PMID- 10535940
OWN - NLM
STAT- MEDLINE
DCOM- 19991210
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 22
DP  - 1999 Oct 26
TI  - Identification of the von Hippel-lindau tumor-suppressor protein as part of an
      active E3 ubiquitin ligase complex.
PG  - 12436-41
AB  - Mutations of von Hippel-Lindau disease (VHL) tumor-suppressor gene product (pVHL)
      are found in patients with dominant inherited VHL syndrome and in the vast
      majority of sporadic clear cell renal carcinomas. The function of the pVHL
      protein has not been clarified. pVHL has been shown to form a complex with
      elongin B and elongin C (VBC) and with cullin (CUL)-2. In light of the structural
      analogy of VBC-CUL-2 to SKP1-CUL-1-F-box ubiquitin ligases, the ubiquitin ligase 
      activity of VBC-CUL-2 was examined in this study. We show that VBC-CUL-2 exhibits
      ubiquitin ligase activity, and we identified UbcH5a, b, and c, but not CDC34, as 
      the ubiquitin-conjugating enzymes of the VBC-CUL-2 ubiquitin ligase. The protein 
      Rbx1/ROC1 enhances ligase activity of VBC-CUL-2 as it does in the
      SKP1-CUL-1-F-box protein ligase complex. We also found that pVHL associates with 
      two proteins, p100 and p220, which migrate at a similar molecular weight as two
      major bands in the ubiquitination assay. Furthermore, naturally occurring pVHL
      missense mutations, including mutants capable of forming a complex with elongin
      B-elongin C-CUL-2, fail to associate with p100 and p220 and cannot exhibit the E3
      ligase activity. These results suggest that pVHL might be the substrate
      recognition subunit of the VBC-CUL-2 E3 ligase. This is also, to our knowledge,
      the first example of a human tumor-suppressor protein being directly involved in 
      the ubiquitin conjugation system which leads to the targeted degradation of
      substrate proteins.
FAU - Iwai, K
AU  - Iwai K
AD  - Department of Molecular Biology, Graduate School of Biostudies, Kyoto University,
      Kyoto, 606-8501, Japan.
FAU - Yamanaka, K
AU  - Yamanaka K
FAU - Kamura, T
AU  - Kamura T
FAU - Minato, N
AU  - Minato N
FAU - Conaway, R C
AU  - Conaway RC
FAU - Conaway, J W
AU  - Conaway JW
FAU - Klausner, R D
AU  - Klausner RD
FAU - Pause, A
AU  - Pause A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Comment
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Carrier Proteins)
RN  - 0 (Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (Ubiquitins)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein)
RN  - EC 6.- (Ligases)
RN  - EC 6.3.2.- (VHL protein, human)
SB  - IM
CON - Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12230-2. PMID: 10535903
MH  - Carrier Proteins/metabolism
MH  - *Genes, Tumor Suppressor
MH  - Humans
MH  - Ligases/*metabolism
MH  - Molecular Weight
MH  - Mutation
MH  - Protein Binding
MH  - Proteins/genetics/*metabolism
MH  - Recombinant Proteins/metabolism
MH  - Tumor Cells, Cultured
MH  - *Tumor Suppressor Proteins
MH  - Ubiquitin-Protein Ligases
MH  - Ubiquitins/chemistry/metabolism
MH  - Von Hippel-Lindau Tumor Suppressor Protein
PMC - PMC22941
EDAT- 1999/10/27 00:00
MHDA- 1999/10/27 00:01
CRDT- 1999/10/27 00:00
PHST- 1999/10/27 00:00 [pubmed]
PHST- 1999/10/27 00:01 [medline]
PHST- 1999/10/27 00:00 [entrez]
AID - 10.1073/pnas.96.22.12436 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12436-41. doi:
      10.1073/pnas.96.22.12436.