et al, 1996) and subsequent tumor angiogenesis. Disruption of the elongin-binding domain also destabilizes pVHL and leads to its rapid degradation indicating an additional function of the elongin B/C complex (Schoenfeld et al, 2000). However, the biochemical function(s) of VHL that when disrupted results in VHL disease and tumorigenesis have not been completely established.…”

Section: Introductionmentioning

confidence: 99%

von Hippel–Lindau protein complex is regulated by cell density

Mohan

Burk

2003

Oncogene

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Mutations in the von Hippel-Lindau (VHL) gene are involved in the VHL family cancer syndrome and sporadic renal cell carcinoma. Previous studies indicated that VHL-induced growth arrest required high cell density and growth on extracellular matrix. In the present study, VHL protein (pVHL) levels were observed to be dramatically increased in cells grown to high cell density compared to cells grown at low cell density. Reverse transcription-polymerase chain reaction and Northern blot analysis indicated that VHL mRNA levels were equivalent in sparse and dense cells. The pVHL was rapidly degraded when cell-cell contact was disturbed by trypsinization or EDTA release. Treatment of cells with a proteasome inhibitor blocked the degradation of pVHL. Using a set of VHL deletions fused to GFP, a cell densitydependent region (CDDR) was identified and localized to the c-terminus of pVHL. In addition, other members of the VBC protein complex also showed a cell densitydependent regulation similar to pVHL. Cell density regulation of VHL did not require elongin binding and density-dependent regulation of other VBC components was not dependent on pVHL. In addition, hypoxia inducible factor-2a protein levels were elevated in sparse cells with low levels of pVHL and reduced or absent in confluent cells containing abundant VHL. These results indicate that pVHL levels and thus function are tightly regulated by cell-cell signaling. In addition, care must be taken when interpreting studies of VHL function and subcellular localization of cells grown at subconfluent conditions.

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Elongin BC complex prevents degradation of von Hippel-Lindau tumor suppressor gene products

Cited by 117 publications

References 30 publications

Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms

Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms

BC-box protein domain-related mechanism for VHL protein degradation

von Hippel–Lindau protein complex is regulated by cell density

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