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PMID: 18806787 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Jade-1 inhibits Wnt signalling by ubiquitylating beta-catenin and mediates Wnt pathway inhibition by pVHL.

Nature cell biology ·Vol. 10 ·No. 10 ·2008-10-00 ·Pages 1208-16

Chitalia VC, Foy RL, Bachschmid MM, Zeng L, Panchenko MV, Zhou MI, Bharti A, Seldin DC, Lecker SH, Dominguez I, Cohen HT

Abstract

The von Hippel-Lindau protein pVHL suppresses renal tumorigenesis in part by promoting the degradation of hypoxia-inducible HIF-alpha transcription factors; additional mechanisms have been proposed. pVHL also stabilizes the plant homeodomain protein Jade-1, which is a candidate renal tumour suppressor that may correlate with renal cancer risk. Here we show that Jade-1 binds the oncoprotein beta-catenin in Wnt-responsive fashion. Moreover, Jade-1 destabilizes wild-type beta-catenin but not a cancer-causing form of beta-catenin. Whereas the well-established beta-catenin E3 ubiquitin ligase component beta-TrCP ubiquitylates only phosphorylated beta-catenin, Jade-1 ubiquitylates both phosphorylated and non-phosphorylated beta-catenin and therefore regulates canonical Wnt signalling in both Wnt-off and Wnt-on phases. Thus, the different characteristics of beta-TrCP and Jade-1 may ensure optimal Wnt pathway regulation. Furthermore, pVHL downregulates beta-catenin in a Jade-1-dependent manner and inhibits Wnt signalling, supporting a role for Jade-1 and Wnt signalling in renal tumorigenesis. The pVHL tumour suppressor and the Wnt tumorigenesis pathway are therefore directly linked through Jade-1.

MeSH Terms
Animals Cell Line Homeodomain Proteins/metabolism Humans Protein Binding Signal Transduction Tumor Suppressor Proteins/metabolism Ubiquitination Von Hippel-Lindau Tumor Suppressor Protein/metabolism Wnt Proteins/antagonists & inhibitors,metabolism Xenopus beta Catenin/metabolism
Chemicals
Homeodomain Proteins JADE1 protein, human Tumor Suppressor Proteins Wnt Proteins beta Catenin Von Hippel-Lindau Tumor Suppressor Protein
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Chitalia Vipul C
Renal Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Foy Rebecca L
Bachschmid Markus M
Zeng Liling
Panchenko Maria V
Zhou Mina I
Bharti Ajit
Seldin David C
Lecker Stewart H
Dominguez Isabel
Cohen Herbert T
References (31)
31 references, click to expand
  1. Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway.
    Mol Cell Biol. 2002 Feb;22(4):1172-83 PMID: 11809808
  2. The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2.
    Mol Cell. 2002 May;9(5):945-56 PMID: 12049732
  3. The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1.
    J Biol Chem. 2002 Oct 18;277(42):39887-98 PMID: 12169691
  4. Beta-catenin-sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer.
    Nat Genet. 2001 May;28(1):53-7 PMID: 11326276
  5. Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein.
    Mol Cell. 2001 May;7(5):927-36 PMID: 11389840
  6. Early development of polycystic kidney disease in transgenic mice expressing an activated mutant of the beta-catenin gene.
    Oncogene. 2001 Sep 20;20(42):5972-81 PMID: 11593404
  7. A novel class of herpesvirus-encoded membrane-bound E3 ubiquitin ligases regulates endocytosis of proteins involved in immune recognition.
    J Cell Biol. 2001 Dec 24;155(7):1265-73 PMID: 11756476
  8. Promoter hypermethylation of tumor suppressor genes in urine from kidney cancer patients.
    Cancer Res. 2003 Dec 15;63(24):8695-9 PMID: 14695183
  9. Ozz-E3, a muscle-specific ubiquitin ligase, regulates beta-catenin degradation during myogenesis.
    Dev Cell. 2004 Feb;6(2):269-82 PMID: 14960280
  10. Tumor suppressor von Hippel-Lindau (VHL) stabilization of Jade-1 protein occurs through plant homeodomains and is VHL mutation dependent.
    Cancer Res. 2004 Feb 15;64(4):1278-86 PMID: 14973063
  11. Protein kinase CK2 is required for dorsal axis formation in Xenopus embryos.
    Dev Biol. 2004 Oct 1;274(1):110-24 PMID: 15355792
  12. The entire mesodermal mantle behaves as Spemann's organizer in dorsoanterior enhanced Xenopus laevis embryos.
    Dev Biol. 1988 May;127(1):64-77 PMID: 3282938
  13. Permeabilizing cells: some methods and applications for the study of intracellular processes.
    Methods Enzymol. 1990;192:280-300 PMID: 2074793
  14. Induction of a secondary body axis in Xenopus by antibodies to beta-catenin.
    J Cell Biol. 1993 Oct;123(2):477-84 PMID: 8408227
  15. Establishment of the dorso-ventral axis in Xenopus embryos is presaged by early asymmetries in beta-catenin that are modulated by the Wnt signaling pathway.
    J Cell Biol. 1997 Mar 10;136(5):1123-36 PMID: 9060476
  16. beta-catenin is a target for the ubiquitin-proteasome pathway.
    EMBO J. 1997 Jul 1;16(13):3797-804 PMID: 9233789
  17. 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
  18. The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro.
    Genes Dev. 1999 Feb 1;13(3):270-83 PMID: 9990852
  19. The human F box protein beta-Trcp associates with the Cul1/Skp1 complex and regulates the stability of beta-catenin.
    Oncogene. 1999 Jan 28;18(4):849-54 PMID: 10023660
  20. The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell.
    Curr Biol. 1999 Feb 25;9(4):207-10 PMID: 10074433
  21. An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin.
    EMBO J. 1999 May 4;18(9):2401-10 PMID: 10228155
  22. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis.
    Nature. 1999 May 20;399(6733):271-5 PMID: 10353251
  23. von Hippel-Lindau partner Jade-1 is a transcriptional co-activator associated with histone acetyltransferase activity.
    J Biol Chem. 2004 Dec 31;279(53):56032-41 PMID: 15502158
  24. Wnt signaling in disease and in development.
    Cell Res. 2005 Jan;15(1):28-32 PMID: 15686623
  25. Cystic renal neoplasia following conditional inactivation of apc in mouse renal tubular epithelium.
    J Biol Chem. 2005 Feb 4;280(5):3938-45 PMID: 15550389
  26. Overexpression of human beta TrCP1 deleted of its F box induces tumorigenesis in transgenic mice.
    Oncogene. 2005 Mar 24;24(13):2271-6 PMID: 15735746
  27. Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways.
    Nat Genet. 2005 May;37(5):537-43 PMID: 15852005
  28. Jade-1, a candidate renal tumor suppressor that promotes apoptosis.
    Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):11035-40 PMID: 16046545
  29. Renal-cell carcinoma.
    N Engl J Med. 2005 Dec 8;353(23):2477-90 PMID: 16339096
  30. Apc deficiency predisposes to renal carcinoma in the mouse.
    Oncogene. 2005 Dec 8;24(55):8205-10 PMID: 16116480
  31. The von Hippel-Lindau tumor suppressor gene product represses oncogenic beta-catenin signaling in renal carcinoma cells.
    Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14531-6 PMID: 16983094
Article Info
Journal
Nature cell biology
Abbr.
Nat Cell Biol
ISSN
1476-4679
DOI
10.1038/ncb1781
Published
2008-10-00
Epub
2008-00-21
Pages
1208-16
Language
English
Region
England
NLM ID
100890575
PMCID
PMC2830866
Subset
IM
Grants
NCI NIH HHS · R01 CA071796 · United States
NIDDK NIH HHS · R01 DK67569 · United States
NCI NIH HHS · R01 CA079830-08 · United States
NIDDK NIH HHS · T32 DK007053 · United States
NCI NIH HHS · R01 CA71796 · United States
NIDDK NIH HHS · T32 DK07053 · United States
NCI NIH HHS · R01 CA079830 · United States
NIDDK NIH HHS · R01 DK067569-05 · United States
NIDDK NIH HHS · T32 DK007053-32 · United States
NCI NIH HHS · R01 CA79830 · United States
NCI NIH HHS · R01 CA071796-11 · United States
NIDDK NIH HHS · R01 DK067569 · United States
Corrections
CommentIn
PMID: 18830218
External Links
PubMed source DOI: 10.1038/ncb1781 PMC Full Text View journal details
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